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Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis

English title Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis
Applicant Bochaton-Piallat Marie-Luce
Number 116595
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Pathophysiology
Start/End 01.04.2007 - 31.03.2010
Approved amount 260'967.00
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Keywords (6)

smooth muscle cells; endothelial cells; restenosis; atherosclerosis; S100A4; alpha-smooth muscle actin

Lay Summary (English)

Lead
Lay summary
Atherosclerosis and its dramatic clinical complications ischemia and infarction of the heart, brain and other vital organs, ruptured aortic aneurysms and peripheral vascular insufficiency, are the leading causes of illness and death in Western civilization. Atherosclerosis affects arteries. The artery wall is divided into 3 distinct concentric layers: 1) the intima composed of the endothelium, which is a barrier between circulating blood and vascular wall, 2) the media that consists of smooth muscle cells (SMCs) responsible of vessel contraction, and 3) the adventitia.During atherosclerosis, SMCs migrate from the media and accumulate into the intima where they undergo phenotypic changes. It has been suggested that the media contains a SMC population prone to built up intimal thickening (IT). This implies that SMCs are heterogeneous. Several research groups, including ours, have obtained phenotypically different SMC populations in the rat. However, attempts to identify biochemical markers of the intimal SMC phenotype relevant to human lesions have failed.In order to develop a model closer to the human situation, we have isolated two distinct SMC populations, spindle-shaped (S) and rhomboid (R) SMCs, from the porcine coronary artery. R-SMCs are characterized by highly proliferative, migratory and proteolytic activities and a dedifferentiated phenotype compared to S-SMCs. R-SMCs are recovered in higher proportion from stent-induced IT compared to media, suggesting that they participate predominantly to IT formation. We have identified S100A4 as being a marker of the R-SMC population in vitro. S100A4 belongs to the S100 Ca2+-binding protein family. It is known to play a crucial role in tumor cell metastasis. The receptor for advanced glycation end products (RAGE) is the putative receptor of S100A4 and is associated to atherosclerotic complications. In vivo, S100A4 is absent in the media and is overexpressed in SMCs of experimentally-induced IT in porcine coronary artery and of IT, atheromatous plaques and restenotic lesions in humans. Therefore S100A4 appears to represent a novel marker of SMC activation during the development of the atheromatous lesions.We hypothesize that S100A4 in addition to be a marker of SMCs accumulating in the intima plays a role in this process. Therefore our first purpose is to test the possibility that modulation of S100A4 expression induces phenotypic and biological changes using the two well characterized porcine coronary artery S- and R-SMC populations. We will also study the expression of S100A4 in porcine coronary artery IT induced after stent implantation and hypercholesterolemic diet and in human atherosclerotic and restenotic lesions. RAGE expression will be also evaluated.We are convinced that our studies will facilitate the understanding of the mechanisms responsible for the progression of atherosclerosis plaque and restenosis. Ultimately, the development of tools influencing S100A4 may prevent SMC accumulation in the intima and facilitate plaque regression.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
130700 Hétérogénéité des cellules musculaires lisses artérielles: implications dans l'athérosclérose et la resténose 01.04.2010 Project funding
130700 Hétérogénéité des cellules musculaires lisses artérielles: implications dans l'athérosclérose et la resténose 01.04.2010 Project funding

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