14,260 research outputs found
Sudden coronary death in the young: Evidence of contractile phenotype of smooth muscle cells in the culprit atherosclerotic plaque
No full textCulprit coronary atherosclerotic plaques (APs) from young sudden cardiac death (SCD) victims are mostly non-atheromatous, i.e., consisting of proliferative smooth muscle cells (SMCs). Coronary vasospasm has been advocated to explain plaque instability in the absence of thrombosis. Our aim was to characterize the SMC phenotype in the intima and media of coronary arteries from young SCD victims
S100A4 is a key player for smooth muscle cell phenotypic transition: implications in atherosclerosis
No full textAtherosclerosis is the leading cause of cardiovascular disease worldwide. In atherosclerosis, smooth muscle cells (SMCs) accumulate in the intima where they undergo a transition from a contractile to a synthetic phenotype. During the two last decades, synthetic SMCs have been considered as beneficial players in atherosclerotic plaque development by essentially contributing to fibrous cap formation that protects plaque from rupture. However, SMCs exhibit a remarkable plasticity, and recent studies have demonstrated that a high proportion of SMCs in atherosclerotic plaques are hardly detectable with the classical SMC markers and acquire proinflammatory macrophage-like phenotype. We have previously identified S100A4 as a marker of the synthetic phenotype, both in vitro and in vivo in pigs and humans. The main project of this thesis aimed at deciphering the role of extracellular S100A4 in phenotypic transition of SMCs and atherosclerotic plaque progression. Our results indicated that extracellular S100A4 is causally related to atherosclerotic plaque progression, putting it forward as a prospective therapeutic target for plaque stabilization and/or regression
Characterization of SMCs isolated from wild type and S100A4 knock-out mice. Implications for Atherosclerosis
No full textAtherosclerosis is the leading cause of cardiovascular disease, the highest worldwide death accountee. It is mainly influenced by genetical and environmental factors. In atherosclerosis, smooth muscle cells (SMCs) play an important role. Our lab has identified two distinct phenotypes of SMCs isolated in vitro from pig coronary arteries: spindle-shaped SMCs (S-SMCs) and rhomboid (R-SMCs). R-SMCs acquire a synthetic phenotype during atherosclerosis and specifically express S100A4 in pig SMCs in vitro and human samples. The aim of this master thesis project was to decipher the role of intracellular S100A4 in the phenotypic switch of SMCs. By using the S100A4 KO mouse model we isolated and compared WT and KO SMCs in vitro using immunohistochemistry, western blot and migration assay experiment. We studied markers and pathways we know to be affected in SMCs during atherosclerosis, such as proliferation, migration, and inflammation. IFs done for a-SMA and S100A4 showed an increase of intracellular S100A4 (in WT cells) when cells are treated with PDGF-BB and S100A4 alone or in combination. We saw a decrease of a-SMA as well but only in PDGF-BB treated cells. Those results were confirmed by western blot and expected regarding previous experiments done on pig SMCs. Western blot analysis showed a higher amount of myosin in KO cells compared to WT. Migration assay with Boyden chamber showed a lack of migratory activity for S100A4 KO SMCs for all conditions which could be related to myosin disregulation. In conclusion, during my thesis, we show that Intracellular S100A4 expression in SMCs seems to have an impact on their migration capacity which they need to move from the media to the intima during early atherosclerosis development. This deficiency might be caused by an impairement of the interaction between S100A proteins family and myosin filaments which they regulate its disassembly. Further experiments should be done in order to confirm this hypothesis
Role of smooth muscle cell-derived S100A4 in mouse experimental models of atherosclerosis and restenosis
No full textCardiovascular disease is still the leading cause of death worldwide, comprising, among others, coronary heart disease, cerebrovascular disease, and peripheral arterial disease. The main cause for cardiovascular disease is atherosclerosis, which develops over decades in the intima of medium and large arteries. Smooth muscle cells (SMCs) play major roles during the development of atherosclerosis, where they are known to migrate from the media and accumulate in the intima, undergoing a transition from contractile to synthetic phenotype. This process is characterized by cell dedifferentiation, which is accompanied by an alteration in the expression of contractile proteins, as well as an increased production of extracellular matrix components. For the last three decades, synthetic SMCs have been addressed as beneficial players since their role in atherosclerosis was to contribute to the fibrous cap formation and prevent plaque rupture. However, this notion has been changing. Thanks to the implementation of cellular lineage-tracing techniques both in mouse (Cre-Lox system) and in human (epigenetic markers), it has been shown that SMCs dedifferentiate towards several distinct phenotypes. Some of them retain the SMC-lineage identity (therefore easily identified), while others lose it almost completely and start expressing markers typical of different cell lineages (e.g. foam cell-like, macrophage-like, and chondrocyte-like). Therefore, there is still a need for specific marker(s) of the synthetic/dedifferentiated phenotypes. Our group previously identified S100A4 as a marker of the synthetic phenotype, both in vitro and in vivo, in mouse, pig and human. This small calcium-binding protein exhibits intra‐ and extracellular functions, which are not fully understood. The aim of my project was to investigate and shed some light on the role of S100A4 in SMC phenotypic transition and atherosclerosis
Role of S100A4 in the crosstalk between smooth muscle and immune cells
No full textDuring atherosclerotic plaque formation, smooth muscle cells (SMCs) accumulate in the intima and undergo a transition from a contractile to a synthetic phenotype, influencing disease progression. In a co-culture model between S100A4-stimulated human aortic SMCs and human monocytes, we demonstrated that monocytes up-regulated markers typical of anti-inflammatory M2 macrophages and adjusted metabolism of cholesterol. In vivo, we identified S100A4-expressing SMCs in the mouse aortic media prior their accumulation in the intima. Characterization of medial SMCs by means of single-cell RNA sequencing revealed heterogeneity among S100A4-expressing medial SMCs. We investigated the impact of blood-derived monocytes and extracellular S100A4 on the atherosclerosis progression in vivo. Unexpectedly, monocyte depletion led to larger atherosclerotic lesions compared to control animals, while S100A4 neutralization had no visible impact on the lesion area. Our findings shed light on the role of S100A4 in the crosstalk between SMCs and monocytes in atherosclerosis.</p
The Politics of Respectability in Luce
No full textAuthor: Apryl Alexander University of Denver Download PDF version What is Luce about? Effects of childhood trauma? Difficulties of adolescence? Transracial adoptions? Teenage psychopaths? All the above? Luce (2019) is the complicated story of a high-achieving Black male high schooler (Luce, played by Kelvin Harrison Jr.) who is facing difficulty with his teacher Ms. Wilson (Octavia Spencer). Luce was adopted by two white parents when he was a young child from Eritrea and his parents all..
Aging, smooth muscle cells and vascular pathobiology: Implications for atherosclerosis
No full textEpidemiological and autopsy studies suggest a close link between aging and the clinical manifestation of atherosclerosis. Several experiments show increased arterial susceptibility to atherogenetic stimuli in aged subjects. All together, these findings support the concept that aging represents an independent atherogenetic risk factor, intimately associated to other parietal, microenvironmental and systemic noxae. Smooth muscle cells (SMCs) represent the major arterial cell population. As aging occurs, SMCs progressively migrate from the tunica media and accumulate into the tunica intima. Myointimal thickening may represent the site where low-grade atherogenic stimuli cause early development and more severe lesion progression. Intimal SMC accumulation is characterized from a switch, from a differentiated to a synthetic phenotype, with reduced myocytic cytoskeletal markers and the expression of new proteins. Aging also associates to changes of SMC proliferative and apoptotic behavior and response to growth factors, such as transforming growth factor-β1. The alteration of SMC properties represents a crucial event in the pathobiology of arterial wall, since it contributes to the vascular remodeling and decline of function with aging and favors the progression of atherosclerosis. Increased knowledge of biomolecular mechanisms regulating these events helps to develop new strategies aimed at contrasting the adverse effect of vascular aging. © 2006 Elsevier Ireland Ltd. All rights reserved
Human arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis
No full textCardiovascular disease is a global health problem. Atherosclerosis, a chronic, systemic inflammatory disease that involves the walls of the large- and medium-sized elastic arteries and large muscular arteries represents the disease underlying the occurrence of cardiovascular disease. Smooth muscle cells (SMCs), the most abundant cell type in blood vessels wall, play a pivotal role in the pathogenesis of atherosclerosis. During atherogenesis SMCs shift from a differentiated/contractile phenotype toward a dedifferentiated/synthetic state, finally culminating in the formation of the atheromatous plaque. The question remains open as to whether intimal SMCs derive from contractile SMCs through a process of dedifferentiation (the expression of SMC plasticity), or whether they result from a pre-existing SMC subpopulation in the media that is prone to be activated (atheroma-prone phenotype) and to migrate into the intima. In the first part (chapter 1) of this thesis, we describe the epidemiology of cardiovascular disease, as well as the pathogenesis of atherosclerosis and the role of SMCs in atherogenesis. In Chapter 2 of this thesis, we describe our observation that a SMC population harbouring the features of an atheroma-prone phenotype, and characterized by high levels of CaM, can be selectively isolated from the human carotid artery media only when in the presence of macrophage-derived foam cells from plaque. In Chapter 3, we demonstrate that a transition from a contractile to a synthetic SMC phenotype takes place within the media of intracranial aneurysms within, thus suggesting that SMC phenotypic switch is not exclusive to atherosclerotic plaque formation but occurs –and likely plays a role- also in aneurysm formation. In Chapter 4, we investigate the histopathology of extracranial venous wall in multiple sclerosis patients affected by chronic cerebrospinal venous outflow insufficiency. We describe alterations of the vessel lumen that are not accompanied by changes in medial SMC phenotype, but rather by a peculiar organisation of advential collagen fibers. In Chapter 5, we review the current literature supporting the underestimated role of the adventitial myofibroblasts in atherosclerosis and vascular remodeling. Finally (chapter 6), the different topics of my thesis are discussed in a systematic manner
Hétérogénéité phénotypique des cellules musculaires lisses artérielles du rat au cours du développement et du vieillissement
No full textLa différenciation des cellules musculaires lisses (CML) artérielles est caractérisée par une accumulation de protéines cytosquelettiques telles que l'actine α-musculaire lisse, la desmine et la myosine musculaire lisse. L'expression de ces protéines diminue fortement lors de la formation de la plaque athéromateuse humaine et l'épaississement intimal expérimental provoqué par une lésion endothéliale. En étudiant les protéines cytosquelettiques et les CML aortiques isolées de rats d'âge différent cultivées comme populations parentales et clonales, nous avons montré que la capacité de réplication et la dédifférenciation des CML augmentent avec l'âge de l'animal. Les CML sont hétérogènes au sein d'une même population, et possèdent des caractéristiques différentes en fonction de l'âge de l'animal. In vivo, la lésion endothéliale de l'aorte stimule la prolifération d'une sous-population de CML qui peut dériver des CML qui soit se sont activement répliquées après la naissance, soit ont arrêté leur réplication avant la naissance. Cette seconde possibilité laisse ouverte la question de l'existence de "cellules souches" dans la média. Nos résultats suggèrent que les CML possèdent des propriétés intrinsèques leur permettant de réagir individuellement à des changements du microenvironnement. L'âge, facteur de risque indépendant pour l'athérosclérose, influence fortement ces propriétés
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