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1
Fellows, Adam Lee. "FOXO3a in vascular smooth muscle cell apoptosis." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275687.
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FOXO3a is a pro-apoptotic transcription factor which shows increased activation in vascular smooth muscle cells (VSMCs) of advanced atherosclerotic plaques, specifically within the intimal layer. Since VSMC apoptosis plays a crucial role in the pathophysiology of atherosclerosis, we investigated the mechanisms underlying FOXO3a-mediated cell death in this particular cell type. We aimed to characterise a novel VSMC system (FOXO3aA3ERTM) and use these cells to validate MMP-13 and TIMP3 as new FOXO3a target genes. Also, we sought to determine the mechanisms of FOXO3aA3ERTM-mediated VSMC apoptosis, particularly regarding MMP-13 and TIMP3, potential MMP-13 substrates in the extracellular matrix and the precise apoptotic signalling involved. Furthermore, we aimed to investigate whether VSMC-specific activation of FOXO3aA3ERTM in mouse affects vascular remodelling during injury and whether this is reliant on MMP-13. Lastly, we aimed to address if endogenous FOXO3a upregulates MMP-13 in mouse and human VSMCs. Our laboratory has created a transgenic rat VSMC line which stably expresses an inducible FOXO3a mutant allele known as FOXO3aA3ERTM and previous microarray experiments identified matrix metalloproteinase 13 (MMP-13) as a potential novel FOXO3a target gene. Initially, we described several key features of the FOXO3aA3ERTM VSMCs used throughout this thesis, and subsequently demonstrated that MMP-13 is a bona fide target whose expression is rapidly upregulated upon FOXO3a activation, leading to markedly higher levels of protein, cleavage and proteolytic capacity. This induction of MMP-13 was responsible for the vast majority of FOXO3a-mediated apoptosis which was accompanied by prominent degradation of fibronectin, a glycoprotein found in the extracellular matrix. However, we could not identify a terminal apoptotic pathway. FOXO3a also downregulated the endogenous MMP inhibitor TIMP3, the recombinant protein of which reduced both MMP-13 proteolysis and FOXO3a-mediated apoptosis. Activation of FOXO3aA3ERTM in the VSMCs of medium and large arteries in mice resulted in heightened expression of MMP-13 in the vessel wall, which contributed to enhanced neointimal formation during carotid ligation. Finally, endogenous FOXO3a activation leads to increased MMP-13 expression in human VSMCs, but not mouse. Overall, we have shown that FOXO3a promotes VSMC apoptosis through MMP-13 both in vitro and in vivo, a novel pathway that has important implications for the pathogenesis and treatment of vascular disease.
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Zhao, Ning. "Notch Signaling Guides Vascular Smooth Muscle Cell Function." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1396890017.
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Wong, Wai-ming. "Effects of isoflavonoids on vascular smooth muscle cell proliferation /." View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36433913.
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Lugano, Roberta. "Low density lipoproteins, vascular smooth muscle cell function and vascular remodeling." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/283471.
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High levels of circulating low-density lipoproteins (LDL) are one of the major cardiovascular risk factors. Hypercholesterolemia induces endothelial dysfunction and chronic intimal inflammatory cell accumulation, hallmarks of the initiation of atherosclerosis. Additionally, growing human atherosclerotic plaques show proliferation and migration of vascular smooth muscle cells (VSMC) towards the intima producing remodeling of the vascular wall. However, those plaques that are most prone to rupture show a progressive loss of VSMC becoming soft and vulnerable and these lipid-rich high risk plaques cause clinical episodes resulting in morbid or fatal ischemic events. The mechanisms involved in the transformation of a plaque into a vulnerable VSMC-depleted atheroma have not been completely elucidated. Lipid-rich-VSMC have an impaired vascular repair function due to changes in cytoskeleton proteins. However, the effects of LDL on VSMC function during plaque remodeling and vascular repair are not fully understood. Thus, the aim of this thesis was to investigate early changes directly induced by LDL on VSMC phenotype and function and to identify the molecular mechanisms involved.
This thesis demonstrates that the cardiovascular risk of hypercholesterolemia involves the interaction of LDL with VSMC and the regulation at a molecular level of different pathways that converge in the cell’s migratory capacity. Migratory function of lipid-loaded VSMC can be restored by inhibition of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) through a Rho kinase and myosin light chain phosphatase dependent mechanism. In addition, the studies performed in this thesis show that LDL affect VSMC adhesion, migration and cytoskeleton dynamics through the abrogation of the urokinase-plasminogen activator (uPA)/uPA receptor (uPAR) system function and by modulation of HSP27 phosphorylation and subcellular localization.El nivel elevado de lipoproteínas de baja densidad (LDL), uno de los principales factores de riesgo cardiovascular, conllevan a una disfunción endotelial y acumulación crónica de células inflamatorias en la íntima arterial en la etapa inicial de desarrollo de la arterosclerosis. Además, la progresión de las placas arterioscleróticas se caracteriza por un proceso de remodelado vascular consecuencia de la proliferación y migración de células musculares lisas vasculares (CML) en la íntima. Sin embargo, las placas ateroscleróticas con mayor susceptibilidad a la ruptura presentan una pérdida progresiva de CML, siendo estas placas ricas en lípidos y altamente vulnerables las que provocan eventos isquémicos mórbidos o fatales. Hoy día desconocemos todavía los mecanismos involucrados en la transformación de las placas en ateromas vulnerables. Las CML ricas en lípidos presentan alteraciones en su capacidad de reparación vascular debido a alteraciones en proteínas del citoesqueleto. Sin embargo, los efectos de las LDL en la función de las CML durante el remodelado de las placas y reparación vascular se desconocen en gran medida. Por ello, el objetivo de esta tesis ha sido investigar los cambios iniciales inducidos directamente por las LDL en el fenotipo y la función de las CML e identificar los mecanismos moleculares involucrados. Esta tesis demuestra que el riesgo cardiovascular de la hipercolesterolemia implica la interacción entre LDL y CML y la regulación a nivel molecular de diferentes vías de señalización que convergen en la migración celular. La capacidad de migración de CML cargadas de lípidos puede restituirse mediante la inhibición de la 3-hidroxi-3-metilglutaril coenzima-A (HMG-CoA), a través de un mecanismo dependiente de la quinasa Rho. Además, los estudios realizados en esta tesis demuestran que las LDL afectan la adhesión, migración y dinámica de formación del citoesqueleto de las CML a través de la alteración de la función del sistema del activador del plasminogeno tipo uroquinasa (uPA)/uPA receptor (uPAR) y mediante la modulación de la fosforilación y localización subcelular de la HSP27.
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Lugano, Roberta 1983. "Low density lipoproteins, vascular smooth muscle cell function and vascular remodeling." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/283471.
Full textAbstract:
High levels of circulating low-density lipoproteins (LDL) are one of the major cardiovascular risk factors. Hypercholesterolemia induces endothelial dysfunction and chronic intimal inflammatory cell accumulation, hallmarks of the initiation of atherosclerosis. Additionally, growing human atherosclerotic plaques show proliferation and migration of vascular smooth muscle cells (VSMC) towards the intima producing remodeling of the vascular wall. However, those plaques that are most prone to rupture show a progressive loss of VSMC becoming soft and vulnerable and these lipid-rich high risk plaques cause clinical episodes resulting in morbid or fatal ischemic events. The mechanisms involved in the transformation of a plaque into a vulnerable VSMC-depleted atheroma have not been completely elucidated. Lipid-rich-VSMC have an impaired vascular repair function due to changes in cytoskeleton proteins. However, the effects of LDL on VSMC function during plaque remodeling and vascular repair are not fully understood. Thus, the aim of this thesis was to investigate early changes directly induced by LDL on VSMC phenotype and function and to identify the molecular mechanisms involved.
This thesis demonstrates that the cardiovascular risk of hypercholesterolemia involves the interaction of LDL with VSMC and the regulation at a molecular level of different pathways that converge in the cell’s migratory capacity. Migratory function of lipid-loaded VSMC can be restored by inhibition of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) through a Rho kinase and myosin light chain phosphatase dependent mechanism. In addition, the studies performed in this thesis show that LDL affect VSMC adhesion, migration and cytoskeleton dynamics through the abrogation of the urokinase-plasminogen activator (uPA)/uPA receptor (uPAR) system function and by modulation of HSP27 phosphorylation and subcellular localization.El nivel elevado de lipoproteínas de baja densidad (LDL), uno de los principales factores de riesgo cardiovascular, conllevan a una disfunción endotelial y acumulación crónica de células inflamatorias en la íntima arterial en la etapa inicial de desarrollo de la arterosclerosis. Además, la progresión de las placas arterioscleróticas se caracteriza por un proceso de remodelado vascular consecuencia de la proliferación y migración de células musculares lisas vasculares (CML) en la íntima. Sin embargo, las placas ateroscleróticas con mayor susceptibilidad a la ruptura presentan una pérdida progresiva de CML, siendo estas placas ricas en lípidos y altamente vulnerables las que provocan eventos isquémicos mórbidos o fatales. Hoy día desconocemos todavía los mecanismos involucrados en la transformación de las placas en ateromas vulnerables. Las CML ricas en lípidos presentan alteraciones en su capacidad de reparación vascular debido a alteraciones en proteínas del citoesqueleto. Sin embargo, los efectos de las LDL en la función de las CML durante el remodelado de las placas y reparación vascular se desconocen en gran medida. Por ello, el objetivo de esta tesis ha sido investigar los cambios iniciales inducidos directamente por las LDL en el fenotipo y la función de las CML e identificar los mecanismos moleculares involucrados. Esta tesis demuestra que el riesgo cardiovascular de la hipercolesterolemia implica la interacción entre LDL y CML y la regulación a nivel molecular de diferentes vías de señalización que convergen en la migración celular. La capacidad de migración de CML cargadas de lípidos puede restituirse mediante la inhibición de la 3-hidroxi-3-metilglutaril coenzima-A (HMG-CoA), a través de un mecanismo dependiente de la quinasa Rho. Además, los estudios realizados en esta tesis demuestran que las LDL afectan la adhesión, migración y dinámica de formación del citoesqueleto de las CML a través de la alteración de la función del sistema del activador del plasminogeno tipo uroquinasa (uPA)/uPA receptor (uPAR) y mediante la modulación de la fosforilación y localización subcelular de la HSP27.
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Wong, Wai-ming, and 黃慧明. "Effects of isoflavonoids on vascular smooth muscle cell proliferation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B45011059.
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Havrda, Matthew C. "Molecular Mechanisms of Notch Signaling Governing Vascular Smooth Muscle Cell Proliferation." Fogler Library, University of Maine, 2006. http://www.library.umaine.edu/theses/pdf/HavrdaMC2006.pdf.
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Izzard, Tanya. "Extracellular matrix and the cell cycle in vascular smooth muscle cells." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322616.
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Haider, Ursula G. B. "Resveratrol Attenuates Vascular Smooth Muscle Cell Hypertrophy and Hyperplasia." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-8688.
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Kemp, Christian R. W. "Mechanical influences on human vascular smooth muscle cell growth." Thesis, University of Leicester, 2001. http://hdl.handle.net/2381/29397.
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The leading cause of death in Western countries is cardiovascular disease with over 1 million people dying each year as a result in the United States alone. One condition identified as a risk factor for cardiovascular disease is an increased blood pressure or "hypertension" which has been shown to result in morphological changes in blood vessels at different sites around the body, including narrowing of pre-capillary "resistance" vessels. This thesis has sought to investigate whether or not this narrowing of resistance vessels might result from the increased physical forces of hypertension exerted upon the vascular smooth muscle cells of the vessel wall and to investigate the intracellular signalling mechanisms initiating this cellular response. Results indicate that cultured human vascular smooth muscle cells undergo cellular proliferation in response to chronic cyclical mechanical strain but only in the presence of suitable concentrations of soluble growth factors. Furthermore, these growth factors do not originate from the cells in response to the mechanical strain. Therefore, the proliferation is a direct response proportional to the strain applied but dependent upon the concentration of growth factors in the overlying media. In addition the magnitude of human vascular smooth muscle cell proliferation in response to mechanical strain is dependent upon interactions between the cells and specific extracellular matrix proteins and involves activation of the mitogen-activating protein kinase intracellular signalling cascade. In conclusion, these results suggest that the narrowing of resistance vessels observed in hypertension subjects may be a direct result of the increased physical forces exerted upon the vascular smooth muscle cells in conjunction with circulating growth factors. This biological response is mediated via specific cell/matrix interactions and involves specific intracellular signalling pathways, which may provide new targets for the effective treatment and/or management of these structural alterations observed in hypertension individuals.
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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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Rowe, Daniel Thomas David. "Calcium stores and human vascular smooth muscle cell proliferation." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392964.
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Mathieson, Fiona A. "Role of sphingolipids in vascular smooth muscle cell function." Thesis, University of Aberdeen, 2006. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU222750.
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The membrane-derived sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) have been implicated in the development of cardiovascular disease (CVD). S1P and SPC are known to accumulate in blood platelets, and are released during platelet activation. In this study, S1P and SPC were found to have differential effects on intracellular signalling pathways in vascular smooth muscle and this may have functional consequences for the development of CVD. Immunoblotting studies revealed S1P to activate the mitogenic kinase ERK 1/2, whilst SPC activated the inflammatory kinase p38MAPK. Furthermore, this differential kinase activation was found to have important consequences for transcription factor activation downstream. Using transcription factor DNA binding arrays we selected transcription factors which showed changes following S1P and SPC stimulation for further investigation. The NF-kappaB and C/EBP transcription factors are important modulators of inflammation, and were interestingly only activated following SPC stimulation in the DNA array. This was confirmed by immunoblotting and electrophoretic mobility shift assay (EMSA) to occur via a p38MAPK dependent pathway. Moreover, this was found to have functional consequences as only SPC could induce expression and production of the cytokine TNF-alpha. Therefore, SPC may play a role in the inflammatory pathway in VSM. The mitogenic transcription factor CREB, however, was activated by both S1P and SPC. This activation was dependent upon both MAPK activation and a rise in intracellular calcium. Consequently, both S1P and SPC were found to induce cellular proliferation in VSM cells.
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Fakhry, Maya. "Molecular mechanisms of vascular smooth muscle cell transdifferentiation into osteochondrocyte-like cells." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10246.
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Chez les patients souffrant d'insuffisance rénale chronique, les calcifications vasculaires représentent la première cause de mortalité. Elles résultent de la trans-différenciation des cellules musculaires lisses (CMLs) en cellules de type ostéoblastique et/ou chondrocytaire, en réponse à des cytokines inflammatoires ou à une hyperphosphatémie. Les CMLs forment alors des cristaux par l'activité de la phosphatase alcaline non-spécifique du tissu (TNAP). A la lumière de résultats récents, nous avons émis l'hypothèse que la TNAP module la trans différenciation des CMLs. Nos objectifs étaient donc de déterminer l'effet de la TNAP dans la trans-différenciation des CMLs, et d'étudier les mécanismes impliqués dans son induction, avec un intérêt particulier pour les microRNAs. Nous avons observé que l'ajout de phosphatase alcaline purifiée ou la surexpression de TNAP stimule l'expression de marqueurs chondrocytaires en culture de CMLs et de cellules souches mésenchymateuses. De plus, l'inhibition de la TNAP bloque la maturation de chondrocytes primaires. Nous excluons un rôle des cristaux formés par la TNAP, puisque l'ajout de cristaux seuls ou associés à une matrice collagénique n'a pas reproduit les effets de la TNAP. Nous suspectons que la TNAP agit en hydrolysant le pyrophosphate inorganique (PPi). En effet, c'est la TNAP qui hydrolyse le PPi en culture de CMLs et de chondrocytes, et le PPi mime les effets de l'inhibition de TNAP en culture de chondrocytes. Enfin, nous rapportons le profil de microRNA des artères cultivées en conditions hyperphosphatémiques. Ces résultats pourraient être particulièrement importants dans le développement de nouvelles approches thérapeutiquesIn patients with chronic kidney disease (CKD), vascular calcification represents the main cause of mortality. Vascular calcification results from the trans-differentiation of vascular smooth muscle cells (VSMCs) into cells similar to osteoblasts and/or chondrocytes, in response to inflammatory cytokines or hyperphosphatemia. Calcifying VSMCs form calcium phosphate crystals through the activity of tissue nonspecific alkaline phosphatase (TNAP). In light of recent findings, we hypothesized that TNAP also modulates VSMC trans-differentiation. Our objectives were therefore to determine the effect of TNAP activity on VSMC trans-differentiation, and secondly to investigate the molecular mechanisms involved in TNAP expression in aortas, with a particular interest in microRNAs. We first observed that addition of purified alkaline phosphatase or TNAP over-expression stimulates the expression of chondrocyte markers in culture of the mouse and rat VSMC lines, and of mesenchymal stem cells. Moreover, TNAP inhibition blocks the maturation of mouse primary chondrocytes and reduces mineralization. We exclude a role for crystals in TNAP effects, since addition of crystals alone or associated to a collagenous matrix fails to mimic TNAP effects. We rather suspect that TNAP acts through the hydrolysis of inorganic pyrophosphate (PPi). Indeed, PPi is hydrolyzed by TNAP in VSMCs and chondrocytes and addition of PPi mimics the effects of TNAP inhibition on chondrocyte maturation. Finally, we report microRNA signature of aortic explants treated under hyperphosphatemic conditions that induce vascular calcification. These results could be of particular importance in patients with CKD
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Lin, Cho-Hao. "Endothelial cell-dependent Notch Signaling Regulates Vascular Smooth Muscle Cell Phenotypes." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429269211.
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Thatcher, Sean Eric. "MLCK/actin interaction in the contracting A7r5 cell and vascular smooth muscle." Huntington, WV : [Marshall University Libraries], 2007. http://www.marshall.edu/etd/descript.asp?ref=736.
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Theses (Ph. D.)--Marshall University, 2007.Title from document title page. Includes abstract. Document formatted into pages: contains x, 102 pages including illustrations. Bibliographical references at the end of each chapter.
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Peden, Ryan Stephen Medical Sciences Faculty of Medicine UNSW. "Activation of vascular smooth muscle cells." Awarded by:University of New South Wales. School of Medical Sciences, 2006. http://handle.unsw.edu.au/1959.4/24925.
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Vascular smooth muscle cells (VSMC) in the healthy adult arterial wall are a highlydifferentiated cell type with low levels of proliferation. However, when activated these cells can undergo a phenotypic change to become proliferative, migratory and excrete higher levels of extra-cellular matrix. While this cellular change is an essential element of the adaptable vasculature, excessive proliferation of VSMC underpins the development of a number of disease states, including atherosclerosis and restenosis after balloon angioplasty. The activation of VSMC is dependent on intracellular signalling pathways broadly altering gene expression. A key feature of this process is the initial potent regulation of transcription factors such as Egr-1, c-Jun and Ets-1, which then drive further transcriptional changes resulting in phenotypic change. The aim of this thesis was to discover novel genes, particularly transcription factors, regulated early upon stimulation and to characterise their contribution to the activation of VSMC. A key stimulus for activation of VSMC is the release of fibroblast growth factor 2 (FGF-2). A microarray used to explore the effects of FGF-2 exposure demonstrated the extensive nature of transcriptional modulation. In addition, it highlighted a number of transcription factors that were not previously described in VSMC: p8, ATF-4 and SHARP-2. In particular, SHARP-2 was potently upregulated and was reconfirmed in animal models of vascular injury. The subsequent contribution these factors make to VSMC activation was also demonstrated. p8 strongly induced VSMC proliferation, while ATF-4 contributed to cytokine production and SHARP-2 potently downregulated VSMC differentiation markers. A second area that was explored related to a gene known as YRDC, which was found to be upregulated upon stimulation of VSMC. YRDC is highly conserved across almost all cellular life, however its function remains unknown. A number of novel splice variants of YRDC were discovered and demonstrated to be differentially regulated in VSMC upon stimulation. Further work to commence characterising its function showed that it interacts with key ribosomal proteins and most likely plays a role in regulating translation. The discovery of the relevance of these genes to vascular biology in addition to their transcriptional regulation makes an important contribution to increasing our understanding of the molecular mechanisms behind vascular remodelling.
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Harman, Jennifer. "Investigating the role of histone H3 lysine 9 dimethylation in regulating disease-associated vascular smooth muscle cell gene expression." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289975.
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Widespread changes in gene expression accompany vascular smooth muscle cell (VSMC) phenotypic switching, a hallmark of vascular disease. Upon insult, VSMCs downregulate contractile proteins and upregulate genes linked to vascular remodelling, such as matrix metalloproteinases (MMPs) and pro-inflammatory cytokines. However, the epigenetic mechanisms which regulate VSMC phenotypic switching remain unclear. This thesis explores the role of histone 3 lysine 9 dimethylation (H3K9me2), a repressive epigenetic mark, in regulating the expression of disease-associated VSMC genes. Intriguingly, murine models of VSMC phenotypic switching revealed reduced levels of H3K9me2 upon loss of the contractile state while chromatin immunoprecipitation (ChIP) identified a subset of IL-1α/injury-responsive VSMC gene promoters enriched for H3K9me2. To test the functional importance of H3K9me2 for VSMC gene regulation the methyltransferase G9A/GLP was pharmacologically inhibited in vitro and in vivo. The resulting loss of H3K9me2 attenuated the expression of contractile VSMC markers and significantly potentiated IL-1α/injury-induced expression of MMP and pro-inflammatory genes. H3K9me2-mediated regulation of contractile and IL-1α-responsive VSMC gene expression was confirmed in cultured human VSMCs (hVSMCs). This prompted the use of hVSMCs to investigate the mechanism underlying H3K9me2-dependent regulation of IL-1α-mediated VSMC genes. Interestingly, G9A/GLP inhibition did not influence the level of IL-1α-induced nuclear localisation of the NFkB transcription factor p65 but significantly increased IL-1α-induced p65 binding to the IL6 promoter, correlating with reduced H3K9me2 levels. In contrast, enrichment of p65 was not observed at reported NFkB sites within the MMP3 promoter after IL-1α stimulation. Rather, IL-1α-induced MMP3 expression was dependent on JNK activity and G9A/GLP inhibition potentiated IL-1α-induced binding of the AP-1 transcription factor cJUN to the MMP3 promoter. Collectively, these findings suggest that H3K9me2 plays a role in maintaining the contractile VSMC state and prevents binding of both NFkB and AP-1 transcription factors at specific IL-1α-regulated genes to possibly block spurious induction of a pro-inflammatory state.
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Alexander, Peter. "The caffeine-sensitive calcium(2+) store in vascular smooth muscle." Thesis, University of Ottawa (Canada), 1994. http://hdl.handle.net/10393/6530.
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The objectives of this study were as follows: (1) to establish a technique to determine (Ca$\sp{2+}\rbrack\sb i$ in single enzymatically isolated vascular smooth muscle cells (VSMCs) from the rat tail artery by means of the fura-2 fluorescent dye, (2) to study the relationship between VSMC shortening and Ca$\sp{2+}$ mobilization by caffeine, (3) to determine the mechanism of caffeine-induced Ca$\sp{2+}$ mobilization by studying the effects of removal of extracellular Ca$\sp{2+}$ and agents that modulate Ca$\sp{2+}$ mobilization (ryanodine, TMB-8, nifedipine, thapsigargin), (4) to determine the possible physiological role of the caffeine-sensitive Ca$\sp{2+}$ store in VSMCs by its interaction with noradrenaline. We conclude that, the fura-2 technique may be successfully employed to measure (Ca$\sp{2+}\rbrack\sb i$ in single vascular smooth muscle cells from the rat tail artery. The (Ca$\sp{2+}\rbrack\sb i$ response was found to be reproducible irrespective of cell length. This is the first study to show this, although others have used single cells to study (Ca$\sp{2+}\rbrack\sb i$ changes, the question of whether cell morphology affects (Ca$\sp{2+}\rbrack\sb i$ has never been addressed. This allows comparative (Ca$\sp{2+}\rbrack\sb i$ studies to be performed on the same single vascular smooth muscle cell regardless of its contractile state. This is important as there can be great heterogeneity in the Ca$\sp{2+}$ signal response between different cells in the same population. On this basis, we have shown that ryanodine reduces the caffeine-induced Ca$\sp{2+}$ response; whereas other agents known to affect Ca$\sp{2+}$ regulation such as thapsigargin, TMB-8, and nifedipine had no effect on the caffeine-induced Ca$\sp{2+}$ response. Extracellular Ca$\sp{2+}$ was found to play an important role in the maintenance of resting and tonic (Ca$\sp{2+}\rbrack\sb i$ levels, as well as being essential to replenishment of the caffeine-sensitive Ca$\sp{2+}$ store. We have also shown that caffeine and noradrenaline are equally effective in releasing intracellular Ca$\sp{2+}$ and inducing a tonic increase in (Ca$\sp{2+}\rbrack\sb i.$ (Abstract shortened by UMI.)
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Whyte, Claire Susan. "The effect of DHA and EPA on fibrosis-related factors in vascular cells." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources. Restricted access until May 19, 2010, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25877.
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Eid, Ali Hussein. "Molecular regulation of vascular alpha 2C adrenoceptors." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu100875938.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xxii, 260 p.; also includes graphics (some col.). Includes bibliographical references (p. 232-260). Available online via OhioLINK's ETD Center
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Refson, Jonathan Simon. "Vein graft stenosis and the human vascular smooth muscle cell." Thesis, Imperial College London, 2000. http://hdl.handle.net/10044/1/7763.
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Koutsouki, Evgenia. "The role of cadherins in vascular smooth muscle cell apoptosis." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420910.
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Assender, Jean W. "Control of vascular smooth muscle cell proliferation by cyclic nucleotides." Thesis, Cardiff University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389966.
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Cheng, George Chen-hsi. "Regulation of vascular smooth muscle cell function by mechanical strain." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/39992.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Whitaker College of Health Sciences and Technology, 1996.Includes bibliographical references (p. 173-192).
by George Chen-hsi Cheng.
Ph.D.
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Torrance, Emma. "MAP kinase phosphatase-2 in vascular smooth cell muscle function." Thesis, University of Strathclyde, 2013. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=23297.
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The progression of major cardiovascular disorders are a consequence of a pathophysiological modification within the blood vessel; a process often driven by vascular smooth muscle cell hyperproliferation. A major mechanism by which smooth muscle cell proliferation occurs involves ligand-induced activation of MAP kinase signalling (Schad et al., 2011). MAP kinases have been noteworthy but troublesome targets in cardiovascular therapeutics; thus exploration of targeting endogenous regulatory dual specificity proteins namely MAP kinase phosphatases has been advancing in recent years. Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear phosphatase with the ability to dephosphorylate and ultimately inactivate MAP kinases ERK and JNK in vitro (Lawan et al., 2012). Therefore, by the use of a novel MKP-2-/- mouse, we assess a role for MKP-2 in smooth muscle proliferation as a potential future therapeutic target in cardiovascular disease. Contrary to current literature, mouse aortic smooth muscle cells cultured from a novel Dusp4 knockout mouse exhibit no significant difference in MAP kinase signalling profiles when compared with wild-type. Interestingly however, a significant reduction in proliferation rate corresponded with MKP-2 knockout cells and further cell cycle investigation elucidated a significant accumulation of MKP-2-/- cells in G2/M phase of the cell cycle. With levels of p-cdc-2 comparable between MKP-2 wild-type and knockout cells, mitotic entry was unaffected by MKP-2 deficiency which therefore diverted our study downstream to cytokinesis. Utilising time-lapse microscopy, smooth muscle cells lacking in MKP-2 exhibited a delay in cytokinesis and failure in abscission, resulting in the dividing cells connected by an intercellular bridge. The molecular mechanism of cytokinesis requires phosphorylation of the mitotic kinase aurora B for successful division of two daughter cells. However nocodazole-arrest studies reveal MKP-2 is required for aurora B phosphorylation and its downstream target histone H3, thus identifying MKP-2 as essential in the effective completion of cytokinesis. Within this thesis, an early investigation into the possible use of Adv.WT-MKP-2 as a vascular therapeutic in human aortic smooth muscle cells (HASMCs) was conducted. The over-expression of MKP-2 negated ERK signalling and consequently resulted in a reduction in cellular proliferation. Furthermore, the reduction in cellular proliferation was shown to be caused by a G1/S accumulation in the cell cycle. Collectively, these data suggest a novel role for MKP-2 in mouse aortic smooth muscle cell proliferation, providing new insights into the understanding of MKP-2 in the completion of cytokinesis. Furthermore, MKP-2 kinase binding domain is required for successful completion of cytokinesis but may not involve the inactivation of ERK or JNK. Therefore, modification of MKP-2 expression or function may represent a new approach in reducing SMC hyperproliferation in vascular disease states.
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Ho, Liza Kwok-Fung. "Proliferation and gene expression of vascular smooth muscle cells." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319970.
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Streeter, Jennifer Lee. "Molecular regulation of Nox1 NADPH oxidase in vascular smooth muscle cell activation." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1767.
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Nox1 is of considerable importance because of its involvement in a wide variety of pathologies. Activation of Nox1 induces generation of reactive oxygen species (ROS) and cell migration, events critical for the pathogenesis of cardiovascular disease, amyotropic lateral sclerosis, gastrointestinal disease, immunological disorders, and multiple forms of cancer [1-8]. In order to best determine how to treat Nox1-mediated disease, we must gain a better understanding of the mechanisms that control Nox1 activation. Within the last decade, many studies have found that protein phosphorylation and protein trafficking are critical regulatory mechanisms that control the activation of multiple Nox proteins. Yet, to date, no studies have characterized Nox1 phosphorylation or trafficking. We hypothesized that the activity of Nox1 is controlled by its phosphorylation at specific residues and by its sub-cellular localization; and that modifying Nox1 phosphorylation or localization will alter Nox1-dependent signaling. To test this hypothesis, we utilized both in vivo and in vitro approaches. We found that phosphorylation of Nox1 is significantly increased under pathological conditions in three in vivo models: (1) in atherosclerotic vs. normal aorta from monkey, (2) in neointimal vascular smooth muscle cells (VSMCs) vs. medial VSMCs from rat following aortic balloon injury, and (3) in ligated vs. normal carotid from mouse. Studies using mass spectroscopy, pharmacological inhibition, siRNA, and in vitro phosphorylation identify PKC-βI as a kinase that mediates Nox1 phosphorylation and subsequent ROS production and VSMC migration. Site-directed mutagenesis of predicted Nox1 phospho-residues revealed that cells expressing mutant Nox1 T429A have a significant decrease in TNF-α-stimulated ROS production, VSMC migration and Nox1 NADPH oxidase complex assembly compared to cells expressing wild-type Nox1. Isothermal calorimetry (ITC) revealed that a peptide containing the Activation Domain of NoxA1 (LEPMDFLGKAKVV) binds to phosphorylated Nox1 peptide (KLK-phos-T(429)- QKIYF) but not non-phosphorylated Nox1 peptide. These findings indicate that phosphorylation of Nox1 residue T429 by PKC-βI promotes TNF-α-induced Nox1 NADPH oxidase complex assembly, ROS production, and VSMC migration. Nox1 localization and trafficking studies reveal that Nox1 endocytosis is necessary for TNF-α-induced Nox1 ROS production; and that mutation of a Nox1 VLV motif inhibits Nox1 endocytosis and ROS production. These studies have provided new evidence that phosphorylation and sub-cellular localization are involved in the regulation of Nox1 ROS production and cell migration and offer new insights as to how Nox1 activity can be targeted for the purpose of treating Nox1-mediated diseases.
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Jagadesham, Vamshi Pulloori. "NK cell mediated lysis of vascular smooth muscle cells in abdominal aortic aneurysms." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578645.
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Abdominal aortic aneurysms (AAA) are characterised by a chronic inflammatory infiltrate within the abdominal aortic wall and aortic smooth muscle cell (AoSMC) apoptosis. It is postulated that the inflammatory infiltrate causes AoSMC apoptosis, with resultant aortic wall weakening and aneurysmal degeneration. This putative immune-mediated reaction against aortic wall component suggests that AAA may have features of an auto immune disease. It has been previously demonstrated that natural killer (NK) cells are elevated in the peripheral blood (PB) of AAA patients and display increased cytotoxicity against AoSMC. This study aimed to identify the molecular basis of the increased NK cell cytotoxicity and why an immune-mediated reaction occurs against AoSMC. Using multi-parametric flow cytometry (FC), expression of the activatory receptors NKp30, NKp44, NKp46 and NKG2D were analysed on PB NK cells from AAA patients and age-sex-matched healthy controls. No difference in activatory receptor expression or cell surface density (ΔMFI) existed between the two groups. Region specific (intra-luminal blood and AAA tissue) activatory receptor phenotypes were also investigated in AAA patients. The significant finding was a reduction in the ΔMFI of NKG2D on tissue NK cells, suggesting an interaction between this receptor and potential cognate ligands within the aortic wall. Characterised AoSMC explanted from AAA tissue were subjected to analysis using qRT-PCR and FC to identify the expression of death receptors (Fas, TRAIL-RI and TRAIL R2) and NKG2D ligands (MICA, MICB, ULBPI-3). AoSMC expressed mRNA for all NKG2D ligands. FC confirmed the cell-surface expression of NKG2D ligands and the death receptors. A significantly greater percentage of NK cells from AAA patients were CD107a+ when co-cultured with AAA AoSMC, thus accounting for the increased cytotoxicity in this group. Despite using anti-NKG2D it was not possible to inhibit NK cell degranulation in response to the NKG2D ligands on AoSMC. This work has demonstrated that AoSMC from AAA express death receptors and NKG2D ligands, potentially accounting for the NK cell molecular mechanism that leads to AoSMC apoptosis. The expression of NKG2D ligands, which have been demonstrated in other auto immune diseases, favours the hypothesis that AAA are an immune-mediated process directed against the abdominal aortic wall.
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Yin, Xiaoke. "Protein changes associated with embryonic stem cell differentiation to vascular smooth muscle cells." Thesis, Queen Mary, University of London, 2006. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1764.
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Embryonic stem (ES) cells can differentiate into many different cell lines, including vascular smooth muscle cells (SMCs). The aim of this project is to characterize protein changes during this differentiation process. Mouse ES cells are pre-differentiated by withdrawal of the leukemia inhibitory factor-1 from the culture medium. Subsequently, stem cell antigen-1 positive (Sca-1) cells are sorted by magnetic labelling cell sorting with anti-Sca-1 microbeads and cultured in differentiation medium with or without platelet-derived growth factor (PDGF). Protein extracts of ES cells and Sca-1+ cells are separated by two-dimensional electrophoresis. About 300 protein species of each cell lines are analyzed by mass spectrometry. Proteome maps are available online (http:/ /vwvw.v ascular-proteomicsc. om). After stimulation with PDGF for 5 passages, Sca-1+ cells differentiate into SMCs (esSMCs) with 95% staining positive for SMC markers such as smooth muscle a-actin, calponin, and smooth muscle myosin heavy chain. Protein profiles of esSMCs and mouse aortic SMCs are compared using the difference gel electrophoresis approach. esSMCs display decreased expression of myofilaments but increased oxidation of redox-sensitive proteins due to higher levels of reactive oxgen species (ROS). While immunoblotting reveals an upregulation of numerous antioxidants in esSMCs, enzymatic assays demonstrate lower glutathione concentrations compared to aortic SMCs despite a 3-fold increase in glutathione reductase activity. Mitochondrial superoxide measurement revealed the mitochondria-derived superoxide is the main source of ROS in esSMCs and inhibition of electron transport chain complex III by antimycin A showed remarkable increase of ROS in esSMCs. Moreover, depletion of glutathione by diethyl maleate or inhibition of glutathione reductase by carmustine (BCNU) results in a remarkable loss of cell viability in esSMCs compared to aortic SMCs while adding 2-mercaptoethanol increased esSMCs survival. These results indicate that esSMCs require additional antioxidant protection for survival and consequently, treatment with anti-oxidants could be beneficial for tissue repair from ES cells.
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Tucka, Joanna Barbara. "Regulation of vascular smooth muscle cell survival by the Akt pathway." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610282.
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Boyle, J. J. "Effects of macrophages on vascular smooth muscle cell survival in vitro." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596835.
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The synthesis of collagen by vascular smooth muscle cells (VSMCs) is a major determinant of structural stability of human atherosclerotic plaques. Ruptured human atherosclerotic plaques are characterised by a relatively low content of VSMCs, but a high inflammatory cell (macrophage and T lymphocyte) content. Plaques show high levels of VSMC apoptosis. VSMC apoptosis is further increased in ruptured plaques. We hypothesised that inflammatory cells may directly induce VSMC apoptosis. Human peripheral blood mononuclear cells were isolated, monocyte and lymphocyte fractions were prepared, and the ability of inflammatory cells to induce human VSMC apoptosis was examined. Macrophages, but not freshly isolated monocytes or lymphocytes, induced dose-dependent VSMC apoptosis. Macrophages induced apoptosis in human VSMCs from 3 sources coronary media, aortic media and carotid plaque. Apoptosis required direct cell-cell contact or proximity, NO, Fas-L, TNF-R1 and Caspases. NO-donors upregulated VSMC surface Fas and TNF-R1, and enhanced apoptosis induced by Fas-L and TNF-α. Macrophage activation to express surface Fas-L required 5 days maturation in culture, autocrine NO, TNF-R1 and TNF-R2. Immunostaining of ruptured plaques showed that plaque macrophages expressed iNOS, Fas-L and TNF-α and that plaque VSMCs expressed Fas and TNF-R1. In conclusion, macrophages induce VSMC apoptosis in vitro. If this phenomenon truly occurs in vivo, it may promote atherosclerotic plaque rupture.
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Allen-Redpath, Keith. "The effects of zinc deficiency on vascular smooth muscle cell function." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=202009.
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Dietary zinc deficiency affects one third of the world’s population and has more recently been associated with the development of atherosclerosis, however, its role in vascular smooth muscle cell (VSMC) function remains uncharacterised. VSMC’s are necessary for maintaining atherosclerotic plaque stability and any complications in VSMC function could have serious implications in vascular disease. The main aim of this study was to utilise in vivo and in vitro models of zinc deficiency to ascertain the effects this has on VSMC signalling processes. Rats were maintained on 2 and 6 weeks marginally zinc deficient diets which induced lower serum zinc concentrations. Carotid and aortic arterial tissue samples dissected from zinc deficient rats had significantly higher levels of VSMC apoptosis compared to those maintained on a zinc adequate diet. This occurred in parallel with increased dephosphorylation of the Bcl-2 associated death promoter (BAD) and attenuation of the pro-survival ERK1/2 pathway which maintains BAD in an inactive phosphorylated state. Two further mechanisms were further elucidated in vitro. Primary rat aortic smooth muscle cells (PRASMC) were incubated with plasma from zinc deficient rats and resulted in increased apoptosis and an overexpression of BAD similar to in vivo observations. However, this also occurred via sustained increases in [Ca2+]i leading to the activation of the BAD phosphatase calcineurin (which promotes activation of BAD via dephosphorylation) and increased oxidative stress. Further results have demonstrated that plasma from zinc deficient rats inhibits VSMC migration via decreased activity of osteopontin (OPN) an integrin receptor ligand and reduced activation of CREB. In addition, VSMC proliferation and differentiation in zinc deficiency was also assessed but no significant change was detected. Furthermore, these results were not due to a direct effect of zinc deficient environment rather secondary mechanisms in vivo via mediators released into the plasma. Taken together these findings demonstrate that marginally zinc deficient diets can induce VSMC apoptosis and decreased migration which may influence cardiovascular diseases such as atherosclerosis by inducing plaque vulnerability and further vascular complications.
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MOORE, ZACHARY W. Q. "APOLIPOPROTEIN E MODULATION OF VASCULAR SMOOTH MUSCLE CELL RESPONSE TO INJURY." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1127219075.
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Sadli, Adem. "Notch3 signalling pathway in vascular smooth muscle cell growth and survival." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/notch3-signalling-pathway-in-vascular-smooth-muscle-cell-growth-and-survival(ee3b0663-5fa9-43bb-a7d3-f9c52fb8ade1).html.
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Notch3 signalling in vascular smooth muscle cell growth and survival VSMCs are the major components of the arterial wall. Under physiological conditions VSMCs exhibit a contractile phenotype, although possessing the capacity of phenotypic transition. The plasticity of VSMCs enables them to gain proliferative features which contribute to the pathologies of common vascular diseases in response to diverse stimuli. Hence, the stability of VSMCs in cell growth and survival is essential for maintaining proper arterial function. Diverse signalling pathways and growth factors have been identified as being important in the regulation of VSMC behaviour, and the Notch signalling is a relatively new participant. Proteins of Notch family are transmembrane receptors that transduce signals from neighbouring cells. Among the four Notch receptor subtypes, Notch3 is mainly expressed in VSMCs in small arteries. NOTCH3 gene mutation causes a human genetic stroke syndrome, CADASIL which is featured by systemic VSMC degeneration, suggesting the importance of Notch3 signalling in VSMC growth and survival. Although there is some knowledge for the Notch3 signalling in the regulation of VSMC proliferation and apoptosis, the molecular mechanisms underlying such regulation are largely unknown. By overexpressing the constitutive active form of human Notch3 (N3IC), it was confirmed that Notch3 promotes VSMC proliferation and protects VSMCs against apoptosis in primary rat aortic SMCs. It was also shown that Akt mediated both Notch3-induced VSMC proliferation and protection of serum-deprivation-induced apoptosis; while Erk 1/2 only contributed to Notch3-induced VSMC proliferation. In addition, the activation of PI3K/Akt was significantly blocked by PDGFR inhibitor, even in serum-free conditions, suggesting an intrinsic effect of Notch3 on PDGFR function without the requirement of the exogenous ligand, PDGF. It was also shown that Notch3 inhibits GSK-3α/ by phosphorylation and this effect was not blocked by the PI3K/Akt inhibitor, suggesting an alternative Akt-independent mechanism exists by which Notch3 regulates GSK-3 activity. Furthermore, using apoptosis pathway PCR arrays a number of apoptotic genes including BCL2 that were regulated by Notch3 activation in human VSMCs were identified. Notch3 also up-regulates the expression of its ligand Jagged1 in a PI3K/Akt dependent manner. Interestingly, Notch2 was significantly down-regulated and Notch1 was mildly upregulated by Notch3. In addition, an age-dependent increase in the expression of Notch3 in SMCs of the aortic root from 8 to 16 weeks old mice was identified, however, this declined in aged mice (24 weeks). These findings suggest a model for Notch3 function which is integrally involved in multiple signalling pathways in the regulation of VSMC growth and survival. It is hoped that these findings will contribute to the current knowledge of vascular biology and provide the basis for future studies on the development of potential therapeutic targets for cardiovascular diseases.
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Sanusi, Morufat Olayide Abisola. "Mitochondrial reactive oxygen species signalling and vascular smooth muscle cell senescence." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37968.
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Ageing is a risk factor for the development of cardiovascular disease. In particular, senescent vascular smooth muscle cells (VSMCs) have been observed within atherosclerotic plaques. Oxidants are widely implicated in vascular ageing and cardiovascular disease with evidence of oxidative stress in cells undergoing senescence. Our previous data showed that Angiotensin II caused stress induced premature senescence (SIPS) in primary human VSMC via oxidant generation. Prevention of senescence with a mitochondria targeted antioxidant, Mito-TEMPO, suggested the mechanism was dependent on mitochondrial superoxide. The current study aimed to investigate if modulation of mitochondrial reactive oxygen species signalling is a general mechanism for senescence induction in human VSMC. The electron transport chain inhibitors Antimycin A and rotenone and the mitochondrial redox cycler, MitoParaquat all stimulated SIPS in VSMC. Interestingly, Antimycin A and rotenone also lead to a reduction in overall H₂O₂ levels suggesting a possible protective mechanism and highlighting the complexity of the signalling mechanism involving mitochondrial oxidants. qPCR Analysis suggested that changes in antioxidant gene expression do not account for the reduction in peroxide levels. Although there was no evidence that Angiotensin II induced senescence in human coronary artery SMC, there was evidence for enhanced mitochondrial hydrogen peroxide production. Senescent cells acquire a senescence associated secretory phenotype (SASP). To determine the composition of VSMC SASP, the tryptically digested secretome of conditioned media was analysed by LC-MS/MS. Bioinformatic analysis identified the NRF2-mediated oxidative stress response pathway and several endogenous antioxidants as amongst the affected responses in the aged VSMC secretome. These new data suggest that senescent VSMC produce a SASP that has multiple effects on neighbouring cell types including the induction of cell senescence and death; but also elements that might serve to preserve cell integrity and function and may limit the expression of a pro-inflammatory phenotype.
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Chen, Pei-Yu. "Fibroblast Growth Factor Receptor-1 (FGFR1) in Vascular Smooth Muscle Cell Phenotypic Switch." Fogler Library, University of Maine, 2009. http://www.library.umaine.edu/theses/pdf/ChenPY2009.pdf.
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Green, Immanuel David. "The role of m6A RNA Modifications in Vascular Smooth Muscle Cell Plasticity." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/26154.
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Vascular smooth muscle cells (VSMCs) display extraordinary phenotypic plasticity. This allows them to differentiate or dedifferentiate, depending on environmental cues. The ability to ‘switch’ between a quiescent contractile phenotype to a highly proliferative synthetic state renders VSMCs as primary mediators of vascular repair and remodelling. When their plasticity is pathological, it can lead to cardiovascular diseases such as atherosclerosis and restenosis. The role of the N6-methyladenosine (m6A) RNA modification in VSMC plasticity is as yet unknown. m6A is the most prevalent chemical modification on messenger RNA and is a highly conserved phenomenon which facilitates altered gene expression control. The aim of this research was to determine how m6A and its regulatory factors are altered in VSMC plasticity, and how these changes impact VSMC gene expression. Using robust primary murine VSMC models in vitro, and arterial injury models in vivo, this study indicated that Mettl14, an essential component of the m6A-depositing machinery, may be an important promoter of VSMC dedifferentiation. Profiling of m6A in Mettl14-deficient VSMCs revealed that essential VSMC gene networks and functional pathways are subject to altered m6A regulation. Furthermore, in-depth study of key m6A-affected VSMC transcripts, including Serpine1, Lpar2 and Klf4 showed that Mettl14 enhances their expression via increased m6A deposition. For Serpine1, this was also found to be strongly reflected at the protein level. The stability of these transcripts was not greatly altered in Mettl14-deficient cells, indicating that their differential expression may be due to co-transcriptional regulation instead. These findings contribute to the growing evidence that m6A is an essential phenomenon in a range of cellular processes, and provides novel insight into the molecular underpinnings of VSMC plasticity.
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Saavedra, García Paula. "FABP4: interactions with endothelial cell plasma membrane and effects on vascular smooth muscle cells." Doctoral thesis, Universitat Rovira i Virgili, 2016. http://hdl.handle.net/10803/348560.
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Fatty acid-binding protein 4 (FABP4) és una adipoquina secretada pel teixit adipós implicada en la regulació del metabolisme energètic i la inflamació. S'han detectat nivells elevats de FABP4 circulant en persones amb factors de risc cardiovascular i aterosclerosi, encara que no hi ha moltes dades sobre FABP4 i l'aterosclerosi en humans. Alguns estudis han demostrat que FABP4 té un efecte directe sobre els teixits perifèrics, concretament promovent la disfunció endotelial. La disfunció endotelial juga un paper clau en el desenvolupament de lesions ateroscleròtiques, així com la migració i proliferació de cèl·lules de múscul llis vascular. No obstant això, el mecanisme d'acció i funcions de FABP4 circulant són poc conegudes. La hipòtesi d'aquest treball és que FABP4 interacciona amb teixits perifèrics contribuint a la disfunció endotelial i remodelació vascular a partir de la interacció amb proteïnes de membrana plasmàtica, que actuarien com a elements d'ancoratge i/o receptors mitjançant rutes de senyalització intracel·lular, i/o internalització.
Els nostres resultats indiquen que FABP4 exògena interactua específicament amb citoqueratina 1 (CK1) en les membranes cel·lulars endotelials i la seva inhibició farmacològica per BMS309403 disminueix lleugerament la formació d'aquests complexos. A més, FABP4 exògena travessa la membrana plasmàtica per entrar al citoplasma i nucli de cèl·lules endotelials (HUVECs). També hem demostrat que FABP4 exògena forma un complex amb CK1 en les cèl·lules del múscul llis vascular (HCASMCs) i que té un efecte directe induint la migració i proliferació de les HCASMCs a través de l'activació de la via de senyalització MAPK per la fosforilació de ERK1/2 i activació dels factors de transcripció nuclears c-myc i c-jun. Aquests resultats suggereixen que FABP4 circulant podria tenir un paper en el remodelat vascular i progressió de l'aterosclerosi. Aquestes dades contribueixen al nostre coneixement actual sobre el mecanisme d'acció de FABP4 circulant.Fatty acid-binding protein 4 (FABP4) es una adipoquina secretada por el tejido adiposo implicada en la regulación del metabolismo energético y la inflamación. Se han detectado niveles elevados de FABP4 circulante en personas con factores de riesgo cardiovascular y aterosclerosis, aunque no hay muchos datos sobre FABP4 y aterosclerosis en humanos. Algunos estudios han demostrado que FABP4 tiene un efecto directo sobre los tejidos periféricos, concretamente promoviendo la disfunción endotelial. La disfunción endotelial juega un papel crucial en el desarrollo de lesiones ateroscleróticas, así como la migración y proliferación de células de músculo liso vascular. Sin embargo, el mecanismo de acción y las funciones de FABP4 circulante son desconocidos. La hipótesis de este trabajo es que FABP4 interacciona con tejidos periféricos contribuyendo a la disfunción endotelial y remodelación vascular a partir de la interacción con proteínas de membrana plasmática, que actuarían como elementos de anclaje y/o receptores mediando rutas de señalización intracelular, y/o internalización. Nuestros resultados indican que FABP4 exógena interactúa específicamente con citoqueratina 1 (CK1) en las membranas celulares endoteliales y su inhibición farmacológica por BMS309403 disminuye ligeramente la formación de estos complejos. Además, FABP4 exógena atraviesa la membrana plasmática para entrar en el citoplasma y núcleo de células endoteliales (HUVECs). También hemos demostrado que FABP4 exógena también forma un complejo con CK1 en las células del músculo liso vascular (HCASMCs) y que tiene un efecto directo sobre la migración y proliferación de HCASMCs a través de la activación de la vía de señalización MAPK por la fosforilación de ERK1/2 y activación los factores de transcripción nucleares c-myc y c-jun. Estos resultados sugieren que FABP4 circulante podría tener un papel en el remodelado vascular y en la progresión de la aterosclerosis. Estos datos contribuyen a nuestro conocimiento actual sobre el mecanismo de acción de FABP4 circulante.
Fatty acid-binding protein 4 (FABP4) is an adipose tissue-secreted adipokine that is involved in the regulation of energetic metabolism and inflammation. Increased levels of circulating FABP4 have been detected in individuals with cardiovascular risk factors and atherosclerosis, although there is not much data on FABP4 in human atherosclerosis. Some studies have demonstrated that FABP4 has a direct effect on peripheral tissues, specifically promoting endothelial dysfunction. Endothelial dysfunction plays crucial roles in the development of atherosclerotic lesions as well as migration and proliferation of vascular smooth muscle cells. However, the mechanism of action and functions of circulating FABP4 are unknown. The hypothesis of this study is that circulating FABP4 has a direct effect on peripheral tissues. In particular at vessel wall level, FABP4 contributes to endothelial dysfunction and artery wall remodelling through interaction with endothelial plasma membrane proteins that act as anchoring elements and/or receptors mediating intracellular signalling, and/or FABP4 internalization. FABP4 acts on smooth muscle cells influencing cell migration and proliferation as well. Our results indicate that exogenous FABP4 interacts with specifically CK1 on endothelial cell membranes and the pharmacological FABP4 inhibition by BMS309403 decreases the formation of these complexes slightly. Furthermore, exogenous FABP4 crosses the plasma membrane to enter the cytoplasm and nucleus in HUVECs. In addition, we also demonstrated that exogenous FABP4 forms a complex with CK1 on vascular smooth muscle cells (HCASMCs) and has a direct effect of FABP4 on the migration and proliferation of HCASMCs through the activation of the ERK1/2 MAPK signalling pathway and activating the nuclear transcription factors c-myc and c-jun. Taking all these results together, it suggests that circulating FABP4 could have a role in vascular remodelling and atherosclerosis progression. These data contribute to our current knowledge regarding the mechanism of action of circulating FABP4.
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Risinger, George M. "Regulation of matrix metalloproteinase-2 in vascular smooth muscle cells." Oklahoma City : [s.n.], 2008.
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Chon, John H. "Mediation of vascular smooth muscle cell adhesion and migration by cell surface heparan sulfate glycosaminoglycans." Diss., Georgia Institute of Technology, 1999. http://hdl.handle.net/1853/11315.
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Chappell, Joel. "Vascular smooth muscle cell heterogeneity and plasticity in models of cardiovascular disease." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/274543.
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Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects of proliferation and the phenotypic changes within individual VSMCs, which underlie vascular disease remain unresolved. In particular, it is not known if all VSMCs proliferate and display plasticity, or whether individual cells can switch to multiple phenotypes. To assess whether proliferation and plasticity in disease is a general characteristic of VSMCs or a feature of a subset of cells, multi-colour lineage labelling is used to demonstrate that VSMCs in injury-induced neointimal lesions and in atherosclerotic plaques are oligo-clonal, derived from few expanding cells, within mice. Lineage tracing also revealed that the progeny of individual VSMCs contribute to both alpha Smooth muscle actin (aSma)-positive fibrous cap and Mac-3-expressing macrophage-like plaque core cells. Co-staining for phenotypic markers further identified a double-positive aSma+ Mac3+ cell population, which is specific to VSMC-derived plaque cells. In contrast, VSMC-derived cells generating the neointima after vascular injury generally retained expression of VSMC markers and upregulation of Mac3 was less pronounced. Monochromatic regions in atherosclerotic plaques and injury-induced neointima did not contain VSMC-derived cells expressing a different fluorescent reporter protein, suggesting that proliferation-independent VSMC migration does not make a major contribution to VSMC accumulation in vascular disease. Similarly, VSMC proliferation was examined in an Angiotensin II perfusion model of aortic aneurysm in mice, oligo-clonal proliferation was observed in remodelling regions of the vasculature, however phenotypic changes were observed in a large proportion of VSMCs, suggesting that the majority of VSMCs have some potential to modulate their phenotype. To understand the mechanisms behind the inherent VSMC heterogeneity and observed functionality, the single cell transcriptomic techniques Smart-seq2 and the Chromium 10X system were optimized for use on VSMCs. The work within this thesis suggests that extensive proliferation of a low proportion of highly plastic VSMCs results in the observed VSMC accumulation after injury, and the atherosclerotic and aortic aneurysm models of cardiovascular disease.
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Yiu, Wai-ki. "The effects of supercooling and re-warming on vascular cells survival and proliferation." Click to view the E-thesis via HKUTO, 2010. http://sunzi.lib.hku.hk/hkuto/record/B44236888.
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Yiu, Wai-ki, and 姚惠琪. "The effects of supercooling and re-warming on vascular cells survival and proliferation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44236888.
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Liu, Po-shiu Jackie. "Effects of flavonoids on proliferation of breast cancer cells and vascular smooth muscle cells /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38480189.
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Mitchell, Lylieth Paula-Ann. "Vascular endothelial and smooth muscle cell apoptosis in vivo and in vitro." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq28795.pdf.
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Stegemann, Jan Philip. "Characterization and control of smooth muscle cell phenotype in vascular tissue engineering." Diss., Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/20120.
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Cooper, W. N. "Control vascular smooth muscle cell phenotype by transcription factors and by cytokines." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597957.
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The phenotype of the vascular smooth muscle cells (VSMC) in atherosclerotic lesions differs from that of the VSMC in the normal arterial wall. The VSMC phenotype is controlled by factors which are only beginning to be defined and these factors will include both transcription factors and cytokines. I have identified a novel number of the POU domain family of transcription factors which have been shown to be important in cell lineage determination. However sequence analysis and RT-PCR suggest that the novel gene is a pseudogene. I have also examined the effect of basic helix-loop-helix (bHLH) transcription factors SRF on expression of smooth muscle expressed genes. VSMC express SRF and the bHLH genes dHAND, Twist and Dermo and I have shown that both dHAND and SRF can activate expression from the SM22α promoter, but that Twist and Dermo cannot. Furthermore dHAND and SRF co-operate to augment expression from the SM22α promoter. I have examined smooth muscle gene expression in mouse models with genetic modification of TGF1β cytokine levels, or signalling pathways. No difference was observed in aortic mRNA expression between wild-type mice and mice expressing a dominant negative TGF1β type II receptor, or mice with a single TGFβ1 allele. However female mice with a single TGFβ1 allele were shown to express lower levels of SM-MHC and SMα-actin proteins than their wild-type litter-mates. Interestingly the mRNA levels of all mice regardless of gender or genotype were similar suggesting that TGFβ1 plays a role in the post transcriptional regulation of a subset of SMC specific genes and this may be overridden by male hormones.
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Winn, Poh Lin. "In vitro studies on the inhibition of vascular smooth muscle cell proliferation." Thesis, University of Strathclyde, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426360.
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Mangiante, Lee Elena Taylor Joan M. "The role of focal adhesion kinase in vascular smooth muscle cell migration." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,2137.
Full textAbstract:
Thesis (M.S.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Pathology and Laboratory Medicine." Discipline: Pathology and Laboratory Medicine; Department/School: Medicine.