Teses / dissertações: "Calcification"

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Harper, Glenn Martin. "Calcification in coccolithophores." Thesis, University of Plymouth, 2017. http://hdl.handle.net/10026.1/8664.

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Coccolithophores are uni-cellular phytoplankton and they form an exceedingly diverse group in the phylum Haptophyta. They produce highly complex structures known as coccoliths by a biomineralisation process known as calcification. The first part of the work undertaken was to investigate the process of calcification in the coccolithophore Coccolithus pelagicus using a combination of Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM) and light microscopy techniques. This allowed better understanding of the formation, transit of the coccolith through the cell until its final placing in the coccosphere. The second part of the work looked at the coccolithophore Emiliania huxleyi which is divided into several morphotypes with the two most widely recognised being A and B, it can be further subdivided into further groups according to genotype by Coccolithophore Morphology Motif (CMM). The CMMs lie in the 3/ untranslated region of the coccolith-polysaccharide associated protein-GPA, which is associated with coccolith structure control and they are labelled I, II, III and IV. The work undertaken used a Scanning Electron Microscope (SEM) to investigate the morphologies of homozygous CMM I and CMMIV cell’s coccoliths. This information was used to establish a significant difference between the CMMI cells and CMMIV cells but only at certain locations. The cause for this is possibly as a result of several factors (temperature, salinity, pCO2, Ca availability and light levels) and requires further investigation.

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Desjardins, Lucie. "Marqueurs de risque des complications de la maladie rénale chronique." Thesis, Amiens, 2015. http://www.theses.fr/2015AMIE0013.

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La maladie rénale chronique (MRC) est un problème majeur de santé publique du fait de l’augmentation constante de son incidence et des complications cardiovasculaires fréquemment rencontrées, de même que l’accumulation dans le sang des patients de molécules appelées toxines urémiques. Le but de cette thèse est de déterminer les potentielles associations entre certaines toxines urémiques et certaines techniques non-invasives avec les paramètres biochimiques et vasculaires, la mortalité globale et cardiovasculaire dans une cohorte de patients à différents stades de la MRC. Dans cette étude, nous avons démontré que les taux de chaînes légères libres (CLL), de sclérostine et de β2 microglobuline (β2M) étaient augmentés de manière précoce dans la MRC et culminaient chez les patients dialysés. Seuls les taux de β2M étaient indépendamment associés à la mortalité globale et cardiovasculaire dans notre cohorte et aux événements cardiovasculaires chez les pré-dialysés. De plus, nous avons démontré que la mesure des calcifications vasculaires (en particulier la mesure du score de calcifications coronaires), ajoutait une valeur prédictive de la mortalité globale et des événements cardiovasculaires, à la mesure des facteurs de risque traditionnels (âge, sexe, tabagisme, hypertension et taux de triglycérides).Malgré la taille relativement petite de notre cohorte, les études menées pour cette thèse ont permis de mettre en évidence des marqueurs des complications de la MRC, comme la β2M et la mesure des calcifications vasculaires. Ces marqueurs ajoutés en pratique de routine pourraient améliorer la prédiction du risque cardiovasculaire et de décès dans cette population Chronic kidney disease (CKD) is a serious public health problem due to the constant increase of its incidence. In particular, CKD patients are at high risk of developing cardiovascular disease further the accumulation of molecules called uremic toxins. The purpose of this thesis was to evaluate risk markers of CKD complications in a cohort of patients at different CKD stages by evaluating some uremic toxins and some non-invasive techniques to determine their potential associations with vascular and biochemical parameters, global and cardiovascular mortality. In this study, we demonstrated that the kappa and lambda free light chain, sclerostin and β2 microglobulin (ß2M) levels were increased in early CKD stage and culminated in dialysis patients. Free light chain and sclerostin levels were associated with inflammation markers but not with vascular parameters. These levels appeared to be associated with mortality, but this association disappeared after adjustment for other factors. On the other side, we have demonstrated that the ß2M levels were independently associated with overall and cardiovascular mortality in our cohort and cardiovascular events in pre-dialysis patients. In addition, we demonstrated that the addition of vascular calcification scores (especially the coronary artery calcification score) to TRFs appears to improve CV risk assessment in a CKD population.This work identified several important markers of CKD complications, as ß2M and measurement of vascular calcification scores. The addition of these two markers in routine practice could improve the prediction of cardiovascular risk and mortality in this population

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3

Byon, Chang Hyun. "Oxidative stress-stimulated vascular calcification." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2010r/byon.pdf.

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Dhore, Cherida Rachel. "Molecular regulation of vascular calcification." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 2005. http://arno.unimaas.nl/show.cgi?fid=6374.

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5

Walker, Charlotte. "Mechanisms of calcification in coccolithophores." Thesis, University of Southampton, 2018. https://eprints.soton.ac.uk/425508/.

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Coccolithophores are unicellular marine algae characterised by the production of calcite coccoliths. As a result of their calcification they contribute significantly to global biogeochemical cycles. Comprehensive understanding of the mechanisms behind calcification remains elusive, due in part to the research focus on one species, Emiliania huxleyi; the most globally abundant of all coccolithophores. It is imperative to investigate calcification in other species to better understand this biogeochemically important process, especially as the ecological success of E. huxleyi may be due to certain physiological differences with other species. This study set out to explore differences between species in the mechanisms of calcification in three primary areas. Firstly, the physiological requirement for calcification remains poorly understood, particularly as non-calcifying strains of E. huxleyi grow normally in laboratory culture. This study identified a contrast in the requirement for calcification between E. huxleyi and the ecologically important Coccolithus braarudii. Calcification disruption had no negative impacts on E. huxleyi but resulted in major growth defects in C. braarudii demonstrating an obligate requirement for calcification in this species. Secondly, the previous identification of Si transporters in some coccolithophores was further investigated using a combination of physiological and expression studies to identify that Si plays a role in heterococcolith calcification during their diploid life stage. C. braarudii Si transporters were also found to be regulated in response to available Si and shown to be expressed in natural populations. Finally, coccolith associated polysaccharides (CAPs) are an integral component of the calcification mechanism known to modulate the precipitation of calcite. The data presented here show that extracellular CAPs differ in structure and composition between species and that they also play an important role in the organisation of the coccosphere, expanding upon their role and importance in calcification. These findings mark crucial physiological differences between coccolithophore species. The identification of a requirement for calcification in coccolithophores highlights the importance of maintaining a coccosphere. The requirement for Si in some species suggests major physiological differences between species which may influence their ecology. Consequently, these contrasting physiological characteristics may contribute to significant differences in the response of coccolithophores to future ocean conditions.

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Pawade, Tania Ashwinikumar. "Imaging calcification in aortic stenosis." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/29589.

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BACKGROUND Aortic stenosis is a common and potentially fatal condition in which fibro-calcific changes within the valve leaflets lead to the obstruction of blood flow. Severe symptomatic stenosis is an indication for aortic valve replacement and timely referral is essential to prevent adverse clinical events. Calcification is believed to represent the central process driving disease progression. 18F-Fluoride positron emission tomography computed tomography (PET-CT) and CT aortic valve calcium scoring (CT-AVC) quantify calcification activity and burden respectively. The overarching aim of this thesis was to evaluate the applications of these techniques to the study and management of aortic stenosis. METHODS AND RESULTS REPRODUCIBILITY The scan-rescan reproducibility of 18F-fluoride PET-CT and CT-AVC were investigated in 15 patients with mild, moderate and severe aortic stenosis who underwent repeated 18F-fluoride PET-CT scans 3.9±3.3 weeks apart. Modified techniques enhanced image quality and facilitated clear localization of calcification activity. Percentage error was reduced from ±63% to ±10% (tissue-to-background ratio most-diseased segment (MDS) mean of 1.55, bias -0.05, limits of agreement - 0·20 to +0·11). Excellent scan-rescan reproducibility was also observed for CT-AVC scoring (mean of differences 2% [limits of agreement, 16 to -12%]). AORTIC VALVE CALCIUM SCORE: SINGLE CENTRE STUDY Sex-specific CT-AVC thresholds (2065 in men and 1271 in women) have been proposed as a flow-independent technique for diagnosing severe aortic stenosis. In a prospective cohort study, the impact of CT-AVC scores upon echocardiographic measures of severity, disease progression and aortic valve replacement (AVR)/death were examined. Volunteers (20 controls, 20 with aortic sclerosis, 25 with mild, 33 with moderate and 23 with severe aortic stenosis) underwent CT-AVC and echocardiography at baseline and again at either 1 or 2-year time-points. Women required less calcification than men for the same degree of stenosis (p < 0.001). Baseline CT-AVC measurements appeared to provide the best prediction of subsequent disease progression. After adjustment for age, sex, peak aortic jet velocity (Vmax) ≥ 4m/s and aortic valve area (AVA) < 1 cm2, the published CT-AVC thresholds were the only independent predictor of AVR/death (hazard ratio = 6.39, 95% confidence intervals, 2.90-14.05, p < 0.001). AORTIC VALVE CALCIUM SCORE: MULTICENTRE STUDY CT-AVC thresholds were next examined in an international multicenter registry incorporating a wide range of patient populations, scanner vendors and analysis platforms. Eight centres contributed data from 918 patients (age 77±10, 60% male, Vmax 3.88±0.90 m/s) who had undergone ECG-gated CT within 3 months of echocardiography. Of these 708 (77%) had concordant echocardiographic assessments, in whom our own optimum sex-specific CT-AVC thresholds (women 1377, men 2062 AU) were nearly identical to those previously published. These thresholds provided excellent discrimination for severe stenosis (c-statistic: women 0.92, men 0.88) and independently predicted AVR and death after adjustment for age, sex, Vmax ≥4 m/s and AVA < 1 cm2 (hazards ratio, 3.02 [95% confidence intervals, 1.83-4.99], p < 0.001). In patients with discordant echocardiographic assessments (n=210), CT-AVC thresholds predicted an adverse prognosis. BICUSPID AORTIC VALVES Within the multicentre study, higher continuity-derived estimates of aortic valve area were observed in patients with bicuspid valves (n=68, 1.07±0.35 cm) compared to those with tri-leaflet valves (0.89±0.36 cm p < 0.001,). This was despite no differences in measurements of Vmax (p=0.152), or CT-AVC scores (p=0.313). The accuracy of AVA measurments in bicuspid valves was therefore tested against alternative markers of disease severity. AVA measurements in bicuspid valves demonstrated extremely weak associations with CT-AVC scores (r2=0.08, p=0.02) and failed to correlate with downstream markers of disease severity in the valve and myocardium and against clinical outcomes. AVA measurements in bicuspid patients also failed to independently predict AVR/death after adjustment for Vmax ≥4 m/s, age and gender. In this population CT-AVC thresholds (women 1377, men 2062 AU) again provided excellent discrimination for severe stenosis. CONCLUSIONS Optimised 18F-fluoride PET-CT scans quantify and localise calcification activity, consolidating its potential as a biomarker or end-point in clinical trials of novel therapies. CT calcium scoring of aortic valves is a reproducible technique, which provides diagnostic clarity in addition to powerful prediction of disease progression and adverse clinical events.

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Zainuddin. "Synthesis and calcification of hydrogel biomaterials /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18693.pdf.

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Chau, Hien Nguyet 1977. "Renal calcification in Npt2 knockout mice." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=78338.

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Mice homozygous for the disrupted renal type 11a sodium/phosphate (Na/Pi) cotransporter gene, Npt2, (Npt2 KO) exhibit renal Pi wasting and hypercalciuria, predisposing factors for renal stone formation. We observed that Npt2 KO mice, but not wild-type littermates form renal stones. The renal stones were evident in newborn, weanling and adult mice and composed of calcium (Ca) and Pi. The presence of renal calcification correlated with the absence of Npt2 gene expression and the presence of genes responsible for the synthesis (1alpha-hydroxylase) and catabolism (24-hydroxylase) of 1,25-dihydroxyvitamin D, whose elevated levels contribute to the hypercalciuria and renal calcification in Npt2 KO mice. The renal calcification was associated with increased osteopontin (OPN) mRNA expression and colocalized with OPN, the latter associates with renal stones in vivo and inhibits Ca mineralization in vitro). These data demonstrate that hyperphosphaturia and hypercalciuria, secondary to Npt2 gene disruption, are sufficient for the development of renal calcification.

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9

Rendeiro, Ana Rita Pimentel do Couto. "Genetics and epidemiology of ectopic calcification." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/54257.

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10

Promsy, Eric. "Calcification du disque intervertébral chez l'enfant." Montpellier 1, 1988. http://www.theses.fr/1988MON11212.

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Zhang, Yinxing. "Bioprosthetic heart valves : ultrastructure and calcification." Master's thesis, University of Cape Town, 1998. http://hdl.handle.net/11427/26921.

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Sumaary in English. Includes bibliographical references. Background: Due to the geographic distance between abattoirs and commercial valve plants delays between harvest and fixation usually range from 48 to 72 hours. In order to assess the pre-fixation tissue damage arising from the hypoxic period and the resulting calcific degeneration after implantation, we used an ultrastructural damage score and transmission electron microscopy. Materials and Methods: In a step by step manner, three major issues were clarified: 1) The degree of pre-fixation tissue damage was determined in the four most widely used commercially produced tissue heart valves. Since stentless bioprostheses represent the latest promising trend in the development of biological heart valves, stentless models of the following makes were compared: Baxter, Medtronic, St. Jude and Biocor. Due to the fact that the aortic wall component of these valves proved most resistant to all anticalcification treatments, aortic wall tissue stood in the centre of our analyses. 2) Subsequently, three main determinants of the fixation process namely: delay, temperature and fixative-concentration were varied with the goal of significantly improving the ultrastructural preservation of the bioprosthetic tissue. 3) Eventually, the influence of improved ultrastructural preservation on calcific degeneration was evaluated under in vivo conditions in the non-human primate and the rat model. Results: The comparison of the four most commonly used stentless bioprosthetic heart valves revealed a disturbing degree of tissue damage in all valves. Using a damage score from 1 to 21 (21 being the worst), aortic wall tissue of commercial valves ranged from 10 to 18 and that of leaflet tissue from 12 to 20. When fixation conditions were permutated, tissue damage could almost be abolished by immediate fixation (within 30 minutes of slaughter), low-temperature fixation(4°C) and high glutaraldehyde concentrations (> 1 %). Our in vivo experiments confirmed that commercially used fixation (delayed fixation, room-temperature and I ow concentrations of glutaraldehyde) with its concomitant high degree of tissue damage results in high levels of calcification. Apart from a distinctly improved calcification potential in ultrastructurally well preserved tissue, there was also an inverse correlation between tissue calcification and the concentration of glutaraldehyde used for fixation. Conclusion: We could demonstrate that commercially produced bioprosthetic heart valves uniformly show badly damaged tissue and that tissue damage contributes to the calcific degeneration of these valves. We were also able to determine ideal fixation conditions which in turn significantly reduced tissue calcification.

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Morony, Sean Edward. "Regulation of vascular calcification by osteoprotegerin." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1472152041&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.

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Rendeiro, Ana Rita Pimentel do Couto. "Genetics and epidemiology of ectopic calcification." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/54257.

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Bouderlique, Élise. "ABCC6 et biominéralisation rénale et vasculaire." Electronic Thesis or Diss., Sorbonne université, 2022. http://www.theses.fr/2022SORUS557.

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La survenue de calcifications ectopiques est un problème majeur de santé publique. Les calculs rénaux notamment affectent 10 % de la population générale et peuvent avoir de multiples complications pouvant aller jusqu’à l’insuffisance rénale chronique terminale. Les calculs de type « oxalo-calciques » sont les plus fréquents. Ils sont souvent générés sur des plaques de Randall, des calcifications interstitielles papillaires faites de phosphate de calcium (apatite). Au cours des dernières décennies, une augmentation importante de la prévalence de ces calculs a été observée chez les jeunes adultes, suggérant que des facteurs environnementaux puissent favoriser l’émergence de ces plaques. Les calcifications vasculaires sont des calcifications ectopiques responsables d’une morbi mortalité élevée. On les distingue en général en deux types : intimales et liées à la survenue de plaques d’athérome ou médiales et associées à des pathologies systémiques telles que l’insuffisance rénale chronique ou le Pseudoxanthome élastique. Le Pseudoxanthome élastique (PXE) est une maladie rare monogénique se manifestant par la survenue de calcifications ectopiques rétiniennes, cutanées, vasculaires et rénales. Cette maladie est due à des mutations du gène ABCC6, impliqué dans le métabolisme du pyrophosphate, un inhibiteur majeur de la bio minéralisation. Le modèle murin invalidé pour Abcc6 est également affecté par des calcifications ectopiques, notamment des vibrisses, des vaisseaux, des papilles rénales (plaque de Randall), et des rétines. Le taux circulant de pyrophosphate est bas chez les patients et chez ces souris. Nous avons évoqué l’implication potentielle de la supplémentation en vitamine D, largement répandue, sur la survenue de plaques de Randall et l’aggravation des calcifications vasculaires. Nous avons donc étudié l’impact de la supplémentation en vitamine D et/ou en calcium sur la survenue de plaque de Randall dans notre modèle murin Abcc6-/-. L’administration chronique de doses modérées de vitamine D et de calcium a suffi a aggravé le développement de ces plaques de façon significative, confortant ainsi notre hypothèse initiale. Dans une deuxième partie, nous avons analysé l’évolution des calcifications vasculaires chez les animaux Abcc6-/- exposés à cette supplémentation en vitamine D et en calcium. Que ce soit au niveau rénal ou vasculaire, on retrouvait une augmentation de volume significative des calcifications vasculaires lors de la supplémentation mixte en calcium et en vitamine D. Cela implique notamment de considérer avec prudence la supplémentation en vitamine D chez les patients atteints de PXE, et suggère qu’en population générale ces suppléments pourraient poser problème chez des individus prédisposés. Dans une dernière partie, nous avons analysé la survenue de calcifications vasculaires au sein du modèle Abcc6-/-, dans un contexte de maladie rénale chronique modérée (MRC) induite par l’acide aristolochique. Ce modèle était utilisé en raison de son caractère modéré et bien toléré sur le long terme (6 mois). Tout d’abord, nous avons noté, que les calcifications vasculaires étaient plus sévères chez les animaux atteints de MRC et prédominaient au niveau de la crosse aortique. Les principaux facteurs mis en cause dans notre modèle était l’élévation de l’expression et de l’activité des phosphatases alcalines tissulaires et le défaut de pyrophosphate circulant. Ensuite, nous avons confirmé que l’administration orale de pyrophosphate était suffisante pour protéger contre les calcifications vasculaires et bien tolérée, faisant de notre modèle une étude préclinique intéressante pour les patients atteints de MRC Biomineralisation is an important issue in global health care. Indeed, concerning kidney stones disease, almost 10 % of whole population is affected. Major complications such as end stage of chronic kidney disease may affect some of these patients. The most frequent stone component is calcium oxalate (especially monohydrate). These stones originate frequently from an interstitial tissue calcification, the Randall’s plaque, which is made of calcium phosphate (apatite). During the past decades, the prevalence of lithiasis associated with Randall plaque has increased, mainly in young adults, raising the issue of environmental factors involved in these processes. Another biomineralization localization of interest is the vascular component. The vascular calcifications are usually divided into two groups: intimal one’s which are associated with atheromatous plaques and the medial one’s which are associated with systemic disease such as chronic kidney disease or pseudoxanthoma elasticum (PXE). PXE is a rare, monogenic disease characterized by ectopic calcifications affecting eyes, skin, vessels and kidneys. ABCC6 mutations are implied, which are linked to pyrophosphate metabolism, a major biomineralization inhibitor. Murine Abcc6 knock out model, mimics human calcifications with phosphocalcics deposits in vibrissae, vessels, kidneys (Randall Plaque) and retina. ABCC6 impairment results in decreased plasmatic and urinary pyrophosphate levels. We hypothesized that vitamin D supplements, widely administered into children population, could be involved in biomineralization process. We studied the Randall plaque status in Abcc6-/- murine model with or without combined administration of calcium and vitamin D. We found an increased volume of papillary calcifications with the combined supplementation of calcium and vitamin D, suggesting that vitamin D administration could be a risk factor of Randall plaque development. In a second part, we studied the vascular calcifications in our Abcc6-/- murine model associated with calcium and vitamin D and found a significant association between these supplements and the calcification volume. These data sound a warning regarding the widespread supplementation in calcium and vitamin D, especially in the PXE population. In a last part, we analyzed the vascular calcifications associated with chronic kidney disease (CKD) induced by aristolochic acid in the Abcc6-/- model. We used this model owing to its well tolerated and moderate status on the long term (6 months). First, we noticed that vascular calcifications were accelerated in the CKD group and predominated in the aorta cross. The two main factors involved were pyrophosphate deficiency (Abcc6-/-) and an increased expression and activity of alkaline phosphatase enzyme. Then, we confirmed that oral supplement in pyrophosphate is sufficient and well tolerated in order to decrease the CKD-induced vascular calcifications, suggesting that oral pyrophosphate might be an interesting strategy to prevent vascular calcification in CKD patients

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Hristova, Gergana. "Calcification in Intervertebral Disc Degeneration and Scoliosis." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86948.

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In degenerative and scoliotic intervertebral discs (IVD), calcification is a pathological process that may lead to impairment of the nutrient supply and a disturbance in disc metabolism. However, the process of calcification in disc degeneration and scoliosis is not well understood. The purpose of this study was to assess the calcification markers in IVD of patients with degenerative disc disease and adolescent idiopathic scoliosis. For this purpose, 34 IVDs from 16 adult patients with degenerative disc disease and 25 IVDs from 9 adolescent patients with adolescent idiopathic scoliosis were obtained after surgery or autopsy. The concave and the convex parts of the scoliotic discs were analyzed separately. Von Kossa staining was performed to visualize calcium deposits, while type X collagen expression, which is associated with endochondral ossification, was measured by immunohistochemistry and Western blot. Alkaline phosphatase (ALP) activity and calcium and inorganic phosphate (Pi) concentrations were used as markers of the calcification process. Results showed the presence of calcium deposits and type X collagen only in degenerative and scoliotic intervertebral discs, but not in control discs. Results also demonstrated a large individual variability in ALP activity and calcium and Pi concentrations in degenerative and scoliotic discs. Moreover, the level of the calcification markers was consistently higher in degenerative and scoliotic discs than in control discs. The results suggest that disc degeneration in adults involves mineral deposition and that mineralization in adolescent idiopathic scoliosis discs might reflect an ongoing premature degenerative process. Dans les disques intervertébraux (DIV) dégénérés et de scoliose, la calcification est un processus pathologique qui peut mener à une diminution de l'apport nutritif et à un débalancement du métabolisme. Cependant, le processus de calcification de ces disques est très peu connu. Le but de la présente étude était d'évaluer le potentiel de calcification des DIVs de patients avec une maladie dégénérative des disques (MDD) ou avec une scoliose idiopathique chez l'adolescent (SIA). Pour ce faire 34 DIVs provenant de 16 adultes avec MDD et 25 DIVs de 9 patients avec SIA ont été obtenus après chirurgie ou autopsie. Les côtés convexe et concaves des disques scoliotiques on été analysés séparément. Une coloration de Von Kossa a été faite afin de visualiser les dépôts de calcium alors que l'expression du collagène de type X, associé à l'ossification endochondrale, a été mesurée par immunohistochimie et par buvardage de type Western. L'activité de la phosphatase alcaline (PA) ainsi que les concentrations de calcium et de phosphate inorganique (Pi) ont servi d'indicateurs du potentiel de calcification. Les résultats montrent la présence de dépôts de calcium et de collagène de type X uniquement dans les DIVs des patients ayant une MDD ou une SIA, mais non dans les disques témoins. Les résultats montrent également une grande variabilité individuelle de l'activité de la PA ainsi que des concentrations de calcium et de Pi. De plus, les niveaux de ces marqueurs du potentiel de calcification était plus élevés dans les disques dégénérés et scoliotiques que dans les disques témoins. Les résultats suggèrent que la dégénération du disque intervertébral adulte est associée à une déposition de minéraux et que la minéralisation du disque scoliotique pourrait refléter un processus de dégénération prématurée.

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Berry, L. S. "Calcification, photosynthesis and nutrient uptake in coccolithophores." Thesis, Swansea University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.636084.

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Emiliania huxleyi is the most abundant coccolithophore in the World's oceans today. These organisms have the ability to calcify and photosynthesise, and may represent an important oceanic sink for dissolved inorganic carbon. As a result, they have the potential to influence the oceanic carbon cycle. It has been proposed that calcification may improve carbon acquisition under CO2 (aqueous) limiting conditions, but may involve high Ca2+ transport costs. In this thesis, results presented show that calcification increases in E. huxleyi (strain L) in response to low phosphorus and/or nitrate, high external pH, and high dissolved inorganic carbon. This information was used to produce calcifying and non-calcifying cells of the same strain allowing comparisons, which avoided the genetic and psychological differences between strains. Calcification correlated with an increase in photosynthetic efficiency (Φ>PSII), relative electron transport rate (REFPSII) and the proportion of photons captured and converted to chemical energy (qP). The mechanisms underlying these correlations are unknown, but may involve the H+ produced during calcification being used to supply an internal CO2 source. High calcifying cells were found to have a lower internal pH than low-calcifying cells, and were able to take up HCO3-. This may influence CO2 availability within the cell, or nutrient requirements and assimilation. Results from X-ray microanalysis and Electron Energy Loss Spectroscopy indicate that the endomembrane system may provide an efficient pathway for Ca2+ transport to the coccolith vesicle. Potentially, this avoids transport of Ca2+ against a concentration gradient, and resolves what was thought to be one of the major cost-aspects of calcification. The most likely advantage of calcification is that it may allow low levels of photosynthesis to occur efficiently, thus increasing survival time during co-limitation by CO2, phosphorous and/or nitrate. Calcification may enable the cell to reduce the nutrient requirements for photosynthesis, or allow internal nutrient recycling.

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Yarra, Tejaswi. "Transcriptional profiling of shell calcification in bivalves." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31408.

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Mollusc shells are unique adaptations that serve to protect the organisms that make them, and are a defining feature of the phylum. However the molecular underpinnings of shell forming processes are still largely unexplored. To further understand mollusc shell formation, I studied three bivalve species in this project: the blue mussel Mytilus edulis, the Pacific oyster Crassostrea gigas, and the king scallop Pecten maximus. While previous analyses of the shell proteomes showed species specificity, transcriptomes of the mantle tissues revealed more commonalities. To reconcile these differences, I studied differential gene expression in shell damage-repair experiments and during the formation of the first larval shell, to produce a comprehensive overview of shell formation processes. Expression data showed large biological variability between individuals, requiring matched-pair experimental designs to detect differential gene expression during shell repair. Loci differentially expressed during shell repair and in the larvae encoded shell matrix proteins, transmembrane transporters, and novel transcripts. A large number of shell matrix proteins, encoded in differentially expressed loci, were common in all three species during shell formation, indicating that shell forming proteins between different species may be more common than previously thought. Differential expression of transmembrane transporters during shell repair indicated that the animals may be regulating bicarbonate ions during shell formation. Finally, the experiments revealed novel transcripts, with unknown annotations to public datasets, that may putatively be involved in shell formation.

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Ponnusamy, Arvind. "The role of prenylation in vascular calcification." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-prenylation-in-vascular-calcification(421c189b-8c72-4a92-bdc7-85d433699c4c).html.

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Vascular calcification is an active, regulated process in which vascular smooth muscle cells (VSMCs) differentiate into osteoblast-like cells and deposit a mineralised matrix. It is well established that patients with chronic kidney disease and diabetes have poor cardiovascular outcomes which is thought to be due to increased vascular calcification and atherosclerosis. Previous work from the host laboratory has shown that nitrogen-containing bisphosphonates attenuate vascular calcification by inhibiting farnesyl pyrophosphate synthase, depleting cells of farnesyl pyrophosphate and geranylgeranyl pyrophosphate which are essential for the prenylation and activation of small GTPases such as Ras and Rho. Therefore, the initial aim of this study was to determine the effects of farnesyl transferase inhibitors (FTI-277 and manumycin A) on vascular calcification using a well validated in vitro model in which VSMCs are induced to deposit a mineralised matrix in the presence of β-glycerophosphate. FTI-277 significantly inhibited β-glycerophosphate-induced calcification of VSMCs in vitro (p<0.001), and this inhibition occurred in a dose- and time-dependent manner. In contrast, manumycin A had no effect on this process. Active Ras pull-down assays and western blotting confirmed that both FTI-277 and manumycin A decreased Ras GTPase activation in VSMCs. Western blot analysis also showed that FTI-277, but not manumycin A, increased Akt phosphorylation in these cells. To determine whether FTI-277 inhibited mineralisation by promoting PI3K/Akt signalling, VSMCs were induced to mineralise in the presence of FTI-277 plus either wortmannin (a PI3K inhibitor), SH6 (an Akt inhibitor) or vehicle alone. These reagents decreased the inhibitory effect of FTI-277 on mineral deposition by VSMCs, demonstrating that the effects of FTI-277 can be negated, at least partially, by preventing downstream PI3K or Akt signalling. Incubation of VSMCs with wortmannin alone significantly promoted mineral deposition by VSMC (p<0.001). In addition, FTI-277 significantly inhibited phosphate-induced apoptosis of human VSMC (p<0.05), and prevented PDGF-induced VSMC migration. FTI-277 also inhibited β-glycerophosphate-induced Runx2, Msx 2 and alkaline phosphatase mRNA expression (p<0.05), promoted matrix Gla protein mRNA expression (p<0.05), and maintained α-smooth muscle actin expression. Using an ex vivo assay, it was also demonstrated that FTI-277 inhibits phosphate-induced mineralisation of aortic rings from rats with early and end stage renal disease and sham-operated controls. To determine the effects of more specific Ras inhibition on VSMC mineralisation, Farnesyl Thiosalicylic Acid (FTS) was used. FTS (40 µM) inhibited mineralisation (p<0.001), decreased Ras GTPase activation and increased Akt phosphorylation but inhibited Erk phosphorylation in vitro. However lower doses of FTS increased mineralisation (p<0.001), but had no effect on Ras activation, or on Akt or Erk phosphorylation. FTS also appeared to delay PDGF-induced VSMC migration and induce apoptosis of human VSMCs in the absence of serum. Ex vivo studies demonstrated that FTS (40 µM) inhibited phosphate induced mineralisation of aortic rings from rats with end stage renal disease and sham-operated controls. This study demonstrates that farnesylation, or Ras specifically, could be a potential novel therapeutic target for the inhibition of vascular calcification.

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19

Skafi, Najwa. "Role of Phospholipase D in Vascular Calcification." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1339/document.

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La calcification vasculaire est l’accumulation de cristaux de calcium dans les vaisseaux sanguins à travers un processus pathologique qui ressemble à la formation de l’os ou du cartilage. Elle apparaît notamment chez les patients diabétiques ou atteints d’une insuffisance rénale chronique. La conséquence principale de la calcification vasculaire est la perte de l’élasticité qui est indispensable pour la fonction des larges artères, elle est de plus associée à la mortalité des patients hémodialysés. Les traitements contre la calcification vasculaire sont généralement limités à ceux qui corrigent les facteurs causatifs des problèmes de santé mais aucune intervention efficace, spécifique et ciblée n’est disponible. Par conséquence, une compréhension profonde des mécanismes moléculaires impliqués dans la calcification vasculaire est nécessaire dans le but de trouver de nouvelles cibles thérapeutiques. La phospholipase D catalyse l’hydrolyse des phospholipides en acide phosphatidique et une tête polaire, elle est aussi impliquée dans différentes fonctions cellulaires et maladies. Il a été démontré qu’elle peut être activée par des facteurs impliqués dans l’ostéogenèse et par d’autres impliqués dans la calcification vasculaire. Ainsi, nous avons étudié le rôle de la phospholipase D dans la calcification vasculaire dans 3 modèles différents. Le premier est un modèle in-vitro de cellules musculaires lisses murines (lignée cellulaire MOVAS), elles sont cultivées en présence d’acide ascorbique et de β-glycérophosphate. Le deuxième est un modèle ex-vivo d’explants d’aortes cultivés en présence de fortes concentrations de phosphate et le troisième est un modèle in-vivo d’insuffisance rénale chronique produite chez des rats. Dans ce dernier modèle, la calcification vasculaire est induite par un régime riche en phosphore et en calcium et par des injections de vitamine D active. La calcification dans ces trois modèles a été suivie par l’analyse de la minéralisation en dosant les dépôts de calcium, de l’activité phosphatase alcaline, et de l’expression de différents marqueurs ostéo-chondrocytaires. Une augmentation de l’expression génique de Pld1 a été observée dans les trois modèles, en particulier au cours des premières étapes de la calcification, et a été accompagnée d'une activité accrue de la phospholipase D dans les modèles in vitro et ex-vivo. L’inhibition de l’activité phospholipase D dans ces deux modèles ou de la phospholipase D1 dans le modèle MOVAS a bloqué complètement la calcification. Par contre, l’inhibition spécifique de la phospholipase D2 n’a pas montré des effets significatifs. Deux voies par lesquelles la phospholipase D peut être activée ont été testées, la voie de la protéine kinase C et la voie de la sphingosine-1-phosphate. Ces deux voies métaboliques se sont révélées être impliquées dans le processus de calcification mais pas forcément dans l’activation de la phospholipase D au cours de ce processus. Des résultats préliminaires ont montré que la phospholipase D pourrait agir après activation de la sphingosine kinase 2 dont l’activité s’est avérée nécessaire pour la calcification dans le modèle MOVAS. Des études supplémentaires sont nécessaires pour comprendre par quels mécanismes la phospholipase D est activée et comment elle agit. La phospholipase D pourrait être une nouvelle cible thérapeutique pour le traitement de la calcification vasculaire vu que son inhibition ne semble pas avoir des effets secondaires chez les patients Vascular calcification is the accumulation of calcium phosphate crystals in blood vessels via a pathological process that resembles physiological bone or cartilage formation. Calcification in the medial layer is mainly seen in diabetic and chronic kidney disease patients. Its main consequence is the loss of elasticity which is indispensable for the function of large arteries. Accordingly, vascular medial calcification was significantly associated with mortality in hemodialysis patients. Vascular calcification treatments are limited to those that correct its causative health problems, but no efficient, specific and targeted interventions are available. Therefore, a deep understanding of its molecular mechanisms is needed to find novel therapeutic targets. Phospholipase D catalyses the hydrolysis of phospholipids into phosphatidic acid and a head group. It is implicated in different cellular functions and diseases. It was found to be activated by factors involved in osteogenesis and others involved in vascular calcification. Thus, we investigated its role in vascular calcification in 3 models: an in-vitro model of murine smooth muscle cell line MOVAS cultured with ascorbic acid and β-glycerophosphate, an ex-vivo model of rat aortas cultured in high phosphate medium, and an in-vivo model of adenine-induced kidney disease in rats in which vascular calcification is induced by further administration of high phosphorus/calcium diet and active vitamin D injections. Calcification was detected in these models using different approaches including alkaline phosphatase activity, calcium dosage, and/or evaluation of osteo-chondrocytic markers expression. Pld1 expression was seen upregulated in all the three models, especially during early stages of calcification, and was accompanied with increased phospholipase D activity in the in-vitro and ex-vivo model. The inhibition of total phospholipase D activity in these two models, or that of phospholipase D1 in case of MOVAS model, abolished calcification. Phospholipase D2-specific inhibition did not induce significant effects. Two pathways by which phospholipase D can be activated were tested, protein kinase C and sphingosine 1-phosphate pathways, but they were found to be involved in calcification but not necessary for phospholipase D activation during this process. Alternatively, the preliminary results showed that PLD may be acting by activation of sphingosine kinase 2 whose activity was found necessary for calcification in the MOVAS model. Further investigations are needed to understand the mechanisms by which phospholipase D is activated and by which it is acting. Phospholipase D could be a novel target for vascular calcification especially that its inhibition in patients did not induce adverse health effects

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Ludwig, Rebecca. "Carbon cycling and calcification in hypersaline microbial mats." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=979757312.

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Osman, Lana. "Cellular and Molecular Mechanisms of Aortic Valve Calcification." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490945.

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Aortic valve calcification is an active inflammatory condition characterised by thickening and calcification of the leaflets. The cellular and molecular mechanisms of the disease are unknown. We hypothesised that valve interstitial cells (lCs) playa key role in the calcification process by acting as a target for inflammatory cytokines that are involved in initiating signalling cascades to promote osteogenic differentiation of the cells, a mechanism that could be manipulated phannacologically. Calcified human aortic valve leaflets were characterised with the presence of calcium nodules and bone lesions. Cultured human aortic valve ICs had the capacity to release a number of inflammatory cytokines and undergo osteogenic differentiation in response to osteogenic mediators, including bone morphogenetic proteins (BMPs) and transforming growth factor-beta (TOF-P). In addition, extracellular nucleotides played an important role in regulating this differentiation process, whereby ATP increased the expression of osteoblast markers, while adenosine had an opposite effect. Activation of major signalling pathways including Wnt3a, were partially responsible for promoting this osteogenic differentiation of valve ICs, leading to upregulation of p-catenin and/or Cbfa-l. These mechanisms were counteracted by HMO-CoA reductase inhibitors (statins), where atorvastatin blocked the induction of osteoblast markers in valve ICs and inhibited the effects of Wnt3a on proliferation and differentiation. In addition, we demonstrated a novel role of pz-adrenergic receptors (Pz-ARs) in aortic valve calcification, whereby stimulation of pz-ARs prevented osteogenic differentiation of valve ICs in response to osteogenic medium. Our findings suggests that valve ICs play an important role in the calcification process and that activation of Wnt3a signalling pathway may present a possible mechanism for bone fonnation in the valve. This study also identifies potential pharmacological targets to prevent the onset or progression of aortic valve calcification.

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Fröhner, Michael, Oliver W. Hakenberg, Andreas Manseck, Sven Oehlschläger, and Manfred P. Wirth. "Unusual Semi-Spheric Perivesical Calcification after Pelvic Radiotherapy." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-133912.

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An uncommon case with semi-spheric perivesical calcification after pelvic radiotherapy is reported and the possible pathogenesis of this phenomenon is discussed Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

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23

Mohamed, Moinuddin Mohammed. "Characterisation of peritoneal calcification in encapsulating peritoneal sclerosis." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-peritoneal-calcification-in-encapsulating-peritoneal-sclerosis(003593cd-01f0-4e7b-a22b-d216451f6a93).html.

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Encapsulating peritoneal sclerosis (EPS) is a rare complication of long-term peritoneal dialysis (PD). EPS is associated with extensive thickening and fibrosis of the peritoneum resulting in the formation of a fibrous cocoon encapsulating the bowel leading to intestinal obstruction. The presence of peritoneal thickening, peritoneal calcification and bowel obstruction is considered to be diagnostic of EPS. The current understanding of the pathogenesis of EPS is through the 'two-hit' fibrosis model. This model, however, does not explain the development of peritoneal calcification in patients with EPS. This thesis addresses the hypothesis that altered bone mineral metabolism in ESRF patients together with the mechanical stress of PD influences mesothelial cells to differentiate into osteoblasts promoting calcification in peritoneal tissue. Peritoneal calcification leads to increased tissue stiffness causing progressive fibrosis and the development of EPS. We compared the temporal evolution of the levels of bone mineral markers during PD between patients who developed EPS and control patients on PD. We found that raised serum levels of calcium, phosphate and alkaline phosphatase during PD increased the risk of development of EPS. We compared peritoneum from patients with EPS with that of PD patients without EPS using histological techniques. We found that calcification, organised fibrillary collagen and elastic fibres were significantly more abundant in the EPS peritoneum. Peritoneal calcification was also generalised and distributed not only on the peritoneal surface but also in the sub-mesothelial zone of fibrosis. EPS peritoneum also exhibited osteocalcin, an osteogenic protein, suggesting a cellular mechanism of calcification. Atomic force microscopy of EPS peritoneum showed increased stiffness when compared to control PD peritoneum with the areas of calcification possibly contributing to the increase in tissue stiffness. Human omental cells (HOMCs) were isolated by protease digestion and characterised using a panel of mesothelial markers. HOMCs were cultured in phosphate rich media and phosphate and calcium rich media. HOMCs when cultured with high extracellular levels of calcium showed accelerated mineralisation with upregulation of osteogenic transcription factor runx-2 suggesting osteoblastic transformation. In summary, this thesis indicates that poorly controlled secondary hyperparathyroidism is a risk factor for the development of EPS. On a background of PD related simple sclerosis, uncontrolled secondary hyperparathyroidism can lead to the transformation of mesothelial cells to osteoblasts. This leads to increased matrix deposition and matrix mineralisation causing increased matrix stiffness. Increase in matrix stiffness leads to progressive fibrosis culminating in EPS. Peritoneal calcification can act as the second hit leading to progressive fibrosis and development of EPS.

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Zhu, Dongxing. "Role of osteocyte markers in medial vascular calcification." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8765.

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Vascular calcification is prevalent in ageing, in atherosclerosis, and especially in patients with Chronic Kidney Disease (CKD), with associated increased morbidity and mortality. The phenotypic transition of Vascular Smooth Muscle Cells (VSMCs) into osteoblastic/chondrogenic-like cells is critical for the development of calcification in CKD patients. Osteocytes, terminally differentiated osteoblasts, have recently emerged as major regulators of calcification in bone. Recently, osteocytelike cells have been observed in human peripheral arteries with medial vascular calcification. However, it remains undetermined as to whether VSMCs can undergo osteocytic differentiation within a calcifying environment and the functional role of osteocyte formation in the development of medial vascular calcification. Initial studies have characterised the ectonucleotide pyrophosphatase/phosphodiesterase 1 knockout (Enpp1-/-) mouse as a valid model of medial vascular calcification, which is employed throughout this thesis. This thesis has compared VSMCs to osteoblasts undergoing osteocytic differentiation in vitro. VSMC in vitro calcification was accompanied by up-regulated expression of osteocyte markers, including Sost, E11, Dmp1, Phex, Mepe and Fgf23. Immunohistochemistry confirmed the appearance of sclerostin and E11 in calcified aortae from the Enpp1-/- mouse. Further studies have identified a direct inhibitory role for the osteocyte specific gene FGF23 in modulating vascular calcification. The inhibitory effect of FGF23 on VSMC calcification was mediated through the MAPK/ERK signalling pathway. This thesis has also determined the role of BMP9, a highly osteogenic bone morphogenic protein, in vascular calcification, which induces VSMC calcification through a Smad signalling mechanism. Furthermore, VSMC expression of the osteocytic marker Sost was markedly increased following BMP9 treatment. Intriguingly, BMP9 was markedly elevated in serum from dialysis patients and a significant correlation was observed between dialysis time and BMP9 concentration in patients receiving haemodialysis. The work described herein has demonstrated that vascular calcification is associated with an osteocyte phenotype, and reports a direct inhibitory effect of the osteocyte specific gene FGF23 on vascular calcification. Furthermore, this thesis has shown that BMP9 induces the expression of the osteocytic marker Sost in VSMCs, and appears to play a critical role in vascular calcification.

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Fröhner, Michael, Oliver W. Hakenberg, Andreas Manseck, Sven Oehlschläger, and Manfred P. Wirth. "Unusual Semi-Spheric Perivesical Calcification after Pelvic Radiotherapy." Karger, 1999. https://tud.qucosa.de/id/qucosa%3A27548.

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An uncommon case with semi-spheric perivesical calcification after pelvic radiotherapy is reported and the possible pathogenesis of this phenomenon is discussed. Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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26

Morris, Thomas. "The role of bioactive sphingolipids in vascular calcification." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-bioactive-sphingolipids-in-vascular-calcification(5235985a-0992-432e-9df2-35519725f87a).html.

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Vascular calcification is the formation of mineralised tissue within the walls of arteries. The pathology has many similarities to embryonic bone formation and involves the osteogenic differentiation of vascular smooth muscle cells (VSMCs) and matrix mineralisation. Recent studies have demonstrated that the bioactive sphingolipids, ceramide and sphingosine-1-phosphate (S1P), regulate embryonic bone formation. Ceramide can be generated by lysosomal acid sphingomyelinase (L-SMase) and neutral sphingomyelinase (N-SMase), and be converted to sphingosine by acid ceramidase (ACDase) and subsequently to S1P by sphingosine kinases (SK1 & SK2). This study tested the hypothesis that ceramide and S1P also regulate VSMC matrix mineralisation. VSMCs were cultured in the presence of 3 mM β-glycerophosphate (BGP) to induce osteogenic differentiation and matrix mineralisation. During VSMC mineralisation there were decreases in the activities of L-SMase and N-SMase and increases in the levels of C18 and C20 ceramide. S1P levels also increased during mineralisation as did SK1 and SK2 mRNA and SK activity. These results demonstrate that ceramide and S1P have the potential to regulate VSMC mineralisation. The exogenous addition of C2 ceramide decreased the rate of VSMC matrix mineralisation. Consistent with this, when VSMCs were cultured with 3 mM BGP and the joint L-SMase and ACDase inhibitor, desipramine, total ceramide levels increased and no matrix mineralisation was detected. These findings suggest that ceramide is an inhibitor of VSMCs matrix mineralisation. It was also noted in the presence of 3 mM BGP and desipramine that the mineralisation-associated increase in S1P was inhibited. In agreement with this, when exogenous S1P was added to the VSMCs an increase in matrix mineralisation was observed. Thus, S1P acts as a promoter of matrix mineralisation. To determine how S1P was promoting matrix mineralisation the signalling roles of the ezrin, radixin and moesin (ERM) proteins were investigated. The short-term stimulation of VSMCs with S1P led to the phosphorylation of the ERM proteins and over the mineralisation time-course, when S1P levels increased, the levels of ERM phosphorylation also increased. When VSMCs were cultured in the presence of 3 mM BGP and the inhibitor of ezrin phosphorylation, NSC668394, a decrease in matrix mineralisation was observed. No increases in ERM phosphorylation were seen in the presence of desipramine during the mineralisation time-course Therefore, S1P may be increasing matrix mineralisation through promoting the phosphorylation of the ERM proteins. This work has demonstrated that ceramide inhibits and S1P promotes VSMC matrix mineralisation in vitro. Additionally, this work identifies activation of ERM proteins, downstream of S1P, as a novel signalling pathway promoting matrix mineralisation. Characterisation of novel regulators of VSMC matrix mineralisation in vitro gives insight into the complex mechanisms contributing to vascular calcification in vivo and will aid in identification of novel therapeutic targets.

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Todd, Alexandra Frances. "The role of angiopoietin-2 in vascular calcification." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10044744/.

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Cardiovascular disease (CVD) is a leading cause of mortality in paediatric patients with chronic kidney disease (CKD), particularly in those undergoing dialysis. One of the earliest events in CVD is endothelial damage, which may result from changes in levels of vascular growth factors that control blood vessel function and stability. Markers of endothelial dysfunction and vascular calcification are observed during CKD, and are documented as early as the first decade of life. Previous research indicates that growth factors controlling blood vessel function and stability are altered in CKD patients; circulating levels of the pro-inflammatory/anti-angiogenic molecule angiopoietin-2 (Angpt2) are notably increased in children on dialysis and correlate with surrogate markers of vascular calcification. I therefore hypothesise that Angpt2 may promote medial calcification in CKD. Through in vitro studies using intact vessel rings and explanted vascular smooth muscle cells (VSMCs) from paediatric pre-dialysis and dialysis patients, I have shown that addition of exogenous Angpt2 in a pro-calcaemic environment (medium supplemented with 2.7 mM calcium, and 2.0 mM phosphate) increases calcium deposition within vessels from dialysis patients, but has no effect on control or predialysis vessels. In endothelial cells, Angpt2 acts through the receptor tyrosine kinase with immunoglobulin-like and EGF-like domains-2 (Tie2); this receptor was detected through immunofluorescence in the media layer of the intact vessels and by protein and RNA analyses of explanted VSMCs. The calcifying effect of Angpt2 in VSMCs could be blocked by downregulating Tie2 expression by small interfering ribonucleic acid (siRNA), but was not prevented by addition of the Angpt2 antagonist, vascular stabiliser and anti-inflammatory molecule, Angpt1. Vascular calcification is driven through several pathophysiological mechanisms including osteogenic gene expression, apoptosis and vesicle release; these have been investigated in both vascular rings and explanted VSMCs. While the full mechanism has yet to be elucidated, this thesis provides evidence to suggest that manipulation of Tie2 and angiopoietin pathways may have potential to decrease the rate of vascular calcification in patients with CKD.

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MANCINELLI, LUIGI. "Role of HMGB1 in vascular aging and calcification." Doctoral thesis, Università degli studi di Pavia, 2020. http://hdl.handle.net/11571/1301313.

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BACKGROUND- Vascular calcification (VC) is an age-associated complication of cardiovascular diseases, in which the main cellular event is the trans-differentiation of vascular smooth muscle cells (VSMCs) from a contractile to an osteochondrogenic phenotype that leads to an accumulation of calcium deposits. Senescence facilitates VSMCs osteogenic transition. VC is strongly associated with inflammation, oxidative stress and high level of DNA damage. HMGB1 is a highly conserved non-histone chromatin binding protein involved in transcription, DNA repair, and maintenance of nucleosome structure that can be actively secreted or passively released in the extracellular space acting as an alarmin. HMGB1 is involved in age-associated nuclear defects, cellular senescence and the acquisition of senescence-associated secretory phenotype (SASP). Finally, HMGB1 is implicated in VSMCs proliferation and migration and in osteochondrogenic transformation of human dental pulp stem cells (hDPCs) and valve interstitial cells (VICs). OBJECTIVE- The role of HMGB1 in vascular aging and calcification has been only partially explored. Herein, we investigated HMGB1 behavior and function human aortic smooth muscle cells (HASMCs) senescence and osteochondrogenic trans-differentiation associated to senescence in vitro and vascular aging and VC in vivo. RESULTS- HMGB1 protein expression decreases in aortas of old mice and during replicative senescence of HASMCs along with an increase of p16 expression. HMGB1 downregulation during senescence is mainly due to decrease of its gene expression and not relocation of the protein to the cytosol and in the extracellular space. HMGB1 declines also in the course of HASMCs calcification induced by hyperphosphatemia and in calcified aortas of a rat model of adenine-induced calcification and inversely correlates with calcium content in human abdominal aneurism of aorta (AAA). Silencing of HMGB1 in young but not in old HASMCs induces senescence-like phenotype through inhibition of cell proliferation and blocking the cell cycle in G0/G1 phase and increase of p21 and senescence-associate β-galactosidase (SA-β-gal) expression, in respect to control cells. Notably, HMGB1 down-regulation reduces HASMCs secretion of pro-inflammatory SASPs factors, DNA damage and ROS content both in young and old cells. Finally, silencing of HMGB1 in HASMCs initially impairs cell calcification and SASP factors release but eventually favours calcium deposition and IL6, IL1β and OPN secretion. In accordance, aortas of vitamin D-treated Hmgb1+/- mice exhibit a lower accumulation of calcium in the early phase of calcification while a higher tissue mineralization later on, in respect to Hmgb1+/+ animals. CONCLUSION- Hence, during vascular aging, the reduction of HMGB1 in VSMC induces a senescence-like phenotype that favours DNA damage repair, avoid SASP spreading and limit cell proliferation. However, this response is initially protective but becomes deleterious after a long-term period in response to pro-calcification conditions. BACKGROUND- Vascular calcification (VC) is an age-associated complication of cardiovascular diseases, in which the main cellular event is the trans-differentiation of vascular smooth muscle cells (VSMCs) from a contractile to an osteochondrogenic phenotype that leads to an accumulation of calcium deposits. Senescence facilitates VSMCs osteogenic transition. VC is strongly associated with inflammation, oxidative stress and high level of DNA damage. HMGB1 is a highly conserved non-histone chromatin binding protein involved in transcription, DNA repair, and maintenance of nucleosome structure that can be actively secreted or passively released in the extracellular space acting as an alarmin. HMGB1 is involved in age-associated nuclear defects, cellular senescence and the acquisition of senescence-associated secretory phenotype (SASP). Finally, HMGB1 is implicated in VSMCs proliferation and migration and in osteochondrogenic transformation of human dental pulp stem cells (hDPCs) and valve interstitial cells (VICs). OBJECTIVE- The role of HMGB1 in vascular aging and calcification has been only partially explored. Herein, we investigated HMGB1 behavior and function human aortic smooth muscle cells (HASMCs) senescence and osteochondrogenic trans-differentiation associated to senescence in vitro and vascular aging and VC in vivo. RESULTS- HMGB1 protein expression decreases in aortas of old mice and during replicative senescence of HASMCs along with an increase of p16 expression. HMGB1 downregulation during senescence is mainly due to decrease of its gene expression and not relocation of the protein to the cytosol and in the extracellular space. HMGB1 declines also in the course of HASMCs calcification induced by hyperphosphatemia and in calcified aortas of a rat model of adenine-induced calcification and inversely correlates with calcium content in human abdominal aneurism of aorta (AAA). Silencing of HMGB1 in young but not in old HASMCs induces senescence-like phenotype through inhibition of cell proliferation and blocking the cell cycle in G0/G1 phase and increase of p21 and senescence-associate β-galactosidase (SA-β-gal) expression, in respect to control cells. Notably, HMGB1 down-regulation reduces HASMCs secretion of pro-inflammatory SASPs factors, DNA damage and ROS content both in young and old cells. Finally, silencing of HMGB1 in HASMCs initially impairs cell calcification and SASP factors release but eventually favours calcium deposition and IL6, IL1β and OPN secretion. In accordance, aortas of vitamin D-treated Hmgb1+/- mice exhibit a lower accumulation of calcium in the early phase of calcification while a higher tissue mineralization later on, in respect to Hmgb1+/+ animals. CONCLUSION- Hence, during vascular aging, the reduction of HMGB1 in VSMC induces a senescence-like phenotype that favours DNA damage repair, avoid SASP spreading and limit cell proliferation. However, this response is initially protective but becomes deleterious after a long-term period in response to pro-calcification conditions.

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Moya, Aurélie. "Approches physiologique et moléculaire de la calcification et de la "light-enhanced calcification" chez le corail Scléractiniaire Stylophora pistillata (Esper, 1797)." Aix-Marseille 2, 2007. http://theses.univ-amu.fr.lama.univ-amu.fr/2007AIX22073.pdf.

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Les récifs coralliens, majoritairement édifiés par les coraux Scléractiniaires, constituent la plus importante construction biologique à l’échelle mondiale. De nombreux coraux Scléractiniaires établissent une symbiose avec un Dinobionte photosynthétique. Cette symbiose est responsable, entre autres, d’une stimulation de la calcification des coraux en présence de lumière, phénomène décrit sous le terme de “light-enhanced calcification” (LEC). Malgré de nombreuses recherches, les mécanismes responsables de ce phénomène de LEC restent méconnus. Ma thèse a consisté en l’étude de la calcification et du phénomène de LEC chez le corail Stylophora pistillata par une double approche physiologique (caractérisation du phénomène chez cette espèce, cycle journalier, temps de transition) et moléculaire (caractérisation moléculaire et localisation tissulaire d’une anhydrase carbonique impliquée dans le processus de calcification, régulation transcriptionnelle entre les conditions "Jour" et "Nuit") Scleractinian corals are the main calcifying organisms of coral reefs. Most scleractinian corals establish a symbiotic relationship with phototrophic Dinoflagellates. This symbiosis is responsible for the stimulation of coral calcification by light, a phenomenon called “light enhanced calcification” (LEC). Despite numerous studies performed on this subject, the mechanisms linking photosynthesis of the symbionts to coral calcification remain largely unknown. The aim of the present work is to gain a better understanding of the calcification process and of the “light-enhanced calcification” phenomenon in the scleractinian coral Stylophora pistillata (Esper, 1797), using both physiological (characterization of the LEC phenomenon in S. Pistillata, daily cycle, time transitions) and molecular approaches (molecular characterization and tissular localization of a carbonic anhydrase involved in the calcification process, transcriptional regulation between light and dark conditions)

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30

Varennes, Olivier. "Le rôle de l'Epoxyde hydrolase soluble (sEH) dans la physiopathologie des calcifications vasculaires." Electronic Thesis or Diss., Amiens, 2018. http://www.theses.fr/2018AMIE0046.

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L'Epoxide Hydrolase soluble (sEH) est une enzyme exprimée dans les vaisseaux. Elle possède un domaine hydrolase à l'extrémité COOH-term (sEH-H) qui métabolise des facteurs vasodilatateurs et anti-inflammatoires comme les acides époxyeicosatriénoïques (EETs). Elle possède également un domaine phosphatase à l'extrémité NH2-term (sEH-P) dont le rôle biologique n'est pas totalement élucidé. Afin de comprendre le rôle de sEH-H et sEH-P dans la calcification vasculaire, des anneaux aortiques de rats et des cellules musculaires lisses vasculaires humaines (CMLVh) ont été exposés à des conditions procalcifiantes pendant 7 et 14 jours respectivement. Le N-acétyl-S-farnesyl-L-cystéine (AFC), un inhibiteur de sEH-P, et le trans-4-(4-(3-adamantan-1-yl-ureido)-)cyclohexyloxy) acide benzoïque (t-AUCB), un inhibiteur de sEH-H, ont été utilisés entre 0,1 et 10 μM. En condition procalcifiante, l'AFC réduit de façon dose-dépendante la calcification vasculaire. Au contraire, le t-AUCB augmente de façon dose-dépendante la minéralisation au sein des anneaux aortiques. Une augmentation de l'activité TNAP a été observée dans les surnageants de culture des anneaux aortiques avec le t-AUCB. Sur les anneaux désendothélialisés ou sur les cultures de CMLVh, les inhibiteurs n'ont pas d'effet sur la calcification, soulignant le rôle crucial joué par les facteurs endothéliaux métabolisés par la sEH. L'ensemble de nos résultats montrent que l'inhibition pharmacologique de la sEH-H augmente la calcification vasculaire in vitro en augmentant la biodisponibilité des EETS. Au contraire, l'inhibition de la sEH-P protège contre la calcification vasculaire à travers un mécanisme dépendant de l'endothélium Expressed in the vasculature, soluble epoxide hydrolase (sEH) exhibits a COOH-terminal hydrolase domain metabolizing endothelial vasodilator and anti-inflammatory factors like epoxyeicosatrienoic acids (EETs) and, a NH2-terminal phosphatase domain whose biological role remains unclear. To assess the role of sEH phosphatase and hydrolase domains in vascular calcification, rat aortic rings and hVSMCs were exposed to procalcifying culture media for 7 and 14 days, respectively. N-acetyl-S-farnesyl-L-cysteine (AFC), an inhibitor of the phosphatase domain, and trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB), a hydrolase domain inhibitor, were used at concentrations ranging from 0.1 to 10 μM. Under procalcifying culture condition, AFC significantly and dose-dependently reduces aortic calcification. Conversely, addition of t-AUCB results in a significant and dose-dependent increase in aortic calcification in rats, without modification of tissue viability. A concomitant increase in TNAP activity was observed in supernatants of aortic rings cultured in the presence of t-AUCB. On de-endothelialized aortic rings or hVSMCs cultures, both inhibitors had no significant effect on the calcification process, pointing out the crucial role played by endothelial factors metabolized by sEH in the control of this biomineralization process. Together, our data demonstrates that pharmacological inhibition of sEH hydrolase increases vascular calcification in vitro by majoring the bioavailability of endothelium- derived EETs. Contrarily, the inhibition of sEH phosphatase is protective against vascular calcification through an endothelium-dependent mechanism

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Boroomand, Seti. "Valvular interstitial cell transformation : implications for aortic valve calcification." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/47138.

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Aortic valve stenosis (AVS) involves the transformation of valvular interstitial cells (VIC) into an osteoblastic phenotype. Such valvular disease is mostly associated with both thickening and calcification of the valve cusps, which is accompanied by inflammation and remodeling of the tissue. This process is mediated by the VIC that carry out an impressive array of functions throughout the calcification process. For this dissertation, I hypothesized that in AVS, VIC transform from a myofibroblast phenotype to osteoblast-like cells and that the canonical Wnt and TGFβ pathways and vitamin D3 interactively and collaboratively contribute to these phenomena. In order to test this hypothesis, I established an in vitro model of calcification by culturing human primary VIC in a pro-calcification conditioned medium. Calcified cells display several molecular characteristic features of human AVS, including increased levels of alkaline phosphatase and the formation of calcium nodules. These changes increased over time and peaked at 28 days of treatment. To define possible mechanisms of AVS, I first characterized human VIC in regards to the process of calcification. I showed for the first time in vitro that these VIC express bone specific markers, the characteristic of normal osteoblasts. To determine the factors involved in osteoblastic transformation in this model, I examined WNT3A and TGFβ, known to be involved in normal bone formation. Both calcified human aortic valve tissues and VIC express excess WNT3A and TGFβ1. Adding WNT3A and TGFβ1 to the VIC cultures increased the levels of cell mineralization. Further, the addition of DKK1, the WNT3A antagonist, decreased VIC calcification in vitro. By using various combinations of WNT3A, TGFB1 and DKK1, I made the novel observation that the suppression of DKK1 by TGFB1 allowed WNT3A to drive calcification in VIC in vitro. Finally, I examined the role vitamin D3 that is associated with vascular calcification in rats. Vitamin D3 can up-regulate VIC calcification in vitro, however its mechanism of action appears to be independent of the Wnt and TGFβ pathways. In conclusion, the canonical Wnt and TGFβ pathways function interactively through DKK1 to transform VIC to osteoblast-like cells and vitamin D3 promotes this process in an independent manner. Medicine, Faculty of Pathology and Laboratory Medicine, Department of Graduate

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Abu-Mansour, Filimban Waheed. "Calcification in diseases of breast: ultrastructural and histological studies." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493438.

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Reynolds, Joanne Lesley. "Mechanisms and regulation of vascular smooth muscle cell calcification." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619743.

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Sim, Alisia Mara. "Detection of calcification in atherosclerotic plaques using optical imaging." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33151.

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PET imaging, using the bone tracer Na18F, allows the non-invasive location of atherosclerotic plaques that are at risk of rupture. However, the spatial resolution of PET is only 4-5 mm, limiting the mechanistic information this technique can provide. In this thesis, the use of fluorescence and Raman imaging to elucidate the mechanism of micro-calcification within atherosclerotic plaques has been investigated. A number of fluorescent probes to detect fluoride and calcium have been synthesised. One of the fluoride probes has been shown to be selective for fluoride however, the concentration of fluoride required to activate the probe is order of magnitudes higher than the amount of Na18F used for PET imaging making it problematic to use for future studies. On the other hand, a calcium probe has been shown to: selectively bind to hydroxyapatite (HAP); permit visualisation and quantification of HAP in both vascular and bone cell models; and effectively stain cultured aortic sections and whole mouse aorta for OPT imaging. Building on these preliminary data, fluorescence imaging and immunohistochemistry (IHC) imaging of both healthy and atherosclerotic tissue that were previously subjected to PET imaging, were successfully carried out showing the ability of the probe to detect HAP in human vascular tissue. IHC staining for Osteoprotegerin (OPG) and Osteopontin (OPN), two bone proteins recently detected in vascular tissue, showed the co-localization of OPG with the probe. Conversely, the OPN was shown to localize in areas surrounding high OPG and probe signal. To determine the exact composition of vascular calcification, Raman spectroscopy was also used. It is believed that the biosynthetic pathway to HAP passes through a series of transitional states; each of these has different structural characteristics which can be studied using Raman spectroscopy. In particular, HAP has a strong characteristic Raman peak at 960 cm-1. An increase in HAP concentration has been detected by Raman in both calcified cell models and aortic sections. When human vascular tissue was analysed, an additional peak at 973 cm-1 was present suggesting the presence of whitlockite (WTK) in this tissue as well as HAP.

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35

Ghatora, Baljit. "Investigation into the calcification and aging of intraocular lenses." Thesis, Kingston University, 2010. http://eprints.kingston.ac.uk/35856/.

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Poly (methyl methacrylate) (PMMA) has been the preferred biocompatible biomaterial for use in intraocular lenses (IOLs) since 1949, when its optical benefits were discovered by Harold Ridley. Calcification of intraocular lenses is an area that is not addressed adequately in literature, but is a problem that requires repeat surgery, which is not usually an option in third world countries. Calcification is a setback to IOLs that needs to be further studied so that possible solutions can be found. The effects of sterilisation and incubation in an extreme calcific environment, namely a metastable calcium salt solution at pH 7.4 at 37°C, on the properties of gamma-irradiated and ethylene-oxide-sterilised medical grade PMMA, was analysed over a period of nine weeks. From these initial studies, energy dispersive X-ray analysis identified deposits containing calcium, chlorine and potassium as soon as one day after incubation. It was proposed that calcification occurred as a result of diffusion of water into the PMMA, which then attracted calcium-containing deposits to accumulate on the surface. Subsequently, as gamma irradiation is the milder and preferred form of sterilisation, this was further studied after incubation in a stimulated aqueous humpur solution, whereby it was discovered that the diffusion coefficient 2.87 x 10[sup]-12m[sup]s[sup[-1] for the gamma sterilised PMMA compared to the un-sterilised PMMA diffusion coefficient of 2.42 x 10[sup]-12m[sup]2s[sup]-1. The approximatley 18% faster diffusion rate within the gamma sterilised PMMA was attributed to the chain scission that had occurred during the sterilisation process. Through the use of triple detection gel permeation chromatography, comparisons of the Mark-Houwink value identified the structural breakdown of the PMMA as a result of the sterilisation process. Surface modification of PMMA via fluorination was carried out using three different approaches to reduce diffusion and, in turn, calcification. The surface modified PMMA after immersion into the simulated aqueous humour solution was examined for surface deposits using analytical techniques. The chemically modified samples showed a promising reduction in calcium-containing deposits when analysed by scanning electron microscopy. However the drawback in the method used for chemical fluorination resulted in the PMMA surface not being evenly fluorinated. Therefore an improved method of applying direct gas fluorination to the PMMA was carried out which produced more consistent recults. This method was better at reducing both calcification and diffusion into the PMMA. PMMA was also doped with a per-fluorinated acridine and cast into a thin film to provide the best reduction of diffusion and hindrance of calcific deposits.

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Kieffer, Pascal. "Calcification de la paroi artérielle : modèles, conséquences et mécanismes." Nancy 1, 2000. http://www.theses.fr/2000NAN12011.

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Thèse de doctorat en sciences du médicament. La calcification de la paroi artérielle au cours du vieillissement peut conduire à la survenue de l'artériosclérose et de l'athérome, qui représentent deux des trois plus importantes pathologies responsables de l'augmentation de morbidité et mortalité cardio-vasculaires dans la population occidentale vieillissante. L'étude des processus de calcification artérielle et de leurs conséquences permettrait d'identifier de nouvelles cible thérapeutiques de l'artériosclérose et de l'athérome. Nous avons étudié le phénomène d'artériosclérose dans différents modèles animaux pouvant mimer la calcification artérielle sur les changements des propriétés mécaniques de la paroi aortique ainsi que sur les éventuelles répercussions cardiaques. [. . . ]

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Woldt, Estelle. "Implication de LRP1 dans l’athérosclérose et la calcification vasculaire." Strasbourg, 2009. https://publication-theses.unistra.fr/public/theses_doctorat/2009/WOLDT_Estelle_2009.pdf.

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La calcification vasculaire est une complication de l'athérosclérose, cependant les mécanismes moléculaires de ce processus sont encore inconnus. Nous avons constaté que PPARγ et LRP1 interagissent fonctionnellement pour contrôler la transformation des cellules musculaires lisse (CML) en cellules cartilagineuses. L’inactivation de LRP1 dans le muscle lisse perturbe l’export du cholestérol et accélère la formation de la plaque d’athérome, cet effet est atténué par la rosiglitazone, un agoniste de PPARγ. L’inactivation de l’expression de PPARγ dans les CML induit la formation de cartilage dans la média vasculaire. Cependant de façon étonnante l’absence de LRP1 dans les CML contrecarre cet effet. En effet, la présence de LRP1 est nécessaire à l'expression de Wnt5a et à la capture et la translocation nucléaire de SPARC, ce qui induit l’expression de Sox9 et de Cart1 et le programme de différenciation chondrocytaire. En revanche, PPARγ induit l'expression de l'antagoniste de Wnt5a, sFRP2, ainsi la présence de LRP1 et de PPARγ dans les CML bloque le processus de calcification. PPARγ et LRP1 contrôlent le remodelage vasculaire en régulant l’état de différenciation des CML. De plus, nous avons constaté que la présence de LRP1 est nécessaire pour activer la cascade de signalisation ShcA/Grb2/Ras/Er1-2 et progresser dans le cycle cellulaire en réponse à l’IGF1, un facteur impliqué dans le développement de l'athérosclérose. Quand LRP1 est absent, c’est Akt/mTOR qui est hyperactivé en réponse à l’IGF1. Ceci montre que LRP1 oriente la voie de l’IGF1 vers la prolifération et la détourne de la différenciation cellulaire. Ainsi LRP1 en contrôlant la cascade de signalisation de l’IGF-1 semble être capable de protéger contre l’accumulation de cellules spumeuses dans la paroi vasculaire Vascular calcification is a hallmark of advanced atherosclerosis but the mechanism for this process remains unknown. We found that the nuclear hormone receptor PPARγ and the LDL receptor-related protein LRP1 functionally interact to control the metaplastic cartilaginous transformation of vSMC. Tissue-specific disruption of LRP1 in smooth muscle disrupts cellular cholesterol export and accelerates atherosclerosis, which is mitigated by the PPARγ agonist rosiglitazone. Loss of PPARγ in vSMC promotes cartilage formation in the medial muscular layer, but surprisingly this is prevented in the absence of LRP1. Wnt5a expression and recapture and nuclear translocation of SPARC, both regulators of the cartilage inducers Sox9 and Cart1, require LRP1. By contrast, PPARγ controls the expression of the Wnt5a antagonist sFRP2. LRP1 and PPARγ both suppress fibrosis- and calcification-promoting TGFβ signals. Thus, PPARγ and LRP1 jointly control the vascular wall architecture, by regulating cellular lipid and extracellular matrix homeostasis, as well as the differentiation state of vSMC. Moreover, we found that LRP1 is required for a full activation of the ShcA/Grb2/Ras/Er1-2 pathway and progression in the cell cycle in response to IGF1, a factor implicated in the development of atherosclerosis. When LRP1 is lacking, the Akt/mTOR pathway is hyperactivated in response to IGF1. These findings prompt us to propose LRP1 as an IGF1 receptor-dependent molecular switch necessary to drive the cell to proliferation instead differentiation. This new role of LRP1 on IGF1 signalling seems to contribute to protect against foam cell accumulation during atherosclerosis

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Blue, Christina R. "Establishing the Physical Basis for Calcification by Amorphous Pathways." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/48167.

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The scientific community is undergoing a paradigm shift with the realization that the formation of carbonate minerals with diverse compositions and textures can be understood within the framework of multiple pathways to mineralization. A variety of common minerals can form via an amorphous pathway, where molecules or clusters aggregate to form a metastable amorphous phase that later transforms to one or more crystalline polymorphs. Amorphous calcium carbonate (ACC) is now recognized in a wide variety of natural environments. Recent studies indicate the chemical signatures and properties of the carbonate polymorphs that transform from an ACC pathway may obey a different set of dependencies than those established for the "classical" step-growth process. The Mg content of ACC and calcite is of particular interest as a minor element that is frequently found in ACC and the final crystalline products of calcified skeletons or sediments at significant concentrations. Previous studies of ACC have provided important insights into ACC properties, but a quantitative understanding of the controls on ACC composition and the effect of mineralization pathway on Mg signatures in calcite has not been established. This study utilized a new mixed-flow reactor (MFR) procedure to synthesize ACC from well-characterized solutions that maintain a constant supersaturation. The experimental design controlled the input solution Mg/Ca ratio, total carbonate concentration, and pH to produce ACC with systematic chemical compositions. Results show that ACC composition is regulated by the interplay of three factors at steady state conditions: 1) Mg/Ca ratio, 2) total carbonate concentration, and 3) solution pH. Findings from transformation experiments show a systematic and predictable chemical framework for understanding polymorph selection during ACC transformation. Furthermore, results suggest a chemical basis for a broad range of Mg contents in calcite, including high Mg calcite. We find that the final calcite produced from ACC is similar to the composition of the initial ACC phase, suggesting that calcite composition reflects local conditions of formation, regardless of the pathway to mineralization. The findings from this study provide a chemical road map to future studies on ACC composition, ACC transformation, polymorph selection, and impurities in calcite. Ph. D.

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Young, Melissa Denton. "Arterial Calcification and the Clinical Implications on Stent Function." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1364999090.

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Furmanik, Malgorzata. "The role of endoplasmic reticulum stress in vascular calcification." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-endoplasmic-reticulum-stress-in-vascular-calcification(a0138614-e3d8-42ef-9cbf-02a01f6e6eaf).html.

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Vascular calcification (VC) is a health problem common in ageing populations, diabetes and chronic kidney disease. It leads to vascular stiffening and heart failure. VC is a regulated process mediated by vascular smooth muscle cells (VSMCs), with similarities to developmental osteogenesis. The exact molecular events responsible for triggering it are unknown. The endoplasmic reticulum (ER) is involved in folding of proteins. ER stress occurs as a result of unfolded protein accumulation and has been implicated in osteoblast differentiation and bone mineralization. Therefore, I hypothesized that ER stress signalling regulates osteogenic differentiation and calcification of VSMCs. I showed that calcification of human aortas was associated with changes in ER stress marker expression. Warfarin and TNFα, which are both established inducers of vascular calcification, increased expression of ER stress markers in VSMCs. ER stress modelled in human primary VSMCs in vitro increased their calcification and was shown to modulate expression of a number of bone related genes, such as BMP-2, Runx2, Osterix, ALP, BSP and OPG in VSMCs in vitro. I also demonstrated that ER stress activated features characteristic of a secretory phenotype in VSMCs, such as downregulation of SMC markers and components of TGFβ signalling related to contractile differentiation, as well as BMP-2. Taken together these results suggested that ER stress can induce changes that lead to osteogenic differentiation. To further explore the relationship between ER stress and osteogenic differentiation of VSMCs Osterix and ALP were studied in more detail. ALP activity was upregulated by ER stress, but did not change when VSMCs calcified. Promoter analysis showed that ALP might be regulated by ER stress via indirect mechanisms and potential regulators of ALP transcription were identified using proteomic analysis.

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Webb, Jason. "Growth, calcification and photosynthesis in the coccolithophorid chrysotila carterae." Thesis, Webb, Jason (2015) Growth, calcification and photosynthesis in the coccolithophorid chrysotila carterae. PhD thesis, Murdoch University, 2015. https://researchrepository.murdoch.edu.au/id/eprint/30271/.

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The mass culture of microalgae for the commercial production of a) low value commodities such as biofuel and food and b) high value products such as polyunsaturated fatty acids, carotenoids, and nano-scaffolds is becoming increasingly attractive. Coccolithophorid algae have been investigated as potential candidates for both low and high value products. This thesis provides data on the specific nutrient and growth requirements in the coccolithophorid, Chrysotila carterae (previously Pleurochrysis carterae). Via the use of oxygen evolution techniques and PAM fluorometry, it is shown that C. carterae is just as susceptible to photoinhibition as some other microalgae with photoinhibition occurring at around 1100-1500 μmol photon m2 s-1. C. carterae also has the ability to recover from short periods of acidification, with recovery from pH 5 when there was no organic carbon assimilation to pH 9 after 20 minutes, Carbon assimilation increased from almost 0, to 3.01 pg CORG cell-1 h-1 . This microalga has a fundamental requirement for selenium, with specific growth rates falling from a μmax of 0.6 d-1, with selenium to 0.1 d-1 in selenium-limited culture. Selenium is also required for coccolith production. In Se-limited culture coccolith production was almost reduced by half, from 70 x105 coccoliths mL-1 to 3.8 x 105 coccoliths mL-1. Diurnal studies of organic and inorganic carbon assimilation showed that C. carterae CCMP647 synthesises coccoliths during the day, and then extrudes them onto the cell surface during the last hours of the dark cycle. Investigations into the effect of various nitrogen sources indicated that with unregulated pH, nitrate achieved the greatest cell density and stable growth: The maximum cell densities reached were nitrate (66.61 x 104 ± 8.2 x 103 cells mL-1) > urea (34.0 x 104 ± 6.2 x 103 cells mL-1) = ammonium (36.08 x 104 ± 4.2 x 103 cells mL-1). Nitrate had the greatest effect on the culture medium ΔpH, (NO3- (0.134 ± 0.003) > urea (0.111 ± 0.003) > NH4+ (0.043 ± 0.001) and urea increased the growth rate of C. carterae by 150 % from 0.17 0.002 d-1 on NO3- to 0.44 ± 0.001 d-1 on urea. However, coccolith production increased with NO3- (73.81± 3.51 ng CaCO3 cell-1> NH4+ 55.18 ± 0.61 ng CaCO3 cell-1 > urea at 12.88 1.62 ng CaCO3 cell-1. Organic carbon (CORG) assimilation using NO3- far exceeded that on NH4+ and urea (CORG assimilated with NO3- = 7 x103 pg CORG cell-1 h-1 vs Urea at 6 x103 pg CORG cell-1 h-1 and NH4+ 5 x103 pg CORG cell-1 h-1 . Inorganic carbon assimilation (CINORG) was also elevated with NO3- producing 3 x103 pg CINORG cell-1 h-1 vs urea at 2 x103 pg CINORG cell-1 h-1 and NH4+ at 2 x103 pg CINORG cell-1 h-1. Thus, nitrate provides long term, stable growth with the highest cell overall cell density under unregulated pH. Under elevated medium pH, urea and ammonium had the highest rate of carbon assimilation far in excess of NO3- for both CORG (Urea 44921.73 ± 2191.08 pg CORG cell-1 h-1 > NH4+ 22006.22 ± 640.39 pg CORG cell-1 h-1 > NO3- 773.59 ± 14.8 pg CORG cell-1 h-1) and CINORG, Urea 773.59 ± 14.8 pg CINORG cell-1 h-1 NO3- 569.44 ± 31.4 pg CINORG cell-1 h-1. Although carbon assimilation rates were elevated under urea and NH4+ at higher pH levels, NO3- at pH 8 had the highest Calcifaction to photosynthsdis ratio (C:P) ratio of 0.158, while closely followed by urea at pH 9 (C:P = 0.150). With enhanced carbon assimilation at pH levels exceeding the pKa of CO2 in the medium pH indicated that this species must be using HCO3- as a carbon source, as cell growth and calcification were elevated at pH levels at which there is a greatly reduced level of CO2 in the medium which is typically in air equilibrated water approximately 10 μmol L-1.

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Rattazzi, Marcello. "Contribution of Interstitial Valve Cells to Aortic Valve Calcification." Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3425639.

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Background. The traditional view of aortic valve calcification as a slow, ineluctable event has been recently questioned by evidence showing the importance of a balance between promoting and inhibiting factors, and the relevance of osteogenic cellular-driven processes. The aortic valve leaflets are comprised of a heterogeneous population of interstitial cells (VIC) whose specific contribution to the degenerating valve has not been defined yet. Aim. The major aim is to identify and describe the phenotypic characteristics of a subpopulation of aortic VIC able to acquire a pro-calcific profile when exposed to pathological stimuli (such as endotoxin [LPS] and inorganic phosphate [Pi]). Methods and Results. Explants-derived primary bovine VIC (BVIC) were cloned by a limited dilution technique. Characterization of BVIC clones was performed by morphological and functional as well as immunophenotyping using markers specific for mesenchymal cells, smooth muscle (SM) cell lineage, endothelial cells, hematopoietic cells, and bone formation process. Among the 40 BVIC clones obtained we selected four clones, morphologically representative of the isolated populations, which displayed different growth pattern and immunophenotype. Both uncloned and cloned cell populations grown on plastics did not show a spontaneous tendency for calcification in the standard medium and were, hence, treated with different combinations of LPS (100 ng/ml) and Pi (2.4 mmol/L, final concentration) for 12 days. Uncloned BVIC showed a progressive increase of alkaline phosphatase (ALP) activity after treatment with LPS that resulted in calcium deposition after addition of Pi. Among the clones, only Clone 1 (fibroblast-like phenotype) showed relevant increase in ALP after LPS treatment, which was paralleled by an increased osteocalcin (OC) expression and prevention of smooth muscle (SM) ??actin (SMA) accumulation, as demonstrated by western blotting and cytofluorimetry analysis. The same treatment had no effect on Clone 4 cells that showed a more stable SM cell-like phenotype. Despite ALP activity and OC increase Clone 1 cells did not undergo calcium deposition after treatment with LPS in long-term culture supplemented with Pi. However, mineralization was observed in co-culture of Clone 1 and Clone 4 treated with LPS plus Pi. Moreover, when cells of Clone 1 were grown on type-I collagen sponges and treated with Pi alone or LPS plus Pi for 12 days we observed an extensive mineralization of the collagen-matrix. Instead, only modest calcium deposition was observed in collagen scaffolds seeded with Clone 4 treated in the same way. A high degree of apoptosis was documented in Clone 1 cells seeded in the collagen scaffolds and treated with LPS plus Pi. No apoptotic degeneration was observed in Clone 4 cells. The proteomic analysis of the cytosolic fraction of Clone 1 cells allowed the identification of 34 proteins which levels of expression were modified with the acquisition the pro-calcific profile. Among these proteins we documented a significant decrease in the expression of antioxidant proteins, such as superoxide dismutase [Cu-Zn] and thioredoxin, together with a downregulation in the level of dimethylarginine dimethylaminohydrolase (DDAH), an intracellular enzyme that degrades asymmetric dimethylarginine (ADMA) (a nitric oxide synthase inhibitor [NOS]). In line with these findings we observed that LPS treatment of Clone 1 cells was accompanied by increased reactive oxygen species (ROS) production. Conclusion. The results of this study demonstrate that BVIC clonal subpopulations are endowed with different calcifying potential when stimulated with the same pathogenic factors. In particular, we identified a specific BVIC subset harbouring a fibroblast-like phenotype that express osteogenic markers and promote collagen-matrix calcification in response to endotoxin and elevated phosphate levels. Introduzione. Tradizionalmente la calcificazione valvolare aortica viene considerata un processo distrofico, ad evoluzione lenta e non modificabile. Tale visione è stata recentemente messa in discussione da evidenze che sottolineano l’importanza, nel corso della calcificazione vascolare, di un bilanciamento fra fattori promuoventi ed inibenti, nonché del ruolo svolto da processi cellulo-mediati. I lembi valvolari aortici sono popolati da cellule interstiziali valvolari (VIC) fenotipicamente eterogenee, il cui contributo specifico nel corso dei processi degenerativi della valvola è solo parzialmente conosciuto. Scopo. Scopo del presente studio è quello di ricercare e caratterizzare una sottopopolazione aortica di VIC in grado di acquisire un fenotipo pro-calcifico in seguito ad esposizione a fattori patogeni (quali endotossina [LPS] e fosfato inorganico [Pi]). Metodi e Risultati. VIC ottenute da espianti di valvole aortiche bovine (BVIC) sono state sottoposte ad un processo di clonazione, mediante tecnica di diluizione limite. I cloni di BVIC sono stati caratterizzati sotto il profilo morfologico ed immunofenotipico mediante l’utilizzo di marcatori tipici per cellule mesenchimali, cellule muscolari lisce (SMC), cellule endoteliali, cellule ematopoietiche e cellule di derivazione ossea. Fra i 40 cloni di BVIC ottenuti sono stati selezionati 4 cloni, morfologicamente rappresentativi delle diverse popolazioni isolate, che mostravano diverse caratteristiche di crescita e di profilo immunofenotipico. Sia la popolazione cellulare di VIC non clonate che i cloni non mostravano la tendenza a fenomeni spontanei di calcificazione in vitro. Le cellule sono state quindi trattate con diverse combinazioni di LPS (100 ng/ml) e Pi (2.4 mmol/L concentrazione finale) per 12 giorni. La popolazione non clonale di BVIC ha mostrato un progressivo incremento nei livelli di espressione della fosfatasi alcalina (ALP) dopo trattamento con LPS, mentre la deposizione di calcio è stata osservata solo nelle cellule trattate con la combinazione di LPS e Pi. Fra i diversi cloni solo il Clone 1 (fenotipo simil-fibroblasto) ha mostrato un significativo incremento nei livelli di espressione dell’ALP. Tale incremento si accompagnava ad un’aumentata espressione di osteocalcina (OC) e ridotto accumulo di ?-actina muscolare liscia (SMA), come documentato da studi in western blotting e citofluorimetria. Il trattamento con LPS non è stato in grado di indurre modifiche simili nel profilo fenotipico del Clone 4 (fenotipo muscolare liscio differenziato). Nonostante il significativo incremento nell’espressione di ALP ed OC, il Clone 1 non ha prodotto fenomeni di calcificazione della matrice dopo trattamento con la combinazione di LPS ed Pi. Tuttavia, aspetti di calcificazione sono stati osservati in esperimenti di co-coltura del Clone 1 e Clone 4, quando trattati con la combinazione di LPS e Pi. Inoltre, dopo semina su spugne di collagene di tipo I, il Clone 1 si è dimostrato in grado di produrre estesi fenomeni di calcificazione della matrice, in seguito a trattamento per 12 giorni con LPS e Pi. Tale combinazione ha indotto solo minimi aspetti di calcificazione nella matrice di collagene popolata dal Clone 4. Fenomeni apoptotici sono stati osservati nel Clone 1 seminato nelle spugne di collagene e trattato con LPS e Pi. Viceversa, nel caso del Clone 4 non sono stati documentati aspetti apoptotici. L’analisi proteomica della frazione citosolica del Clone 1 ha permesso di identificare 34 proteine i cui livelli di espressione si modificano con l’acquisizione del profilo pro-calcifico. Fra queste proteine è stata documentata una significativa riduzione nei livelli di molecole antiossidanti, come la superossido dismutasi [Cu-Zn] e la tioredoxina. Un significativo decremento è stato osservato anche per i livelli di dimetilarginina dimetilaminoidrolase (DDAH), un enzima intracellulare che degrada la dimetilarginina asimmetrica (ADMA) (inibitore dell’ossido nitrico sintetasi [NOS]). In linea con questi dati è stato osservato un aumento della produzione di specie reattive dell’ossigeno (ROS) da parte del Clone 1 trattato con LPS. Conclusioni. I risultati di questo lavoro dimostrano che le popolazioni clonali di BVIC sono dotate di un diverso potenziale pro-calcifico quando stimolate con uno stesso fattore patogeno. In particolare, è stata identificata una specifica sottopopolazione di BVIC, caratterizzata da un profilo fenotipico simil-fibroblasto, che si è dimostrata in grado di esprimere marcatori osteogenici e di calcificare matrice di collagene, in risposta a trattamento con endotossina ed alti livelli di fosfato inorganico.

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Akodad, Mariama. "Marqueurs pronostiques biologiques et morphologiques du TAVI à l’ère de l’évolution des pratiques." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT061.

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La prise en charge du rétrécissement aortique a connu une véritable révolution avec l’avènement du remplacement valvulaire aortique percutané (TAVI). Cette technique, s’adressant initialement à des patients à haut risque chirurgical, a été étendue à des patients à moindre risque du fait de l’amélioration des résultats et s’est accompagnée, au fil des années, d’une simplification de la procédure. Cependant, la sélection rigoureuse des patients en amont de la procédure reste la clé du succès de cette technique. Les facteurs cliniques et échographiques sont insuffisants pour permettre une évaluation précise du profil de risque. Certains biomarqueurs et les calcifications de la valve aortique, permettraient d’améliorer la stratification du risque. L’objectif de ce travail était d’évaluer la valeur pronostique de la troponine et du score calcique valvulaire dans le TAVI à l’ère de l’évolution des pratiques. Le premier chapitre de cette thèse a permis de confirmer la valeur pronostique de la troponine en pré et post-procédure TAVI et celle du score calcique avec les valves de la précédente génération. Le deuxième chapitre de ce travail a permis de mettre en évidence l’impact de la prédilatation sur l’élévation de troponine post-procédure avec un rôle pronostique potentiel Management of aortic stenosis was revolutionized by the advent of transcatheter aortic valve replacement (TAVI). This technique, initially targeting patients at high surgical risk, was extended to lower risk patients regarding to improved outcomes and was accompanied, over the years, by a simplification at each step of the procedure. However, the careful selection of patients upstream of the procedure remains the key to success. Clinical and echographic factors are not sufficient to allow an accurate assessment of their risk profile. Thus, biomarkers and aortic valve calcifications evaluation may improve risk profile stratification. The objective of this thesis was to evaluate the prognostic value of troponin and aortic valve calcium score in patients undergoing TAVI in the era of TAVI simplificationThe first chapter of this thesis confirmed the prognostic value of pre- and post-procedure troponin (myocardial injury) in patients undergoing TAVI and of calcium score with previous generation prosthesis.The second chapter highlighted the impact of predilatation on this post-procedure troponin elevation with a potential prognostic impact

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Herfort, Lydie Marie-Claude Catherine. "Photosynthesis and calcification in the coccolithophore, Emiliania huxleyi, and two hermatypic corals, Porites porites and Acropora sp." Thesis, Queen Mary, University of London, 2002. http://qmro.qmul.ac.uk/xmlui/handle/123456789/28588.

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Most global calcification is carried out by organisms which are also photosynthetic. In this study, the coccolithophore Emiliania huxleyi (Lohmann) Hay and Mohler and two species of hermatypic coral were used to: examine the effect of dissolved inorganic carbon (DIC) and light on photosynthesis and calcification; and determine the extent to which these two processes interact. A novel method of producing coccolith-less (non-calcifying) cells from calcifying cells of the same strain of E huxley! was developed thus allowing photosynthesis and calcification to be studied separately. The kinetics of photosynthesis in both types of cell, and of calcification in coccolith-bearing cells, were shown to be biphasic with respect to DIC concentration. The hiatus in all three cases was located at 1 mM DIC. This unusual pattern was shown to be the product of two carbon uptake mechanisms: an anion exchanger working at all DIC concentrations and an external carbonic anhydrase active only at low DIC concentrations. In contrast to the commonly-held view, this study demonstrated that calcification did not promote photosynthesis in E. huxleyi. Nevertheless, there was clearly strong biological control of calcification in this alga since DIC uptake was mediated by an anion transporter and a dehydroxylating enzyme. This work also showed that in E huxleyi, DIC addition enhanced photosynthesis at both limiting and saturating photon flux densities and that bicarbonate affected photochemical processes directly. Photosystem II activity was stimulated and non-photochemical quenching was reduced, possibly protecting the photosynthetic apparatus from damage by light. In the two corals; Porites porites and Acropora sp., strong biological control of calcium carbonate precipitation was also evident. Again, calcification did not stimulate photosynthesis. Calcification rates of Acropora sp. were monitored in the dark and although these were lower than in the light, they still increased dramatically with bicarbonate addition. This showed that high concentrations of the bicarbonate ion can compensate for the lack of light. Hence, it seems that in hermatypic corals, light-dependence of calcification may be facultative and not obligate. It is therefore clear from the results of this study that calcification and photosynthesis are not as closely coupled as has been previously thought. In neither E. huxleyi, nor in the hermatypic corals, were photosynthetic and calcification rates saturated at the present ambient DIC concentration of seawater.

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Rosa, Mickael. "Athérosclérose et sténose valvulaire aortique : implication des macrophages et des cellules interstitielles de valve dans les calcifications cardiovasculaires." Thesis, Lille 2, 2016. http://www.theses.fr/2016LIL2S046.

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Les pathologies cardiovasculaires sont le plus souvent l’aboutissement des processus liés à l’athérosclérose. Elles représentent la première cause de morbi-mortalité dans le monde et leur incidence s’accroit avec le vieillissement de la population et l’expansion de facteurs de risques comme le diabète ou l’obésité. La sténose valvulaire aortique (SVA) est la valvulopathie la plus fréquente dans les pays développés présentant de nombreux points communs avec l’athérosclérose vasculaire. En plus des facteurs de risque, les lésions valvulaires et les lésions vasculaires partagent des similitudes dans les processus physiopathologiques impliqués comme l’inflammation, la fibrose, l’angiogenèse et la calcification. Ce dernier processus apparait dans les stades avancés des pathologies liées à l’athérosclérose et joue un rôle critique via son implication dans la stabilité de la plaque ou l’épaississement des cuspides valvulaires aortiques. Les macrophages, cellules issues de la différenciation des monocytes infiltrés, jouent un rôle prépondérant dans ces lésions via les phénotypes classiques (M1) et alternatifs (M2). Néanmoins cette dichotomie ne reflète pas complètement la variété de leur plasticité et les différents phénotypes induits notamment par le microenvironnement des monocytes/macrophages (zones riches en lipides, zones riches en fer ou zones riches en calcification). Dans la valve aortique, les cellules interstitielles de valve (VIC) forment la population cellulaire la plus présente au sein de la valve aortique. Ces cellules jouent un rôle déterminant dans le maintien du tissu valvulaire, mais également dans les processus de calcification menant à la SVA. Dans un premier temps, cette thèse a pour but d’étudier la capacité des macrophages à former des ostéoclastes, cellules responsables de la dégradation de la matrice osseuse, au sein des plaques d’athérosclérose. Dans un second temps, ce travail se focalisera sur les processus de calcification de la valve aortique via l’étude du rôle de la leptine dans les calcifications valvulaires (étude a priori) puis dans une étude transcriptomique sans a priori de VIC issues de valve sténosées et non-sténosées. Nos résultats sur les macrophages montrent ex vivo que les cellules en bordure des calcifications vasculaires sont des macrophages alternatifs de type M2. In vitro, ces cellules sont incapables de se différencier en ostéoclastes et de résorber une matrice osseuse. Pour l’étude de l’effet de la leptine sur les VIC, nous montrons que la leptine sérique est plus élevée chez des patients présentant une SVA, nous confirmons que la leptine et son récepteur sont exprimés au sein des valves aortiques et que la leptine favorise la différenciation ostéoblastique des VIC de manière dépendante des voies Akt et ERK. Enfin, l’étude transcriptomique a permis de mettre en évidence une nouvelle voie métabolique dérégulée dans les VIC. Cette enzyme est sous exprimée dans les VIC issues de valves pathologiques et dans les zones calcifiées des valves aortiques sténosées. Par ailleurs, le traitement des VIC par le produit de cette enzyme en milieu procalcifiant inhibe la calcification. Cette thèse met en avant de nouveaux indices sur les processus de calcification observés dans les plaques d’athérosclérose et les valves aortiques sténosées. Ces résultats décrivent l’impossibilité des M2 à former des ostéoclastes capables de résorber les calcifications. Il sera intéressant d’étudier le phénotype des macrophages en bordure des calcifications des valves aortiques sténosées. D’autre part, il sera intéressant d’étudier l’origine de la leptine dans la valve et son mécanisme d’action sur les VIC. Enfin, ce travail a mis à jour une nouvelle voie métabolique, impliquée dans le développement des calcifications valvulaires, qui pourrait constituer une voie thérapeutique innovante dans le traitement médicamenteux de la SVA Cardiovascular diseases (CVD) are the most often outcome of atherosclerosis processes. CVD are the first leading cause of death rate with an increasing incidence due to ageing populations and expansion of risk factors such as diabetes mellitus or obesity. Aortic valve stenosis (AVS) is the most frequent valvulopathy in developed countries sharing common points with vascular atherosclerosis. More than only risk factors, valvular and vascular lesions share common pathophysiological processes implicated in the development of the disease such as inflammation, fibrosis, angiogenesis and calcification. This last process appears in late stages of atherosclerosis diseases and play critical roles via implication in plaque stability or thickening of the aortic valve. Macrophages are cells deriving from infiltrated monocytes, playing an important role in the inflammatory state of lesions via classical (M1) or alternative phenotypes (M2) phenotypes. Nevertheless, this dichotomy does not reflect completely the variety of their plasticity and different phenotypes induced by the microenvironment of monocytes/macrophages (lipid riche zone, iron riche zone or calcium rich zone). In the aortic valve, valvular interstitial cells (VIC) are the most prominent cell type found in the aortic valve. These cells play a major role not only in the valve tissue homeostasis but also in the calcification processes leading to AVS. In a first part, the aim of this thesis is to elucidate the ability of macrophages to differentiate into osteoclasts, cell type responsible for bone matrix remodeling, inside atherosclerosis plaques. In a second part, this work will focus on the calcification processes occurring in the aortic valve via the study of the role of leptin in valvular calcification (association study) and then in a transcriptomic analysis of VIC isolated from calcified versus non calcified aortic valves (genome-wide expression study). Our results about macrophages show that ex vivo cell surrounding vascular calcification are alternative M2 macrophages. In vitro, these cells are no able to differentiate into true osteoclasts nor to resorb calcium deposits. Concerning the role of leptin on VIC, the results show that serum leptin is higher in patients with AVS, leptin and its receptors are expressed in the aortic valves and leptin enhances the osteoblast différenciation of VIC in an Akt and ERK dependant manner. Finally, the transcriptomic analysis allowed to highlight a new pathway deregulated in VIC. This enzyme is underexpressed in VIC isolated from calcified aortic valves and in the calcified zonesAbstract4of stenosed aortic valves. Otherwise, treating VIC with the product of this enzyme in a procalcifying medium inhibits calcification processes.This thesis highlights new insights into the calcification processes occurring in atherosclerosis lesions and calcified aortic valves. These results describe that M2 macrophages cannot differentiate into osteoclasts and reverse calcification formation inside atherosclerosis plaques. In parallel, it would be interesting to study the macrophages phenotypes surrounding calcium deposits in stenosed aortic valves. Then, it will be interesting to decipher the origin of leptin and its precise mechanism of action on VIC. Finally this work points out a new metabolic pathway implicated in the development of valvular calcification which could be a medical treatment of SVA

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Després, Audrey-Anne, and Audrey-Anne Després. "Lipoprotéine(a) et microcalcification de la valve aortique." Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/38301.

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La sténose aortique (SA) est la maladie valvulaire la plus fréquente dans notre société. Elle est caractérisée par un remodelage fibrocalcique conduisant à une obstruction progressive du flux sanguin. La lipoprotéine(a) (Lp[a]), une lipoprotéine similaire à la lipoprotéine de faible densité, est un facteur de risque génétique fortement associé à la SA. Malheureusement, les concentrations plasmatiques de Lp(a) sont très peu influencées par des facteurs extrinsèques, tels qu’un régime alimentaire ou une médication hypolipidémiante. Des études suggèrent que la Lp(a) serait associée aux processus de calcification dans le développement de la SA. La tomographie par émission de positons couplée à la tomographie axiale permet de détecter le processus précoce lié à calcification de la valve aortique. En effet, cette technique d’imagerie nucléaire permet d’identifier et de quantifier la microcalcification au niveau de la valve aortique, un marqueur fortement lié au développement futur de calcium. L’impact de la Lp(a) sur la microcalcification de la valve aortique n’a jamais été évalué. La mesure de la microcalcification chez des individus sans SA ayant des concentrations plus ou moins élevées de Lp(a) a été effectuée. Notre hypothèse était que les individus ayant des concentrations élevées de Lp(a) ont une microcalcification plus élevée, lorsque comparée aux individus ayant des concentrations plus faibles de Lp(a). Les résultats de cette étude ont révélé que les individus sans SA mais ayant des concentrations élevées de Lp(a) présentent une microcalcification plus importante que les individus ayant de plus faibles concentrations de Lp(a). La réalisation de ce projet de recherche nous a permis d’observer cliniquement un processus actif de calcification chez des individus avec des concentrations élevées de Lp(a), et ce, malgré l’absence clinique de la maladie, illustrant l’importance de cette lipoprotéine dans le développement de la SA. La sténose aortique (SA) est la maladie valvulaire la plus fréquente dans notre société. Elle est caractérisée par un remodelage fibrocalcique conduisant à une obstruction progressive du flux sanguin. La lipoprotéine(a) (Lp[a]), une lipoprotéine similaire à la lipoprotéine de faible densité, est un facteur de risque génétique fortement associé à la SA. Malheureusement, les concentrations plasmatiques de Lp(a) sont très peu influencées par des facteurs extrinsèques, tels qu’un régime alimentaire ou une médication hypolipidémiante. Des études suggèrent que la Lp(a) serait associée aux processus de calcification dans le développement de la SA. La tomographie par émission de positons couplée à la tomographie axiale permet de détecter le processus précoce lié à calcification de la valve aortique. En effet, cette technique d’imagerie nucléaire permet d’identifier et de quantifier la microcalcification au niveau de la valve aortique, un marqueur fortement lié au développement futur de calcium. L’impact de la Lp(a) sur la microcalcification de la valve aortique n’a jamais été évalué. La mesure de la microcalcification chez des individus sans SA ayant des concentrations plus ou moins élevées de Lp(a) a été effectuée. Notre hypothèse était que les individus ayant des concentrations élevées de Lp(a) ont une microcalcification plus élevée, lorsque comparée aux individus ayant des concentrations plus faibles de Lp(a). Les résultats de cette étude ont révélé que les individus sans SA mais ayant des concentrations élevées de Lp(a) présentent une microcalcification plus importante que les individus ayant de plus faibles concentrations de Lp(a). La réalisation de ce projet de recherche nous a permis d’observer cliniquement un processus actif de calcification chez des individus avec des concentrations élevées de Lp(a), et ce, malgré l’absence clinique de la maladie, illustrant l’importance de cette lipoprotéine dans le développement de la SA. Aortic stenosis (AS) is the most common valve disease in our society. It is characterized by fibrocalcific remodelling leading to progressive obstruction of blood flow. Lipoprotein(a) (Lp[a]), a lipoprotein similar to low-density lipoprotein, is a genetic risk factor strongly associated with AS. Plasma concentrations of Lp(a) are very little influenced by extrinsic factors, such as diet or lipid-lowering medication. Studies suggest that Lp(a) would be associated with calcification processes in the development of AS. Positron emission tomography coupled with computed tomography allows the early process related to calcification of the aortic valve to be detected. This nuclear imaging technique identifies and quantifies microcalcification at the aortic valve, a marker strongly linked to the future development of calcium. The impact of Lp(a) on aortic valve microcalcification has never been evaluated. Microcalcification measurements in individuals without AS with high or low concentrations of Lp(a) were performed. Our hypothesis was that individuals with high concentrations of Lp(a) have higher microcalcification when compared to individuals with lower concentrations of Lp(a). The results of this study revealed that individuals without AS but with high concentrations of Lp(a) have a higher microcalcification than individuals with lower concentrations of Lp(a). The completion of this research project allowed us to observe clinically an active calcification process in individuals with high concentrations of Lp(a) despite the clinical absence of the disease, illustrating the importance of this lipoprotein in the development of AS. Aortic stenosis (AS) is the most common valve disease in our society. It is characterized by fibrocalcific remodelling leading to progressive obstruction of blood flow. Lipoprotein(a) (Lp[a]), a lipoprotein similar to low-density lipoprotein, is a genetic risk factor strongly associated with AS. Plasma concentrations of Lp(a) are very little influenced by extrinsic factors, such as diet or lipid-lowering medication. Studies suggest that Lp(a) would be associated with calcification processes in the development of AS. Positron emission tomography coupled with computed tomography allows the early process related to calcification of the aortic valve to be detected. This nuclear imaging technique identifies and quantifies microcalcification at the aortic valve, a marker strongly linked to the future development of calcium. The impact of Lp(a) on aortic valve microcalcification has never been evaluated. Microcalcification measurements in individuals without AS with high or low concentrations of Lp(a) were performed. Our hypothesis was that individuals with high concentrations of Lp(a) have higher microcalcification when compared to individuals with lower concentrations of Lp(a). The results of this study revealed that individuals without AS but with high concentrations of Lp(a) have a higher microcalcification than individuals with lower concentrations of Lp(a). The completion of this research project allowed us to observe clinically an active calcification process in individuals with high concentrations of Lp(a) despite the clinical absence of the disease, illustrating the importance of this lipoprotein in the development of AS.

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De, Bodt Caroline. "Pelagic calcification and fate of carbonate production in marine systems." Doctoral thesis, Universite Libre de Bruxelles, 2010. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210156.

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Human activities have contributed to the increase in atmospheric greenhouse gases such as carbon dioxide (CO2). This anthropogenic gas emission has led to a rise in the average Earth temperature. Moreover, the ocean constitutes the major sink for anthropogenic CO2 and its dissolution in surface waters has already resulted in an increase of seawater acidity since the beginning of the industrial revolution. This is commonly called ocean acidification. The increase in water temperature could induce modifications of the physical and chemical characteristics of the ocean. Also, the structure and the functioning of marine ecosystems may be altered as a result of ocean acidification. Phytoplankton productivity is one of the primary controls in regulating our climate, for instance via impact on atmospheric CO2 levels. Coccolithophores, of which Emiliania huxleyi is the most abundant species, are considered to be the most important pelagic calcifying organisms on Earth. Coccolithophores are characterized by calcium carbonate platelets (coccoliths) covering the exterior of the cells. They form massive blooms in temperate and sub-polar oceans and in particular along continental margin and in shelf seas. The intrinsic coupling of organic matter production and calcification in coccolithophores underlines their biogeochemical importance in the marine carbon cycle. Both processes are susceptible to change with ocean acidification and warming. Coccolithophores are further known to produce transparent exopolymer particles (TEP) that promote particle aggregation and related processes such as marine snow formation and sinking. Thus, the impact of ocean warming and acidification on coccolithophores needs to be studied and this can be carried out through a transdisciplinary approach.The first part of this thesis consisted of laboratory experiments on E. huxleyi under controlled conditions. The aim was to estimate the effect of increasing water temperature and acidity on E. huxleyi and especially on the calcification. Cultures were conducted at different partial pressures of CO2 (pCO2); the values considered were 180, 380 and 750 ppm corresponding to past, present and future (year 2100) atmospheric pCO2. These experiments were conducted at 13°C and 18°C. The cellular calcite concentration decreases with increasing pCO2. In addition, it decreases by 34 % at 380 ppm and by 7 % at 750 ppm with an increase in temperature of 5°C. Changes in calcite production at future pCO2 values are reflected in deteriorated coccolith morphology, while temperature does not affect coccolith morphology. Our findings suggest that the sole future increase of pCO2 may have a larger negative impact on calcification than its interacting effect with temperature or the increase in temperature alone. The evolution of culture experiments allows a better comprehension of the development of a bloom in natural environments. Indeed, in order to predict the future evolution of calcifying organisms, it is required to better understand the present-day biogeochemistry and ecology of pelagic calcifying communities under field conditions.The second part of this dissertation was dedicated to results obtained during field investigations in the northern Bay of Biscay, where frequent and recurrent coccolithophorid blooms were observed. Cruises, assisted by remote sensing, were carried out along the continental margin in 2006 (29 May – 10 June), 2007 (7 May – 24 May) and 2008 (5 May – 23 May). Relevant biogeochemical parameters were measured in the water column (temperature, salinity, dissolved oxygen, Chlorophyll-a and nutrient concentrations) in order to determine the status of the bloom at the time of the different campaigns. Calcification has been shown to be extremely important in the study area. In addition, TEP production was significant at some stations, suggesting that the northern Bay of Biscay could constitute an area of important carbon export. Mortality factors for coccolithophores were studied and the first results of lysis rates measured in this region were presented. Results obtained during culture experiments and comparison with data reported in the literature help to better understand and to predict the future of coccolithophores in a context of climate change. Data obtained during either culture experiments or field investigations allowed a better understanding of the TEP dynamics. Finally, the high lysis rates obtained demonstrate the importance of this process in bloom decline. Nevertheless, it is clear that we only begin to understand the effects of global change on marine biogeochemistry, carbon cycling and potential feedbacks on increasing atmospheric CO2. Thus, further research with a combination of laboratory experiments, field measurements and modelling are encouraged. Doctorat en Sciences info:eu-repo/semantics/nonPublished

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Dubois, Philippe. "Tissu squelettique et calcification chez Asterias rubens L.(Echinodermata: Asteroidea)." Doctoral thesis, Universite Libre de Bruxelles, 1988. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/213314.

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Jie, Gerard Kon Siong. "The role of vitamin K-dependent proteins in tissue calcification." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 1995. http://arno.unimaas.nl/show.cgi?fid=8340.

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Cirka, Heather Ann. "Mechanical Regulation of Apoptosis and Calcification within Valvular Interstitial Cells." Digital WPI, 2016. https://digitalcommons.wpi.edu/etd-dissertations/213.

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Calcific aortic valvular disease (CAVD) is the most common valvular pathology in the developed world. CAVD results in calcifications forming on the aortic valve leaflets, inhibiting proper closure and causing complications of stenosis and regurgitation. Although, the mechanisms behind the disease initiation are unknown, it is believed to be a cell-mediated phenomenon, and not the result of passive degradation of the valve as once believed due to the increased prevalence with age. Currently, there are no pharmaceutical options for the prevention or reversal of calcifications, the only treatment option is complete valve replacement, an imperfect solution. Hindering the development of potential therapeutics is that currently there are no adequate animal models which replicate the calcification and cell death seen in disease explanted valves. An in vitro model has been develop where valvular interstitial cells (VICs), the main cell type of the valve, are seeded at high density into tissue culture polystyrene dishes and cultured with TGF-β1. This results in VICs activating to the myofibroblast phenotype and forming cell aggregates. Due to currently unknown mechanisms, apoptosis occurs within the center of the aggregates and calcification ensues. Although simplistic, this model has been used to show that rate and frequency of aggregation is affected by cellular tension; conditions of high tension increase aggregation response, while conditions of low tension prevent aggregation and calcification from occurring. It is important to note; however, that despite its wide usage, the current model is limited as the aggregation and subsequent calcification are random occurrences and are not consistent across literature where same conditions for control samples are used. The motivation of the presented work is two-fold. First, high intracellular tension has been suggested as one of the mechanisms leading to disease in the valve. Despite the clear and important role of cell tension, VIC tension has never before been measured in a dynamic environment. The ways in which dynamic stimulation affects individual VIC tension is not known. In aim one, a method is developed to allow for long-term cyclic stretch of VICs with measurement of cell traction force. It was found that cyclic stretch decreased cell tension in cells with high prestress and increased cell tension for conditions of low prestress. Combined, these findings indicate a homeostatic cellular tension which is dependent upon the mechanical environment. In the second aim, a novel method for creating VIC aggregates is validated. Micro-contact printing, essentially â€œstampingâ€� of a protein in a defined pattern, is used to create circular aggregates on polyacrylamide gels. This method allows for the separation of the aggregation from the subsequent calcification, an improvement over the current in vitro model. The method is then used to explore the role of the distribution of tension in the initiation of disease

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