Dissertations / Theses on the topic 'Arterial Smooth Muscle Cell'
To see the other types of publications on this topic, follow the link: Arterial Smooth Muscle Cell.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Arterial Smooth Muscle Cell.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Arshad, Haroon. "Mathematical modelling of pulmonary arterial smooth muscle cell subtypes." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/mathematical-modelling-of-pulmonaryarterial-smooth-muscle-cell-subtypes(c1110807-d94d-487c-90b8-8714d5e42d16).html.
Full textAbstract:
Alteration in the tone of pulmonary arteries may lead to disease such as pulmonary hypertension often associated with major cardiac complications. This dysfunction is partly in the pulmonary arterial smooth muscle cells (PASMCs) where the excitation-contraction coupling is modified by ion channel behaviour to increase the contractile force. Mathematical models of systemic smooth muscle cells (SMCs) that incorporate electrophysiological and chemomechanical mechanisms to understand the underlying cellular physiology have been successfully employed. Models of pulmonary arterial smooth muscle cells (PASMCs) are only beginning to emerge. Mathematical model prototyping with available experimental data and model investigation from different parameter values is a time-consuming and complex process. This thesis is concerned with the development and validation of mathematical models of excitation-contraction coupling in three types of PASMCs of the rat species, one homogeneous type originating from the distal pulmonary arteries and two from proximal pulmonary arteries. Some key novel additions from previous vascular SMC models include the distinct modelling of Ca2+ in the subplasmalemmal cytosolic region, incorporation of subunit-specific currents from the K+ channel family and a generic G-protein receptor model able to reproduce complex Ca2+ profiles. The main pulmonary and systemic arteries statistically differ in its response to phenylephrine in a wire myograph. The ionic currents of the models were validated against experimental data largely from rat species. The models replicate the recordings of Ca2+ and the resting potential (Em) profiles arising from agonist-induced cytosolic Ca2+ ([Ca2+]i) stimulation (G-protein activation), nifedipine, ryanodine, caffeine and niflumic acid. The distal PASMC model was sensitive to an increase in [Ca2+]i from G-protein activation although were less likely to reproduce Ca2+ oscillations than proximal PASMCs. The proximal models determined the likely proximal PASMC type in literature experiments recording [Ca2+]i and Em. I have developed software that enables other users to simulate Ca2+ and Em changes in SMC studies and the ability to parse a master file describing the mathematical model into different language formats to increase productivity. These models provide a foundation for further studies to better understand PASMC function in the context of normal physiology as well as pathological conditions.
2
Beattie, David Keith. "The influence of altered haemodynamics on human smooth muscle cell behaviour." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369122.
Full text
3
Hartley, S. A. "ATP regulated ion channels in arterial smooth muscle cells." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298264.
Full text
4
Curinga, Gabrielle Mercedes. "The role of runt-related transcription factor 2 in arterial smooth muscle cell mineralization /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/6353.
Full text
5
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.
Full text
6
Suttie, Andrew William. "Allylamine toxicity and dedifferentiation of arterial smooth muscle cells in vitro." Thesis, Queen Mary, University of London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390596.
Full text
7
Proudfoot, Diane. "Effects of macrophage factors on the growth of arterial smooth muscle cells." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321094.
Full text
8
Wahl, Joel. "Development of Methods to Investigate Pulmonary Arterial Smooth Muscle Cells under Hypoxia." Licentiate thesis, Luleå tekniska universitet, Strömningslära och experimentell mekanik, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:ltu:diva-77140.
Full textAbstract:
Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to localized alveolarhypoxia that is intrinsic to the pulmonary circulation. By hypoxia-induced contractionof pulmonary arterial smooth muscle cells (PASMCs), the pulmonary capillary bloodflow is redirected to alveolar areas of high oxygen partial pressure, thus maintaining theventilation-perfusion ratio. Although the principle of HPV was recognized decades agothe underlying pathway remains elusive. The patch clamp technique, imaging and Ramanspectroscopy are methods that can be used to investigate parts of the mechanisms. Toenable measurements at controlled oxygen concentrations a gas-tight microfluidic systemwas developed. In this thesis preparatory experiments to couple the gas-tight systemto a microscope that enabled simultaneous measurements with patch clamp, imagingand Raman spectroscopy are discussed. The patch clamp technique is to be used formeasurements on the dynamics of the ion-channels in the cellular membrane as well aschanges in membrane potential as a response to hypoxia. Imaging of PASMCs is requiredto successfully apply the patch clamp technique. Further, imaging will also reveal whetherthe mechanical response of HPV has been triggered, for this purpose image analysis forestimation of optical flow can be used. Raman spectroscopy enables measurements ofbiochemical changes in redox biomarkers, cytochrome c and NADH, of the mitochondrialelectron transport chain. This thesis shows that the gas-tight microfluidic system providesoptimal control of the oxygen content, in an experimantal setting where the patch clamptechnique can be applied. Raman measurements showed significantly larger variationsin spectra compared to an open fluidic system, which is the conventional approach.However, the results showed a need for improved Raman preprocessing. For this purposea Convolutional Neural Network (CNN) was trained using synthetic spectra that providedoptimal reconstruction of the Raman signal. Finally, simultaneous imaging and Ramanspectroscopy of red blood cells were performed in a home built microscope. The resultspave the way for measurements on PASMCs.
9
Winter, Polly. "Endothelial and smooth muscle cell-to-cell communication within rat small mesenteric arteries." Thesis, University of Bath, 2007. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436804.
Full text
10
Myllärniemi, Marjukka. "Regulation of arterial smooth muscle cell proliferation after endothelial injury : an experimental approach to restenosis and transplant arteriosclerosis." Helsinki : University of Helsinki, 1999. http://ethesis.helsinki.fi/julkaisut/laa/trans/vk/myllarniemi/.
Full text
11
Pannu, Parveer Singh. "Regulation of ATP-binding cassette transporter A1 In intimal-type arterial smooth muscle cells." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44171.
Full textAbstract:
The removal of cholesterol from cells and formation of high-density lipoprotein (HDL) particles is critically dependent on the membrane lipid transporter ATP-binding cassette transporter A1 (ABCA1). Previous studies from the Francis laboratory have determined that the regulation of ATP-binding cassette transporter A1 (ABCA1) expression is impaired in model intimal-type arterial smooth muscle cells (SMCs) and human intimal SMCs in atherosclerotic coronary arteries, providing a novel explanation for cholesterol accumulation and foam cell formation in human atheroma. Growing evidence appears to emphasize the importance of the lysosomal-mitochondrial oxysterol pathway in regulating ABCA1 expression. We hypothesized that the reduced expression of ABCA1 in model intimal-type arterial SMCs is due to impaired enzyme sterol 27-hydroxylase (CYP27A1) expression, resulting in impaired oxysterol production critical for the activation of ABCA1 gene expression via the Liver X receptor (LXR) pathway.
Our results show that intimal-type arterial SMCs exhibit a reduced expression of CYP27A1 mRNA and protein. Exogenous treatment of these cells with LXR agonists increases ABCA1 expression, indicating an intact LXR-mediated activation of ABCA1 gene expression. Despite successful transfection of CYP27A1 in these SMCs, intimal-type arterial SMCs do not increase their expression of ABCA1. The expression of steroidogenic acute regulatory protein D1 (StARD1), responsible for the delivery of cholesterol to CYP27A1, is also reduced in intima-type SMCs. We also show preliminary results of reduced human arterial intimal SMC-specific CYP27A1 expression in coronary arteries with native atherosclerosis. The findings of this thesis provide a narrative highlighting the importance of the intracellular transport of cholesterol via StaRD1 to CYP27A1 for the activation of LXR-dependent ABCA1 expression in arterial SMCs, and provide further insight into the dysregulation of ABCA1 expression in human atherosclerotic arterial SMCs that may contribute to the foam cell population and subsequent plaque formation in human atherogenesis.
12
Dawson, Sarah Helen. "Identification and characterisation of a putative osteoprotegerin receptor on pulmonary arterial smooth muscle cells." Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/9029/.
Full text
13
Patel, J. "Smooth muscle cell proliferation and endothelin pathway in pulmonary arterial hypertension : comparative effects of current and putative therapeutic agents." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1400121/.
Full textAbstract:
Pulmonary arterial hypertension (PAH) is characterised by a progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular failure or a premature death. Its prevalence varies from 15-50 patients per million populations with an average age of 45 years. Prostacyclin (PGI2) analogues are used to treat PAH, but do not cure the condition. PGI2 binds to prostacyclin receptors (IP) in the cell membrane stimulating adenylate cyclase to increase intracellular cyclic 3’5’-adenosine monophosphate (cAMP). Once elevated, cAMP is rapidly broken down by phosphodiesterases (PDEs), specifically 1, 3, 4 which appear responsible for regulating levels in the lungs. One of the reasons for the ineffectiveness of PGI2 in PAH could be high activity of these PDE isoforms that specifically break down cAMP. So in chapter 3, I sought to evaluate the effect of prostacyclin analogues (e.g. treprostinil) on cAMP and cell proliferation in PAH. I was also interested to check whether phosphodiesterase inhibitors could potentiate the effects of PGI2 analogues. Elevated levels of endothelial ET-1 in idiopathic PAH have been shown to be correlated with increased right atrial pressure, pulmonary artery oxygen saturation and pulmonary vascular resistance. This has led to the use of ET-1 antagonists to treat PAH alone or in combination with other classical drugs. In chapter 4, I investigated the interaction between treprostinil, and endothelin antagonists on the ET-1 levels and growth characteristics of pulmonary smooth muscle cell cells (PASMCs) derived from IPAH patients. Vascular remodelling has been considered a pseudo-malignant disorder and mediators from cancer research have been described as targets for therapeutic interventions for PAH (Paulin et al., 2011). In chapter 5 I evaluated the antiproliferative effects of an already established anti-cancer drug ispinesib (Purcell et al., 2010) and thus established a rationale for investigating this agent in PAH settings.
14
Charolidi, Nicoletta. "Gap junctions in arterial smooth muscle cells : relationship between Connexin43 expression, intercellular communication and phenotype." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501473.
Full text
15
Van, Den Diepstraten Caroline H. "Analysis of apolipoprotein(a) fragments on proliferation and migration of human arterial smooth muscle cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0017/MQ52958.pdf.
Full text
16
Shaikh, Mohsin Ahmed. "Models of coupled smooth muscleand endothelial cells." Thesis, University of Canterbury. Centre for Bioengineering, 2011. http://hdl.handle.net/10092/6190.
Full textAbstract:
Impaired mass transfer characteristics of blood borne vasoactive species such
as ATP in regions such as an arterial bifurcation have been hypothesized as a
prospective mechanism in the aetiology of atherosclerotic lesions. Arterial endothelial
(EC) and smooth muscle cells (SMC) respond differentially to altered
local hemodynamics and produce coordinated macro-scale responses via intercellular
communication. Using a computationally designed arterial segment comprising
large populations of mathematically modelled coupled ECs & SMCs, we
investigate their response to spatial gradients of blood borne agonist concentrations
and the effect of micro-scale driven perturbation on the macro-scale. Altering
homocellular (between same cell type) and heterocellular (between different
cell types) intercellular coupling we simulated four cases of normal and pathological
arterial segments experiencing an identical gradient in the concentration of
the agonist. Results show that the heterocellular calcium (Ca2+) coupling between
ECs and SMCs is important in eliciting a rapid response when the vessel segment
is stimulated by the agonist gradient. In the absence of heterocellular coupling,
homocellular Ca2+ coupling between smooth muscle cells is necessary for propagation
of Ca2+ waves from downstream to upstream cells axially. Desynchronized
intracellular Ca2+ oscillations in coupled smooth muscle cells are mandatory for
this propagation. Upon decoupling the heterocellular membrane potential, the
arterial segment looses the inhibitory effect of endothelial cells on the Ca2+ dynamics
of underlying smooth muscle cells. The full system comprising hundreds
of thousands of coupled nonlinear ordinary differential equations simulated on the
massively parallel Blue Gene architecture. The use of massively parallel computational
architectures shows the capability of this approach to address macro-scale
phenomena driven by elementary micro-scale components of the system.
17
McKean, Jenny Susan. "The role of the cAMP mediator Epac in vascular smooth muscle cell migration." Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=227109.
Full textAbstract:
Surgical intervention can result in endothelial denudation, driving growth factor-stimulated vascular smooth muscle cell (VSMC) migration towards the intima, leading to luminal narrowing and restenosis. Clinically approved PGI₂ analogues, including beraprost, activate the cyclic adenosine monophosphate (cAMP) signaling pathway to inhibit VSMC migration in vitro. This pathway is a potential therapeutic target, however the downstream proteins involved in the inhibitory effects of cAMP on migration remain unknown. The aims of this study were to determine the signalling pathways involved in inhibiting VSMC migration through cAMP downstream mediators, protein kinase A (PKA) and the more recently characterised exchange protein activated by cAMP (Epac), and delineate the mechanisms involved. In human saphenous vein VSMCs, Epac activation using an Epac analogue inhibited VSMC migration. Therapeutic concentrations of beraprost (1 nM) also resulted in an inhibition of VSMC migration. The use of fluorescence resonance energy transfer (FRET) confirmed 1 nM beraprost activated Epac, but not PKA. Epac is a guanine nucleotide exchange factor (GEF) for Rap1 thus Rap1 siRNA was used to inhibit the Epac pathway. This blocked the inhibitory effects of beraprost on VSMC migration. Epac1 was localised to the leading edge of migrating VSMCs. Another G-protein, RhoA, was investigated since it is essential for cell migration and is involved in several processes including actin regulation. Epac signaling inhibited PDGF-induced RhoA activation and disassembled F-actin at the leading edge, where Epac1 was previously located. This indicates that beraprost activated the Epac pathway, which inhibited RhoA to decrease VSMC migration. The clinical relevance of this study has discovered the mechanisms of Epac's inhibitory action on VSMC migration and this pathway could be targeted therapeutically to reduce restenosis. In the future the potential use of beraprost on a drug eluting stent might be beneficial to prevent restenosis formation following surgical intervention.
18
Su, Enming Joseph. "Role of angiotensin II in regulating smooth muscle cell replication in the vessel wall /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/6349.
Full text
19
Stickel, Diana [Verfasser], and Alexander [Akademischer Betreuer] Dietrich. "Cytosolic and mitochondrial Ca2+ handling in pulmonary arterial smooth muscle and endothelial cells / Diana Stickel ; Betreuer: Alexander Dietrich." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1127527908/34.
Full text
20
Kiskin, Fedir. "Developing an induced pluripotent stem cell model of pulmonary arterial hypertension to understand the contribution of BMPR2 mutations to disease-associated phenotypes in smooth muscle cells." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/285324.
Full textAbstract:
Mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) are the most common genetic cause of heritable pulmonary arterial hypertension (PAH). However, given the reduced penetrance of BMPR2 mutations in affected families, a major outstanding question is the identity of additional factors or pathways that are responsible for the manifestation of clinical disease. Furthermore, limited human tissue is available for study and usually only from patients with end-stage disease, making it difficult to understand how PAH is established and progresses. Alternative human models of PAH are therefore required. This thesis describes the characterisation of the first human iPSC-derived smooth muscle cell (iPSC-SMC) model of PAH and elucidates the role of BMPR2 deficiency in establishing PAH-associated phenotypes in iPSC-derived SMCs. To achieve this, I used CRISPR-Cas9 gene editing to generate wild-type and BMPR2+/- iPSC lines with isogenic backgrounds which were subsequently differentiated into lineage-specific iPSC-SMCs that displayed a gene expression profile and responses to BMP signalling akin to those present in distal pulmonary artery smooth muscle cells (PASMCs). Using these cells, I found that the introduction of a single BMPR2 mutation in iPSC-SMCs was sufficient to recapitulate the pro-proliferative and anti-apoptotic phenotype of patient-derived BMPR2+/- PASMCs. However, acquisition of the mitochondrial hyperpolarisation phenotype was enhanced by inflammatory signalling and required an interaction between BMPR2 mutations and environmental stimuli provided by exposure to serum over time. Furthermore, I showed that BMPR2+/- iPSC-SMCs had an altered differentiation state and were less contractile compared to wild-type iPSC-SMCs, phenotypes which have not been observed previously in PAH-derived PASMCs. Finally, RNA sequencing analysis identified genes that were differentially expressed between wild-type and BMPR2+/- iPSC-SMCs and may hence provide further insights into PAH pathobiology. The iPSC-SMC model described in this study will be useful for identifying additional factors involved in disease penetrance and for validating therapeutic approaches that target BMPR2.
21
Zhao, Jun, and e52677@ems rmit edu au. "The functional study of Na+/Ca2+ exchanger in vascular smooth muscle cells." RMIT University. Medical Sciences, 2007. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080617.163746.
Full textAbstract:
Na+/Ca2+ exchanger (NCX) is a membrane protein which can mediate either Ca2+ entry (reverse mode) or exit (forward mode) in cells. As one of the major Ca2+ transport systems, NCX is postulated to play a critical role in the vascular smooth muscle cell. The aims of the present study are to firstly demonstrate the functional existence of NCX in vascular smooth muscle (including aorta and arteriole); to clarify the modulation of NCX; to explore the selectivity of NCX inhibitor KB-R7943; and lastly to investigate the role of NCX in the myogenic response. KB-R7943 has been widely used as a NCX inhibitor. The study investigated its pharmacological actions in rat aorta on a variety of Ca2+ dependent systems. Rat aortic rings were used. The constriction to low extracellular [Na+] is a functional response mediated by NCX operating in reverse mode. The data demonstrate that 10 µM KB-R7943 inhibited L-type Ca2+ channel, the capacitative Ca2+ entry and adrenergic receptor pathway. Nevertheless, KB-R7943 can be used as a selective inhibitor of NCX at the lower concentration of 1 µM in rat aortic rings. The study investigated whether the endothelium could modulate NCX in rat aortic rings. Lowering extracellular [Na+] to 1.18 mM induced constriction in endothelium denuded rat aortic rings, but only a small constriction in endothelium intact rat aortic rings. In endothelium intact rat aortic rings, the guanylate cyclise inhibitor ODQ (1 µM) and the nitric oxide synthase inhibitor L-NAME (50 µM) greatly amplified the vasoconstriction to lowering extracellular [Na+], but had no effect when the endothelium was removed. The adenylate cyclise inhibitor SQ 22536 (100 µM) and the cyclooxygenase inhibitor indomethacin (10 M) showed no significant effect on the low-Na+ induced vasoconstriction in either endothelium denuded or intact aortic rings. The results suggest that endothelium modulated the NCX operation via the nitric oxide/guanylate cyclase, not the adenylate cyclase system; further prostanoids including prostacyclin was not involved. The interaction between nitric oxide and NCX was furt her explored using the nitric oxide donor sodium nitroprusside. Endothelium denuded rat aortic rings were preconstricted to the same extent with either low Na+ (1.18 mM), or the thromboxane A2 agonist U46619 (0.1 µM) or high K+ (80 mM). The vasorelaxation of SNP (30 nM) in low Na+ constriction was significantly larger compared to other agents. This indicates that NO has a special antagonism of low Na+ constriction and a hypothesis is proposed involving Na+/K+ ATPase. The investigation of NCX is mainly conducted in large vessels; much less evidence is available for small resistance vessels. The study investigated the role of NCX on myogenic response in pressurized cremaster muscle arterioles. Reducing extracellular [Na+] resulted in graded vasoconstriction which was inhibited by NCX inhibitor SEA0400 (1 µM). Myogenic vasoconstriction and the concomitant rise in internal [Ca2+] were induced by a transmural pressure increase from 70 to 120 mmHg which was prevented by NCX inhibitor: SEA0400 (1 µM). In conclusion, the present study suggests that NCX contributes to the myogenic response in cremaster arteriole.
22
Hassan, Dhiya. "Forced Overexpression of Translationally Controlled Tumor Protein (TCTP/TPT1) Induces a Growth-Dysregulated Phenotype in Endothelial and Smooth Muscle Cells: Role of TCTP Exosomal Export in Paracrine Cell-Cell Signaling Induced by Endothelial Injury." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38674.
Full textAbstract:
Background: Pulmonary arterial hypertension (PAH) is a lethal disease for which the fundamental molecular mechanisms are only partially understood. Existing therapies, which primarily focus on endothelial dysfunction, have limited effects on improving outcomes. Increases in pulmonary vascular resistance in PAH may be attributed to complex lung arterial remodeling which result in obliterative “plexiform” lesions, a pathological hallmark of this disease. Recent studies have shown that endothelial cell (ECs) apoptosis may be a central trigger for PAH, resulting in the emergence of growth-dysregulated and apoptosis-resistant ECs that contribute to the formation of complex neoplastic-like vascular lesions. However, the mechanism which links ECs apoptosis to dysregulated growth is not yet known. Previous studies in our lab have identified increased expression of translationally controlled tumor protein (TCTP) and its gene (TPT1), previously implicated in the transformation of neoplastic cells in cancer, and in blood outgrowth ECs from patients with PAH. Moreover, TCTP expression was found to be elevated in the lungs of patients with PAH, and tightly localized to complex arterial lesions. In addition, it was detected in obliterative intimal lesions of an experimental rat model of severe PAH.
Hypothesis: TCTP represents a central molecular mechanism linking ECs apoptosis to the emergence of growth-dysregulated lung vascular cells and occlusive, complex arterial remodelling in PAH.
Specific Hypotheses:
- Lentiviral overexpression of TCTP in human umbilical vein endothelial cells (HUVECs) and pulmonary artery smooth muscle cells (PASMCs) leads to a hyperproliferative and apoptosis-resistant phenotype.
- Overexpression of TCTP will increase its export into apoptotic extracellular vesicles, thereby augmenting cell-cell signalling between ECs and neighbouring SMCs.
Purpose: My objective was to examine the effects TCTP overexpression on ECs and SMCs survival in terms of proliferation and apoptosis, and TCTP release on the survival of nontransduced ECs and SMCs.
Methods and Results: The effect of TCTP overexpression on ECs growth and survival was studied using in vitro models. TCTP was overexpressed via a lentivirus vector in HUVECs and PASMCs. Compared to non-transfected or null transfected cells, TCTP overexpression led to increases in BrdU incorporation, consistent with hyper-proliferation, and decreases in caspase activity, consistent with apoptosis resistance. As well, TCTP was selectively exported into the conditioned media of apoptotic ECs, but not SMCs, despite similar levels of overexpression. In addition, the level of release was greater in serum starved conditioned media in comparison to the exosome fraction. Finally, our data demonstrates a selective effect of conditioned media (CM) from serum-starved ECs on PASMCs, but not ECs, in terms of an increase in proliferation and a decrease in apoptosis.
Conclusions: These support the idea that TCTP overexpression confers an increase in the survival of SMCs and HUVECs. Moreover, TCTP released from apoptotic ECs leads to a growth-dysregulated phenotype within SMCs (but not ECs) and may contribute to the formation of complex lung arterial lesions, leading to arteriolar obliteration in PAH. Finally, an increase in the level of TCTP expression via lentiviral transduction led to an increased TCTP export into the media, but this appeared to be mostly in the soluble portion, and less was associated with exosomes.
23
Simic, Damir. "Disclosure of novel mechanisms in which nicotine triggers structural and functional alterations of arterial smooth muscle cells, implications to pathogenesis of the occlusive arterial diseases." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ63106.pdf.
Full text
24
Tharp, Darla L. "Role of the intermediate-conductance Ca²⁺-activated K⁺ channel (K[ca]3.1) in coronary smooth muscle cell phenotypic modulation." Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/5936.
Full textAbstract:
Thesis (Ph. D.)--University of Missouri-Columbia, 2007.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "December 2007" Includes bibliographical references.
25
Holland, Michael. "A patch clamp study of pharmacological and physiological regulators of large conductance calcium-activated potassium channels in arterial smooth muscle cells." Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/29937.
Full textAbstract:
In the 1980s a group of vasodilator drugs were found to possess a common mechanism which involved opening KATP channels located in the cell membrane of smooth muscle cells, leading to vasorelaxation via membrane hyperpolarisation. A number of additional K+ channels have been identified in vascular smooth muscle cells and one of these channels, the large conductance calcium-activated K+ channel (BKCa), is a promising therapeutic target.;This thesis uses the various configurations of the patch-clamp technique to examine the effects of NS1619, nitric oxide (NO) and compounds resulting from the activation of the cGMP signalling pathway by NO, on the activity of ion channels.;Using single smooth muscle cells enzymatically isolated from the rat basilar artery, NS1619 was confirmed as an effective BKCa channel opener and hyperpolarising agent. Studies of the mechanism of action of NS1619 concluded that it has a direct effect on the BKCa channel itself or an associated regulatory site, possibly leading to an increase in the Ca2+-sensitivity of the BKCa channel. NS1619 also blocked at least two other channels, voltage-activated K+ channels and DHP-sensitive Ca2+ channels, and this latter effect almost certainly explains the functional vasorelaxation produced by NS1619 actions which will certainly limit the use of NS1619 in defining physiological roles for BKCa channels.;Nitric oxide activated whole cell currents when applied to single smooth muscle cells, which were blocked by specific BKCa channel blockers. Additional experiments determined that this action of NO could not be explained by a direct effect on BKCa channels but probably occurred by a mechanism involving a phosphorylation reaction catalysed by cGMP-dependent protein kinase. This stimulatory effect of cGMP-dependent protein kinase on BKCa channels may be involved in the vasorelaxation produced by nitric oxide and nitrovasodilators.
26
Lai, Ying-Ju [Verfasser]. "The Prostanoid EP4 receptor in prostacyclin sensing by pulmonary arterial smooth muscle cells in Monocrotaline-induced pulmonary hypertension in rats / Ying-Ju Lai." Gießen : Universitätsbibliothek, 2009. http://d-nb.info/1060450615/34.
Full text
27
Smith, Andrew Hart. "THE ROLE OF CANONICAL TRANSIENT RECEPTOR POTENTIAL CHANNEL SUBTYPE-6 IN PHENOTYPIC MODULATION OF VASCULAR SMOOTH MUSCLE CELLS AND ARTERIAL HEALING AFTER VASCULAR INTERVENTION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case160710077734737.
Full text
28
Seifert, Elena. "Metabolic Changes in Pulmonary Arterial Smooth Muscle Cells Exposed to Increased Mechanical Forces from an Ovine Model of Congenital Heart Disease with Increased Pulmonary Blood Flow." Scholarship @ Claremont, 2019. https://scholarship.claremont.edu/cmc_theses/2094.
Full textAbstract:
An important cause of pulmonary arterial hypertension (PAH) in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To gain a better understanding of the disease process, the changes in biochemical pathways and metabolism of pulmonary arterial smooth muscle cells (PASMCs) were studied using a unique surgical ovine model of increased pulmonary blood flow. PASMCs isolated from 4-week-old lambs with increased PBF (shunt) showed lower oxygen consumption rates and lower extracellular acidification rates linked to glutamine metabolism when compared to controls. Shunt and control PASMCs both exhibited a switch into the reverse tricarboxylic acid (TCA) cycle, while only shunt cells showed a decrease of glucose being transformed into Acetyl CoA to enter the forward TCA cycle. Shunt PASMCs also demonstrated increased levels of yes-associated protein 1 (YAP1) expression in the nucleus. These results indicate changes in glutamine metabolism, glucose metabolism, and protein signaling cascades associated with increased mechanical forces in the setting of increased PBF, as seen in PAH in children with CHD.
29
Sharmin, Nahid. "Therapeutic Targeting of BMP and TGF-β Signalling Pathways for the Resolution of Pulmonary Arterial Hypertension." Thesis, University of Bradford, 2018. http://hdl.handle.net/10454/17177.
Full textAbstract:
Vascular remodelling due to excessive proliferation and apoptosis resistance of
pulmonary arterial smooth muscle (PASMCs) and endothelial cells (ECs) has
been attributed to the pathogenesis of pulmonary arterial hypertension (PAH). It
is an incurable cardiovascular disorder, which leads to right heart failure and
death, if left untreated. Heterozygous germline mutations in the bone
morphogenetic protein receptor type II (BMPR2) have been linked with the
majority (~75%) of the familial form of the disease (HPAH). Mutations in the
BMPR2 gene impinge upon the BMP signalling which perturbs the balance
between BMP and TGF-β pathways leading to the clinical course of the disease.
Current therapies were discovered prior to the knowledge that PAH has
substantial genetic components. Hence, this study aims to identify novel
therapeutic intervention and provide novel insights into how the dysfunctional
BMPRII signalling contributes to the pathogenesis of PAH. This work
demonstrates that cryptolepines and FDA approved drugs (doxorubicin, taxol,
digitoxin and podophyllotoxin) inhibit the excessive proliferation and induce
apoptosis in BMPR2 mutant PASMCs by modulating the BMP and TGF-β
pathways. Moreover, established drug PTC124 has also been tested but has
failed to promote translational readthrough. I have also shown that dysregulated
apoptosis of PASMCs and HPAECs is mediated through the BMPRII-ALK1-BclxL
axis. Finally, the siRNA screen targeting approximately 1000 genes has
identified novel proteins including PPP1CA, IGF-1R, MPP1, MCM5 and SRC
each capable of modulating the BMPRII signalling. Taken together, this study for
the very first time has identified novel compounds with pro-BMP and anti-TGFβ
activities which may provide therapeutic intervention prior to or after the onset of
PAH.Commonwealth Scholarship Commission in the UK
The full text will be available at the end of the embargo period, 31st July 2024.
30
Quatredeniers, Marceau. "Dérégulation du récepteur NMDA dans l'hypertension artérielle pulmonaire : conséquences et perspectives." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS574.
Full textAbstract:
L’hypertension artérielle pulmonaire (HTAP) est une maladie rare définie par une augmentation de la pression artérielle pulmonaire moyenne due à un remodelage progressif des artérioles pulmonaires, menant à une défaillance du ventricule cardiaque droit. Le remodelage vasculaire est la conséquence d’une dysfonction endothéliale conduisant à une hyperprolifération et à un défaut d’apoptose des cellules vasculaires pulmonaires. Le récepteur NMDA (NMDAR), un récepteur au glutamate connu pour son rôle dans la plasticité neuronale et la transmission synaptique, a été récemment identifié comme acteur de ce remodelage vasculaire. Cependant, le sous-type de NMDAR impliqué n’est pas connu. Le développement de traitements potentiels ciblant le NMDAR nécessite de mieux comprendre quelles sous-unités du récepteur sont mobilisées dans la maladie. Dans la mesure où la sous-unité GluN2A est impliquée dans la survie des neurones et la sous-unité GluN2B dans leur mort, nous avons fait l’hypothèse que la composition des NMDARs vasculaires pulmonaires devait être dérégulée dans l’HTAP. Par conséquent, cette thèse a pour objectifs i) d’étudier la composition du NMDAR dans l’HTAP, ii) d’en identifier les conséquences fonctionnelles, et iii) d’explorer son intégration au sein de la physiopathologie de l’HTAP.Nous avons montré que l’expression de la sous-unité GluN2B est réduite dans les artères pulmonaires des patients HTAP comparés à des sujets non-HTAP, malgré l’augmentation de l’expression de la sous-unité obligatoire GluN1, suggérant une commutation de l’expression des NMDARs de type GluN2B vers d’autres sous-types. Nous avons également montré que les NMDARs de type GluN2B sont rapidement et transitoirement recrutés à la membrane des cellules musculaires lisses (CMLs) en réponse à un facteur de croissance, le PDGF, par l’intermédiaire des Src family kinases (SFKs). En utilisant un inhibiteur spécifique des NMDARs de type GluN2B, nous avons observé qu’ils réduisaient la prolifération et la migration dépendantes du PDGF, indiquant une boucle de rétrocontrôle négatif. Ces résultats suggèrent une signalisation croisée entre le PDGFR-β, les SFKs et les NMDARs de type GluN2B. Ainsi le déficit en NMDARs de type GluN2B chez les patients HTAP pourrait potentialiser la réponse proliférative et migratoire au PDGF, une voie suractivée dans l’HTAP. De plus, nous avons montré que les NMDARs de type GluN2A sont recrutés de façon prolongée à la membrane des CMLs lors d’une stimulation par le PDGF. Néanmoins, le rôle précis des récepteurs de type GluN2A dans l’HTAP reste à découvrir. Pour approfondir le rôle du NMDAR dans la physiopathologie de l’HTAP, nous avons mené une étude bio-informatique complémentaire afin de modéliser les voies de signalisation impliquant le NMDAR dans l’HTAP. Nous avons construit et connecté en réseau les bases de connaissance sur les acteurs de l’HTAP d’une part, et les voies de signalisation impliquant le NMDAR dans le système nerveux central d’autre part. Nous avons montré que ces réseaux positionnent le NMDAR au cœur de nombreuses voies de signalisation caractéristiques de l’HTAP, dont celle du PDGFR-β.Ainsi, nous avons montré que l’expression membranaire des récepteurs de type GluN2A et GluN2B est dérégulée dans l’HTAP, orientant probablement la réponse au glutamate dépendante du PDGF vers les récepteurs de type GluN2A. Les conséquences d’un tel déséquilibre sont l’augmentation de la prolifération et de la migration des CMLs vasculaires pulmonaires. De plus le manque de récepteurs de type GluN2B est une caractéristique physiopathologique nouvelle dans l’HTAP et dans la compréhension du mode d’action des NMDARs périphériques en général. Enfin, le NMDAR semble être un acteur central dans la physiopathologie de l’HTAP, interagissant avec de nombreuses voies de signalisation impliquées dans la maladie, suggérant de nouvelles pistes pour avancer dans la compréhension des mécanismes physiopathologiques de l’HTAPPulmonary arterial hypertension (PAH) is a rare disease defined by an increase in mean pulmonary arterial pressure due to progressive obstruction of the small pulmonary arteries, leading to right heart failure and death. The vascular remodeling is a consequence of complex and multiple patho-mechanisms, including endothelial cells dysfunction and hyperproliferation of smooth muscle cells in the pulmonary vascular wall. The N-methyl-D-aspartate receptor (NMDAR), a glutamate receptor, has been recently identified as playing an active role in this vascular remodeling. It has been shown that in pulmonary arteries of PAH patients, NMDAR is overexpressed and overactivated and is involved in the proliferation and resistance to apoptosis of pulmonary vascular cells. However, the NMDAR subtype involved in this process remains unknown. The development of potential treatments targeting the NMDAR requires a better understanding of its subunit involvement in the disease. Since the GluN2A subunit is involved in the survival of neurons and the GluN2B subunit in their death, we hypothesized that the pulmonary vascular NMDAR subunit composition could be dysregulated in PAH. Therefore, in this thesis study we aimed to: i) study the composition of NMDAR in PAH, ii) explore its functional consequences in the pathophysiology of PAH, and iii) uncover its integration in the pathophysiology of PAH.We showed that the expression of the GluN2B subunit is reduced in the pulmonary arteries of PAH patients compared to non-PAH subjects. This occurs despite the overall increased expression of the obligatory GluN1 subunit, suggesting a switch from GluN2B-type receptors to, at least, another GluN2-type receptor. We also showed that in the presence of PDGF-BB, there is an immediate increase in the levels of phosphorylated Src family kinases (SFKs), associated to an increase in phosphorylated GluN2B (the active form) that were relocated to the cell membrane, suggesting the cross-talk between PDGF, SFKs and NMDAR. To validate the pathway, we inhibited the activation of PDGFR-β or SFKs, and in both cases the phosphorylation of GluN2B after PDGF stimulation was aborted. To assess the functional importance of this pathway, proliferation and “wound healing” tests were performed. The results clearly showed that selective inhibition of GluN2B, in the presence of PDGF, significantly increased both migration and proliferation of PASMCs. These results suggest that the lack of GluN2B-type receptors in PAH may potentiate SMC proliferative and migratory response to PDGF, a well-known overactivated pathway in PAH. In addition, we showed that GluN2A-type NMDARs arerecruited to the SMC membrane following PDGF stimulation, but the precise role of GluN2A-type NMDARs in PAH remains elusive. To further explore the crosstalk between the NMDAR and the PDGF receptor (PDGFR) pathways, we conducted a complementary bioinformatics study. To provide a model of the NMDAR signaling pathways in PAH we constructed and connected comprehensive knowledge bases of the actors involved in PAH on one hand and the signaling pathways involving NMDAR within the central nervous system on the other hand. Within these networks the NMDAR was revealed as a central downstream effector of the hallmark signaling pathways of PAH, including that of PDGFR.These results indicate that the membrane expression of GluN2A-type and GluN2B-type receptors is dysregulated in PAH, presumably switching the PDGF-dependent glutamate response towards GluN2A-type receptors. The consequences of such imbalance are the increased proliferation and migration of pulmonary vascular SMCs. Moreover, the lack of GluN2B-type NMDARs is a new feature in the pathophysiology of PAH and in the understanding of peripheral NMDA receptors in general. Besides, the NMDAR seems to be a central effector in PAH, interacting with multiple hallmark pathways of the disease, suggesting new tracks to further understanding the pathophysiology of PAH
31
Régent, Alexis. "Étude du rôle des cellules musculaires lisses vasculaires (CMLV) et des anticorps anti-CMLV dans la pathogénie de l’artérite à cellules géantes (maladie de Horton)." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05S021/document.
Full textAbstract:
Rationnel : L’artérite à cellules géantes (ACG) est une vascularite primitive des gros vaisseaux dont le diagnostic repose sur la mise en évidence d’un infiltrat inflammatoire et de cellules géantes à la biopsie d’artère temporale (BAT). On note également un remodelage de la paroi vasculaire lié à une prolifération des cellules musculaires lisses vasculaires (CMLV) pouvant aboutir à une occlusion artérielle. Objectif : Caractériser les auto-anticorps dirigés contre les cellules endothéliales (CE) et les CMLV au cours de l’ACG et préciser le rôle des CMLV dans le remodelage pariétal. Méthodes : La recherche d’auto-anticorps a reposé sur un immunoblot 2D couplé à la spectrométrie de masse. Les protéomes des CMLV d’artère ombilicale, d’artère pulmonaire et d’aorte humaines normales a été comparés par protéomique différentielle (2D-DIGE). Nous avons utilisé la 2D-DIGE et des puces d’expression pan-génomiques pour comparer les CMLV issues de BAT de patients suspects d’ACG (avec un diagnostic final d’ACG ou non), afin d’identifier les mécanismes contribuant à la prolifération des CMLV. Résultats : Chez 15 patients atteints d’ACG, nous avons notamment identifié la lamine, la vinculine et l’annexine A5 comme cible des auto-anticorps anti-CMLV. Les antigènes cibles identifiés sont liés à Grb2, une protéine adaptatrice impliquée dans la prolifération des CMLV. Nous avons mis en évidence des protéomes différents au sein des CMLV humaines normales selon leur origine vasculaire et avons principalement identifié des protéines du cytosquelette et du métabolisme énergétique.A partir des CMLV isolées des BAT et à l’aide d’Ingenuity®, nous avons identifié l’endothéline 1 (ET-1) et la paxilline comme des molécules impliquées dans le remodelage vasculaire. En immunohistochimie et par qPCR, nous avons confirmé l’expression de l’ET-1 et de ses récepteurs ETAR et ETBR au sein des artères temporales de patients atteints d’ACG. Enfin, nous avons inhibé la prolifération des CMLV avec du macitentan, un inhibiteur d’ETAR et en particulier avec son métabolite actif, mais pas avec d’autres inhibiteurs des récepteurs de l’ET-1. Conclusion : Nous avons identifié chez les patients atteints d’ACG des anticorps anti-CMLV dont le rôle pathogéne potentiel reste à définir. Les différences protéiques observées à partir des CMLV humaines normales pourraient correspondre à des phénotypes différents. A partir d’un matériel biologique unique, nous avons pu montrer que la prolifération excessive des CMLV au cours de l’ACG pouvait être inhibée par le macitentan ce qui permet d’envisager un usage thérapeutique de cette moléculeBackground : Giant cell arteritis (GCA) is a large vessel vasculitis and its diagnosis usually relies on the identification of an inflammatory infiltrate made of mononuclear cells and giant cells upon temporal artery biopsy. There is also a remodeling process in the arterial wall due to an excessive proliferation of vascular smooth muscle cells (VSMC) which can sometimes lead to arterial occlusion. Purpose: Identify auto-antibodies targeting either endothelial cells (EC) and/or VSMC during GCA and better understand the role of VSMC in the remodeling process. Methods : Auto-antibodies were detected by a 2-dimensionnal immunoblot and their target antigens were identified by mass spectrometry. Proteoms of umbilical artery, pulmonary artery and aorta VSMC were compared by 2 dimension differential in gel electrophoresis (2D-DIGE). In order to identify mechanisms involved in VSMC proliferation in GCA, we used both 2D-DIGE and pan genomic chips in order to compare VSMC isolated at the time of temporal artery biopsy (TAB) from patients with a final diagnosis of GCA or another diagnosis. Results : In 15 patients with GCA, we identified lamin, vinculin and Annexin A5 as target antigens of anti-VSMC antibodies. Target antigens were linked with Grb2, an adaptator protein involved in VSMC proliferation. Normal VSMC originating from different vascular beds have differ in protein contents with differential expression of cytoskeleton and energy metabolism proteins. We compared VSMC from TAB with Ingenuity software and identified endothelin-1 (ET-1) and paxillin as proteins involved in vessel remodeling. We confirmed by immunohistichemistry and qPCR that ET-1 and its receptor ETAR and ETBR were expressed in temporal arteries from patients with GCA. Last, we reduced VSMC proliferation with Macitentan, an ETAR and ETBR antagonist and significantly inhibited VSMC proliferation with its active metabolite whereas other ET-1 inhibitors had no effect. Conclusion : We identified anti-VSMC auto-antibodies in patients with GCA. Their pathogenic role remains to be determined. Normal VSMC from different vascular locations differ in protein conten which might reflect different phenotypes and different properties. The escessive proliferation of VSMC from patients with GCA was inhibited by Macitentan. This drug might constitute a future therapeutic option
32
Wadsworth, R. M. "Regulation of contraction of arterial smooth muscle." Thesis, University of Strathclyde, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248764.
Full text
33
Belozertseva, Ekaterina. "Effets du récepteur minéralocorticoïde, de l’intégrine αv et de vimentine sur les fonctions des cellules musculaires lisses vasculaires et la rigidité artérielle." Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0165/document.
Full textAbstract:
La rigidité artérielle et la fibrose ont une valeur prédictive dans le développement des maladies cardiovasculaires (CV). Ces 2 phénotypes impliquent les cellules musculaires lisses vasculaires (CMLVs) notamment des récepteurs membranaires et les protéines du cytosquelette. Les objectifs ont été d’étudier : (i) l’influence du récepteur minéralocorticoïde (MR) sur la réactivité vasculaire, (ii) le rôle de l’intégrine αvβ3 dans le développement de la rigidité artérielle et la fibrose vasculaire, et (iii) l’impact de la vimentine et la synémine sur la structure et la fonction artérielle. Ces trois études ont utilisées des souris avec invalidation génétiques des protéines d’intérêt. Résultats : l’absence du MR diminue la réactivité vasculaire en altérant le couplage contraction/relaxation des CMLVs via des mécanismes Ca2+- et NO-dépendants (une diminution de la vasoconstriction en réponse au Ca2+ extracellulaire et une altération de la vasorelaxation endothélium-dépendante en réponse à l’acétylcholine). L’invalidation de la sous-unité αv prévient la fibrose en réponse à l’administration d’angiotensine II. L’absence de la vimentine et non celle de la synémine augmente la rigidité artérielle via des changements des adhésions focales des CMLVs mais aussi des cellules endothéliales. En conclusion, les récepteurs membranaires et protéines intracellulaires étudiées influencent la fonction et la structure des artères grâce à des actions spécifiques sur le tonus musculaire, la mécanotransduction et l’organisation ultra-structurale des CMLVs. Ces études montrent au niveau cellulaire et moléculaire le déterminisme plurifactoriel des phénotypes de rigidité-fibrose de la paroi artérielle. Ces résultats nécessitent des travaux plus mécanistiques pour affirmer l’implication de ces protéines dans les maladies CV liées au vieillissementArterial stiffness and fibrosis have a predictive value in the development of cardiovascular diseases (CV). These two phenotypes involve vascular smooth muscle cells (VSMCs) including membrane receptors and cytoskeletal proteins. The objectives were to examine: (i) the influence of the mineralocorticoid receptor (MR) on vascular reactivity, (ii) the role of avb3 integrin in the development of arterial stiffness and vascular fibrosis, and (iii) the impact of vimentin and synemin on arterial structure and function. The mice with genetic invalidation of the proteins of interest were used in these three studies. Results: the absence of MR decreased vascular reactivity by altering the contraction/relaxation coupling of VSMC through Ca2+- and NO-dependent mechanisms (a decrease of vasoconstriction in response to extracellular Ca2+ and impaired endothelium-dependent vasorelaxation in response to acetylcholine). The invalidation of the αv subunit prevented fibrosis in response to the administration of angiotensin II. The absence of vimentin, and not that of the synemin, increased arterial stiffness via changes in focal adhesions of VSMCs as well as endothelial cells. In conclusion, the studied membrane receptors and intracellular proteins that influenced the structure and function of arteries through specific actions on muscle tone, the mechanotransduction and the ultra-structural organization of VSMCs. These studies show the multifactorial dependency of the stiffness-fibrosis phenotypes of the arterial wall at the cellular and molecular levels. These results require more mechanistic work to determine the role of these proteins in CV diseases related to aging
34
Hautefort, Aurélie. "Etude des mécanismes inflammatoires, génétiques et épigénétiques impliqués dans la physiopathologie de l'hypertension artérielle pulmonaire." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS278.
Full textAbstract:
L’Hypertensions Artérielle Pulmonaire (HTAP) résulte de l’obstruction progressive des artères pulmonaires de petits calibres due à un remodelage de la paroi vasculaire ainsi qu’à une vasoconstriction. Cette thèse repose sur 3 piliers de la physiopathologie de l’HTAP : l’inflammation, l’épigénétique et la susceptibilité génétique de la maladie.Le premier projet démontre que les cellules dendritiques des patients atteints d’HTAP sont moins sensibles à l’action immunomodulatrice des glucocorticoïdes et orientent la réponse des lymphocytes T vers une réponse Th17, souvent impliquée dans les maladies autoimmunes.Le second projet a pour but de comparer le profil de méthylation des cellules endothéliales d’artères pulmonaires (CE-AP) de patients atteints d’HTAP comparé aux CE-AP de patients contrôles. Nous avons mis en évidence des clusters de gènes ayant un profil de méthylation différents entre les CE-HTAP comparé aux CE-CTR. Un gène différentiellement méthylé s’est dégagé durant l’étude bioinformatique : ABCA1 (ATP binding cassette 1). L’altération de son expression prédite par l’étude bioinformatique a été validée chez l’homme et le modèle de rat monocrotaline.Enfin, le dernier projet décrit la caractérisation d’un nouveau modèle animal de susceptibilité génétique à l’HTAP liée à des mutations dans le gène Bmpr2 chez le rat, au niveau hémodynamique, histologique, vasculaire, moléculaire et électrophysiologique. Nous avons démontré que ce modèle reproduit des schémas physiopathologiques pertinents vis-à-vis de la maladie humaine, ces résultats font de ce modèle un nouveau outil d’étude de la physiopathologie de l’HTAPPulmonary arterial hypertension (PAH) is characterized by a progressive pulmonary arterial obstruction due to pulmonary vascular remodeling of distal arterioles as well as abnormal vasoconstriction. This project allowed to study three biological process clearly establish to be implicated in physiopathology of PAH.The first project demonstrated a dendritic cells dysfunction and a Th17 immune polarization of idiopathic PAH patients.The objective of the second project was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation. We identified clusters of probes that discriminates controls and PAH patients. During bioinformatics study, ABCA1 (ATP binding cassette 1) gene was emphasized. Alteration of ABCA1 expression predicted during bioinformatics study has been validated in human and in monocrotaline rat model.The last project described the validation of a new PAH model by a hemodynamic, histological, vascular, molecular and electrophysiological characterization of heterozygous rat mutated to Bmpr2 gene. Whole functional and molecular dysregulation define this animal model like a useful tool in the study of BMPRII signaling alteration in PAH physiopathology
35
Goonetilleke, Lakshman. "Two-pore domain potassium channels in arterial smooth muscle." Thesis, University of Liverpool, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485866.
Full textAbstract:
The membrane potential of arterial smooth cells, and consequently arterial tone, is. regulated by the activity of plasmalemmal K+ selective ion channels. K2P channels are responsible for background K+ (KB) conductances which contribute to generation of the resting membrane potential. They have been identified in arterial smooth muscle cells but their significance is poorly understood. A Ks conductance is expressed in rat femoral arterial smooth muscle cells (rFASMCs), and the aim of this project was to (i) determine the expression profile of K2P subunits in rat femoral artery and (ii) identify the molecular correlate of the KB conductance in rFASMCs. Using RT-PCR, we identified transcripts encoding TWIK-2, TASK-I, TASK-2, TREK-I, TREK-2 and THIK-I in total rat femoral artery RNA. TWIK-2, TASK-I, TASK-2 and TREK-I were further identified at the protein level in isolated FASMCs by antibody staining. Only TWIK-2 was detected at the cell surface, while TASK-I, TASK-2 and TREK-I had a predominantly intracellular localisation. Immunohistochemistry of femoral artery sections may also support the expression of TWIK-2, TASK-I and TASK-2 (but not TREK-I) in the endothelium. To allow comparison between cloned and native conductances, the open reading frames of rTWIK-2, rTASK-2 and rTREK-I were cloned by PCR amplification. The sequence encoding rTASK-2 was cloned de novo and submitted to the EBI gene data base (Accession no: AM229406). Functional expression ofrTWIK-2 and rTASK-2 was investigated in Xenopus 'laevis oocytes. rTWIK-2 did not exhibit strong expression in the Xenopus laevis expression system. Conversely, recombinant rTASK-2 channels formed K+ selective, extracellular pH sensitive ion channels. The basic pharmacological properties of cloned rTASK-2 channels were also investigated. Currents were insensitive to extracellular TEA, 4-AP and Cs+, but were sensitive to inhibition by Ba2+, Zn2+and quinidine. Inhibition by extracellular Ba2+was strongly time and voltage-dependent. Ba2+ inhibition of rTASK-2 was characterised by steady-state analysis and voltage pulses. Although we were unable to describe the functional correlate of the KB conductance in rFASMCs, this thesis has established the groundwork for further correlative studies. The information provided will assist in the identification of native TASK-2 conductances.
36
Costa, Edilene de Souza. "Efeito da proteína dissulfeto isomerase na ativação do receptor do fator de crescimento epidermal (EGFR) durante o desenvolvimento da hipertensão arterial. Papel da Nox1 NADPH oxidase." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-16082016-103430/.
Full textAbstract:
Estudos caracterizaram o envolvimento da PDI na modulação da geração de EROs pela Nox1 como moduladores da migração de células do músculo liso vascular (VSMC) mediados por fatores de crescimento derivados de plaqueta (PDGF). Outros estudos vêm demonstrando o envolvimento do fator de crescimento epidermal (EGFR) no remodelamento vascular, após a transativação via Angiotensina II. Entretanto o papel da PDI na ativação do EGFR via Nox1 na hipertensão arterial ainda permanece desconhecido. Objetivo foi caracterizar o papel da PDI na expressão de Nox1 dependente do EGFR durante o desenvolvimento da hipertensão arterial. Resultados demonstram um aumento da expressão de HB-EGF e ativação de ERK 1/2 na aorta de animais SHR com 8 semanas e 12 semanas de idade, e no plasma de animais SHR com 12 semanas. Ainda, a OvxPDI acarretou em um aumento na expressão gênica de Nox-1 tanto na OVXPDI quanto na forma OvxPDIMUT. Resultados mostram um novo papel da PDI na expressão gênica de Nox-1 via EGFR e a participação desta tiol oxido redutase na gênese da hipertensão arterial.Studies characterizing the involvement of PDI in the modulation of ROS by Nox1 as modulators of cell migration of vascular smooth muscle (VSMC) mediated by growth factors derived from platelets (PDGF). Other studies have demonstrated the involvement of the epidermal growth factor receptor (EGFR) on vascular remodeling after transactivation via Angiotensin II. However the role of PDI in the activation of EGFR via Nox1 in hypertension remains unknown. Objective was to characterize the role of PDI in Nox1 dependent EGFR expression during the development of hypertension. Results show an increase of HB-EGF expression and ERK 1/2 activation in the aortic SHR at 8 weeks and 12 weeks of age, and plasma SHR at 12 weeks. Still, the OvxPDI resulted in an increase in gene expression of Nox-1 both in OVXPDI and in OvxPDIMUT way. Results show a new role of PDI in gene expression of Nox-1 via EGFR and the participation of this thiol reductase oxide in the pathogenesis of hypertension.
37
Schnetzer, Karen Joan. "Effects of in vitro uniaxial cyclic stretch upon rat aortic smooth muscle cells." Diss., Georgia Institute of Technology, 1995. http://hdl.handle.net/1853/10236.
Full text
38
Brennan, Sean. "KV7 potassium channels : a focus on human intra-pulmonary arteries." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/kv7-potassium-channels-a-focus-on-human-intrapulmonary-arteries(46f5ff0e-1674-4ab1-916d-2f43e3c585e5).html.
Full textAbstract:
Pulmonary arterial hypertension (PAH) is a disease in which pulmonary vascular resistance increases. The cell membrane of pulmonary artery smooth muscle cells (PASMC) in PAH patients is depolarised, resulting in disrupted Ca2+ signalling leading to smooth muscle constriction and PASMC proliferation and migration. In rat pulmonary artery (PA) smooth muscle the KV7 K+ channels, encoded by the KCNQ genes, have been proposed to contribute to the resting K+ current, promoting low resting tone by maintaining a negative membrane potential and low intracellular Ca2+. KV7 channel activating drugs have the potential to counteract the dysfunctional signalling during PAH by causing hyperpolarisation. This study set out to determine if the KV7 channels are expressed in human PA and if so whether they can alter vascular tone, PASMC proliferation and/or migration due to their ability to reduce intracellular Ca2+ indirectly. The effects of KV7 K+ channel modulators on human PA tone were measured using myography, while KCNQ gene expression was examined with quantitative PCR. Markers of proliferation (5-bromo-2'-deoxy-uridine (BrdU) and Ki67 antigen), were used to measure PASMC proliferation, while migration was assessed using the scratch-wound assay. Human PASMCs express all KCNQ genes, except KCNQ2. The KV7 channel blockers XE991, linopirdine and (-)chromanol 293B, constricted PAs. The KV7 channel activators retigabine and zinc pyrithione (ZnPy) relaxed PAs pre-constricted with agonists. The retigabine response was enhanced in PAs constricted with Bay K 8644, abolished in ionomycin constricted PAs and reduced in the presence of 90 mM K+, suggesting inhibition of voltage-gated Ca2+ influx. Similar experiments on rat PAs suggest that only part of the ZnPy-induced relaxation can be attributed to KV7 channel activation. The KCNQ5 gene remained in cultured PASMCs while no KV7 channel modulator altered proliferation or migration. Thus KV7.5 channels could possibly be a marker of differentiated PASMCs and/or be involved in the regulation of cell phenotype. The results imply that KV7 channels play a role in regulating PA tone and Ca2+ signalling in PA smooth. It is concluded that although KCNQ5 transcripts are preserved in proliferating PASMC, it is unlikely they play a role in PASMC proliferation or migration. In summary, KV7 channel activators may be useful in the treatment of PAH since they can prevent vasoconstriction.
39
Fellows, Adam Lee. "FOXO3a in vascular smooth muscle cell apoptosis." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275687.
Full textAbstract:
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.
40
McSherry, Iain Neil. "Endothelial cell modulation of smooth muscle contraction." Thesis, University of Bath, 2005. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423481.
Full text
41
Ruiz, Matthieu. "Rôle de PGC-1α dans le système cardiovasculaire : recherche d’activateurs cœur-spécifiques et étude de ses mécanismes de régulation dans le muscle lisse aortique." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114830/document.
Full textAbstract:
L’insuffisance cardiaque (IC) reste la cause majeure de morbimortalité dans les pays industrialisés justifiant ainsi la recherche de traitements plus ciblés. Caractérisée par des désordres métaboliques importants qui impliquent notamment une dysfonction mitochondriale, le métabolisme énergétique apparait comme une composante majeure du développement de l’IC. Ces dernières années, le co-activateur transcriptionnel PGC-1α a été proposé comme un acteur central du contrôle de la fonction mitochondriale et constitue ainsi une cible thérapeutique d’intérêt. Ainsi, l’objectif principal de ce travail est de développer un test cellulaire robotisé permettant la recherche d’activateurs de PGC-1α dans un contexte cardiaque.La mise en place de ce test cellulaire de criblage dans des cellules H9c2 différenciées en cellules pseudo-cardiaques a permis l’identification de trois familles majeures : les hormones stéroïdiennes, les vitamines B et les acides gras, capables d’activer l’expression de PGC-1α et par ce biais d’induire une biogenèse mitochondriale ainsi qu’une augmentation de la respiration mitochondriale. La validation de ces effets dans des cardiomyocytes de rat adulte a permis d’une part de valider la pertinence du test et du choix du modèle cellulaire et d’autre part de vérifier qu’une induction de l’expression de PGC-1α se répercute bien sur la cascade transcriptionnelle de la biogenèse mitochondriale. Ce test constitue donc un atout majeur dans le recherche de nouveaux activateurs de PGC-1α pour mieux comprendre ses mécanismes de régulation dans le cœur, mais offre aussi des perspectives intéressantes pour la recherche de composés pharmacologiques à visée thérapeutique.Par ailleurs, peu de connaissances sont disponibles dans la littérature concernant le contrôle de la biogenèse mitochondriale dans le muscle lisse vasculaire et plus particulièrement dans l’hypertension artérielle. Ainsi, la deuxième partie de ce travail a été de caractériser la biogenèse mitochondriale dans un contexte d’hypertension. A travers l’utilisation d’un modèle expérimental d’hypertension et après confirmation dans des cellules musculaires lisses en culture, nous avons montré une induction importante de la biogenèse mitochondriale dans l’hypertension par un mécanisme stress oxydant-dépendant. De plus, cette induction est corrélée à une forte activation de la CaMKII, totalement bloquée par la présence d’un anti-oxydant : le resvératrol. Ces résultats suggèrent donc un contrôle de la biogenèse mitochondriale dépendante de la balance pro/anti-oxydante via l’activation de la CaMKII dans le muscle lisse vasculaireHeart failure (HF) is still the major cause of morbimortality in industrialized countries that justify the research of new treatments. Characterized in part by metabolic disorders including mitochondrial dysfunction, energetic metabolism appears as an essential component in HF development. These last years, PGC-1α has been proposed as a central actor of mitochondrial function control and thus as a therapeutic target of interest.The development of a cellular robotized assay in cardiac-like differentiated H9c2 cells allowed identification of three families: steroid hormones, B vitamins and fatty acids, able to induce the expression of PGC-1α and thus up-regulate mitochondrial biogenesis and mitochondrial respiration. The validation of these effects in adult rat cardiomyocytes lets in the one hand to validate the suitability of the assay and in the other hand to confirm that PGC-1α induction leads to mitochondrial biogenesis activation. Consequently, this assay constitutes a major asset to find new activators of PGC-1α to better understand its regulation in heart and provides interesting perspectives for the research of therapeutic pharmacologic compounds.Mechanisms controlling mitochondrial biogenesis in response to hypertension in vascular smooth muscle remain unclear. In this context, the second part of this work was to identify how mitochondrial biogenesis is modulated in arterial hypertension. Using an experimental model of hypertension and after validation in cultivated smooth muscle cells, we show a mitochondrial biogenesis induction in response to hypertension in relation with an increase in oxidative stress. Moreover, this induction is associated with a significant increase in CaMKII activity which was totally blocked by an antioxidant: resveratrol. These results suggest a regulation of mitochondrial biogenesis by oxidative stress via a CaMKII mechanism in vascular smooth muscle
42
Brown-Turner, Dawn Leah. "Regulation of alpha- and beta-actin isoforms in the contracting A7r5 smooth muscle cell." [Huntington, WV : Marshall University Libraries], 2009. http://www.marshall.edu/etd/descript.asp?ref=1009.
Full text
43
Zhao, Ning. "Notch Signaling Guides Vascular Smooth Muscle Cell Function." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1396890017.
Full text
44
Kinnear, Nicholas Patrick. "An investigation on NAADP-dependent Ca²⁺ signalling mechanisms in arterial smooth muscle /." St Andrews, 2007. http://hdl.handle.net/10023/364.
Full text
45
Turner, Joanne L. "Ionic currents in pulmonary arterial smooth muscle and the effect of hypoxia." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360012.
Full text
46
Kinnear, Nicholas P. "An investigation of NAADP-dependent Ca²⁺ signalling mechanisms in arterial smooth muscle." Thesis, University of St Andrews, 2007. http://hdl.handle.net/10023/364.
Full textAbstract:
Previous investigations on pulmonary artery smooth muscle cells have shown that nicotinic acid adenine dinucleotide diphosphate (NAADP) evokes highly localised intracellular Ca²⁺ bursts by mobilising thapsigargin-insensitive Ca²⁺ stores. Such localised Ca²⁺ signals may initiate global Ca²⁺ waves and contraction of the myocytes through the recruitment of ryanodine receptors (RyR) located on the sarcoplasmic reticulum (SR) via Ca²⁺-induced Ca²⁺-release (CICR). In this thesis I have shown that NAADP evokes localised Ca²⁺ signals through the mobilisation of a bafilomycin A1-sensitive, lysosome-related Ca²⁺ store. Lysosomal Ca²⁺ stores facilitate this process by colocalising with a subpopulation of RyRs on the surface of the SR to comprise a highly specialised trigger zone for Ca²⁺ signalling by NAADP. I have also shown that the proposed trigger zone for NAADP-dependent Ca²⁺ signalling may be formed between lysosomes and clusters of RyR subtype 3 (RyR3) located in close proximity to one another in the perinuclear region of cells. Localised Ca²⁺ bursts generated by NAADP-dependent Ca²⁺ release from acidic Ca²⁺ stores and subsequent CICR via RyR3 on the SR may then amplify Ca²⁺ bursts into a propagating Ca²⁺ signal by recruiting clusters of RyR subtype 2 (RyR2) located in the perinuclear and extra-perinuclear regions of the cell. The presence of this trigger zone may explain, in part, why Ca²⁺ bursts by NAADP induce, in an all-or-none manner, global Ca²⁺ signals by CICR via RyRs on the SR. Consistent with a role for NAADP and lysosomes as a discrete and agonist-specific Ca²⁺ signalling pathway utilised by vasoconstrictors, I have shown that endothelin-1 (ET-1), but not phenylephrine or prostaglandin-F2α, mobilises Ca²⁺ stores by NAADP, and that ET-1 initiates Ca²⁺ signalling by NAADP in a receptor subtype-specific manner through the activation of ETB receptors. These findings further advance our understanding of how that spatial organisation of discrete, organellar Ca²⁺ stores underpin the generation of differential Ca²⁺ signalling patterns by different Ca²⁺-mobilising messengers.
47
Chaudhry, Adil Anthony. "Transient postnatal pulmonary arterial smooth muscle cytoskeletal disassembly and its functional implications." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327049.
Full text
48
Jia, Yanlin. "Nitric oxide and airway smooth muscle responsiveness." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=29052.
Full textAbstract:
Airway hyperresponsiveness to bronchoconstrictors has been found in asthma and related to the severity of the disease. The factors which result in hyperresponsiveness are not completely understood. A possible mechanism is an imbalance between endogenous bronchoconstrictors and dilators. NO is known to relax tracheal smooth muscle by activating soluble guanylate cyclase and increasing the level of intracellular cyclic guanosine monophosphate (GMP). The first hypothesis tested was that the NO-cyclic GMP-relaxant pathway is involved in the regulation of airway responsiveness. Inhibition of endogenous nitric oxide by N$ sp{ omega}$-nitro-L-arginine (L-NNA) significantly increased airway responsiveness to inhaled methacholine in normoresponsive Lewis rats but less so in hyperresponsiveness Fisher rats. In addition, carbachol increased cyclic GMP levels in tracheal tissues from both strains; this cyclic GMP accumulation in tracheal tissues was also less in Fisher than in Lewis rats and abolished by L-NNA in both strains, indicating that it was mediated by a NO-dependent mechanism. These results suggest that endogenous NO plays a role in regulation of airway responsiveness and contributes to the strain-related difference in airway responsiveness in rats. To investigate the NO-cyclic GMP-relaxant pathway in rat airway, the effect of sodium nitroprusside (SNP, a NO donor) on airway responsiveness to a cholinergic agonist was measured in hyperresponsive Fisher rats and compared with the less responsive Lewis strain. Fisher rats were resistant to SNP as evidenced by less relaxation of carbachol contracted tracheal rings by SNP and less cyclic GMP accumulation induced by SNP in cultured airway smooth muscle cells in Fisher rats compared with Lewis rats, indicating an impaired response to SNP in Fisher airways.NO is known to be synthesized from L-arginine in a reaction catalyzed by NO synthase (NOS). Liver cytochrome P450 also catalyzes the oxidative cleavage of C=N bonds of compounds containing a -C(NH$ sb2$)NOH function, producing NO in vitro. We hypothesized that the biosynthesis of NO in airway smooth muscle cells could result from P450 enzymes acting on appropriate substrates. NO can be synthesized in a number of lung cell types. However, to date, no constitutive form of NOS activity has been found in airway smooth muscle cells. We next examined the possibility that airway smooth muscle itself might be able to synthesize NO. Formamidoxime, a compound containing the -C(NH$ sb2$)NOH function, was found to produce NO in cultured airway smooth muscle cells. As well, formamidoxime relaxed pre-contracted trachealis and cyclic GMP accumulation in airway smooth muscle cells in culture. These effects were inhibited by P450 inhibitors but not by NOS inhibitors. Thus, an L-arginine-independent pathway for production of NO was demonstrable in airway smooth muscle cells. This NO production was catalyzed by P450 but not by NOS.
In conclusion, my studies have demonstrated an important role for endogenous NO production in determining the airway responsiveness of normal rats to inhaled cholinergic agonists. This mechanism contributes to strain-related differences in airway responsiveness in the rat.
49
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.
Full text
50
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.
Full text