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Hétérogénéité des cellules musculaires lisses artérielles: implications dans l'athérosclérose et la resténose

English title Arterial smooth muscle heterogeneity: implications for atherosclerosis and restenosis
Applicant Bochaton-Piallat Marie-Luce
Number 130700
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 01.04.2010 - 31.03.2013
Approved amount 288'000.00
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Keywords (6)

Smooth muscle cells; Foam 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 proposed that SMCs from the arterial wall are phenotypically heterogeneous and hence that the media contains a SMC population prone to built up intimal thickening. The major goal of our research is to identify biomarkers typical of the atheroma-prone phenotype and subsequently to explore their role in the phenotypic modulation of intimal SMCs.We have isolated two distinct SMC populations, spindle-shaped (S) and rhomboid (R) SMCs, from the porcine coronary artery. R-SMCs are recovered in higher proportion from stent-induced intimal thickening and exhibit biological features that explain their capacity of accumulating in the intima. We have identified S100A4, a Ca2+-binding protein, as being a marker of the R-SMC population in vitro and of intimal SMCs in vivo, both in pig and human coronary arteries. We are investigating whether S100A4 is not only a biomarker of activated SMCS but also plays a role in phenotypic changes of SMCs. For this purpose we are exploring 2 possibilities: either decrease S100A4 in S100A4-containing SMCs i.e. R-SMCs or increase S100A4 in SMCs devoid of S100A4 i.e S-SMCs. Phenotypic SMC changes are explored using diverse criteria available for a long time in our laboratory such as proliferative, migratory, proteolytic and contractile activities, apoptosis, and cytoskeletal protein expression. We will also study the expression of S100A4 in arteries of hypercholesterolemic pigs and in human atherosclerotic and restenotic lesions. We have also isolated distinct SMC populations in human carotid arteries and plan to compare them by a proteomic approach to identify novel biomarker(s) of the atheroma-prone phenotype.Taken together, our results suggest that a better understanding of S100A4 expression, secretion and regulation in SMCs will help to shed light on the mechanisms of SMC accumulation in the intima. The ultimate aim of our work is the development of tools to influence the evolution of atherosclerotic and restenotic lesions.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Altered collagen expression in jugular veins in multiple sclerosis.
Coen Matteo, Menegatti Erica, Salvi Fabrizio, Mascoli Francesco, Zamboni Paolo, Gabbiani Giulio, Bochaton-Piallat Marie-Luce (2013), Altered collagen expression in jugular veins in multiple sclerosis., in Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 22(1), 33-8.
Smooth muscle cells of human intracranial aneurysms assume phenotypic features similar to those of the atherosclerotic plaque.
Coen Matteo, Burkhardt Karim, Bijlenga Philippe, Gabbiani Giulio, Schaller Karl, Kövari Enikö, Rüfenacht Daniel A, Ruíz Diego San Millán, Pizzolato Giampaolo, Bochaton-Piallat Marie-Luce (2013), Smooth muscle cells of human intracranial aneurysms assume phenotypic features similar to those of the atherosclerotic plaque., in Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 22(5), 339-44.
Autologous transplantation of culture-born myofibroblasts into intact and injured rabbit ligaments.
Laumonier Thomas, Michel Marlene, Gabbiani Giulio, Hoffmeyer Pierre, Bochaton-Piallat Marie-Luce, Menetrey Jacques (2012), Autologous transplantation of culture-born myofibroblasts into intact and injured rabbit ligaments., in International orthopaedics, 36(8), 1733-8.
Increased expression of adenosine triphosphate-sensitive K+ channels in mitral dysfunction: mechanically stimulated transcription and hypoxia-induced protein stability?
Raeis-Dauvé Véronique, Philip-Couderc Pierre, Faggian Giuseppe, Tessari Maddalena, Roatti Angela, Milano Aldo D, Bochaton-Piallat Marie-Luce, Baertschi Alex J (2012), Increased expression of adenosine triphosphate-sensitive K+ channels in mitral dysfunction: mechanically stimulated transcription and hypoxia-induced protein stability?, in Journal of the American College of Cardiology, 59(4), 390-6.
Targeting olfactomedin-like 3 inhibits tumor growth by impairing angiogenesis and pericyte coverage.
Miljkovic-Licina Marijana, Hammel Philippe, Garrido-Urbani Sarah, Lee Boris P-L, Meguenani Mehdi, Chaabane Chiraz, Bochaton-Piallat Marie-Luce, Imhof Beat A (2012), Targeting olfactomedin-like 3 inhibits tumor growth by impairing angiogenesis and pericyte coverage., in Molecular cancer therapeutics, 11(12), 2588-99.
Myofibroblast-mediated adventitial remodeling: an underestimated player in arterial pathology.
Coen Matteo, Gabbiani Giulio, Bochaton-Piallat Marie-Luce (2011), Myofibroblast-mediated adventitial remodeling: an underestimated player in arterial pathology., in Arteriosclerosis, thrombosis, and vascular biology, 31(11), 2391-6.
α-Smooth muscle actin and TGF-β receptor I expression in the healing rabbit medial collateral and anterior cruciate ligaments.
Menetrey Jacques, Laumonier Thomas, Garavaglia Guido, Hoffmeyer Pierre, Fritschy Daniel, Gabbiani Giulio, Bochaton-Piallat Marie-Luce (2011), α-Smooth muscle actin and TGF-β receptor I expression in the healing rabbit medial collateral and anterior cruciate ligaments., in Injury, 42(8), 735-41.
Endocellular polyamine availability modulates epithelial-to-mesenchymal transition and unfolded protein response in MDCK cells.
Prunotto Marco, Compagnone Alessandra, Bruschi Maurizio, Candiano Giovanni, Colombatto Sebastiano, Bandino Andrea, Petretto Andrea, Moll Solange, Bochaton-Piallat Marie Luce, Gabbiani Giulio, Dimuccio Veronica, Parola Maurizio, Citti Lorenzo, Ghiggeri Gianmarco (2010), Endocellular polyamine availability modulates epithelial-to-mesenchymal transition and unfolded protein response in MDCK cells., in Laboratory investigation; a journal of technical methods and pathology, 90(6), 929-39.
HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress.
Deakin Sara P, Bioletto Silvana, Bochaton-Piallat Marie-Luce, James Richard W (2010), HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress., in Free radical biology & medicine, 50(1), 102-9.

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Bridging gaps in cardiovascular knowledge International 2012

Associated projects

Number Title Start Funding scheme
116595 Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis 01.04.2007 Project funding
146790 Hétérogénéité des cellules musculaires lisses artérielles: implications dans l'athérosclérose et la resténose 01.04.2013 Project funding
116595 Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis 01.04.2007 Project funding

Abstract

During atherosclerosis and restenosis, smooth muscle cells (SMCs) migrate from the media toward the intima where they proliferate and undergo phenotypic changes. It has been proposed that SMCs from the arterial wall are phenotypically heterogeneous and hence that a subset of medial SMCs is prone to accumulate into the intima. The major goal of our research is to identify biomarkers typical of the atheroma-prone phenotype and subsequently to explore their role in the phenotypic modulation of intimal SMCs. We have isolated two distinct SMC populations, spindle-shaped (S) and rhomboid (R) SMCs, from the porcine coronary artery. R-SMCs are recovered in higher proportion from stent-induced intimal thickening (IT) and exhibit biological features that explain their capacity of accumulating in the IT. We have identifed S100A4, a Ca2+-binding protein, as being a marker of the R-SMC population in vitro and of intimal SMCs, both in pig and human coronary arteries.We have further investigated whether S100A4 plays a role in SMCs accumulating in the intima and thus tested the possibility that modulation of S100A4 expression induces phenotypic and biological changes in porcine coronary artery S- and R-SMC populations. Phenotypic SMC changes are explored using diverse criteria available for a long time in our laboratory such as proliferative, migratory, proteolytic and contractile activities, apoptosis, and cytoskeletal protein expression. Using silencing RNA and cDNA transfections in R- and S-SMCs, respectively, we have shown that S100A4 induces a switch from S- to R-phenotype with enhanced proliferation. We will continue this project by investigating the role of S100A4 in the migratory and contractile SMC activities. S100A4 can exist as an extracellular protein. We have hence set up a competitive ELISA assay using our homemade monoclonal S100A4 antibody and shown that S100A4 is secreted by the R-SMCs. We will explore the role of extracellular S100A4 on SMC phenotypic changes using tools such as recombinant S100A4 (rS100A4), specific peptides and neutralizing S100A4 antibodies. To examine in vivo the role of S100A4 in intimal SMC accumulation, we have set up a collaborative study with M. Grigorian (Institute of Cancer Biology, Copenhagen, Denmark) who will provide S100A4 genetically modified mice; we will then carry out balloon-induced IT, a technique available for a long time in our laboratory. In addition S100A4 distribution will be analyzed in experimental atherosclerotic plaques induced in hypercholesterolemic small-size pigs (supplied by L. Drouet, Lariboisière Hospital, Paris, France), an animal model that exhibits lesions close to the human one. Taken together, our results suggest that a better understanding of S100A4 expression, secretion and regulation in SMCs will help to shed light on the mechanisms of SMC accumulation in the intima.In parallel to the porcine study, we have isolated two distinct SMC populations, small and large, from the media of human carotid arteries (provided by F. Mascoli, University Hospital, Ferrara, Italy). It is noteworthy that atherosclerotic plaque macrophage-derived foam cells promote selective migration of small SMCs. Small SMCs exhibit biological features, including expression of S100A4, which explain their capacity of accumulating in the IT and hence represent an atheroma-prone phenotype. In the frame of this grant, we plan to compare the two populations by a proteomic approach in order to identify novel biomarker(s) of the atheroma-prone phenotype. We will test whether the newly identified molecules play a role in SMC phenotypic changes and whether they are expressed in human lesions. Moreover we plan to identify factor-derived foam cells and/or atherosclerotic plaque tissues involved in the selective growth of small SMCs. The effect of oxidized low density lipoproteins will be evaluated as well. We plan to use cytokine-antibody arrays that allow the profiling of cytokines release from foam cells or plaque tissues. Once identified, the role of different cytokine(s) on SMC phenotypic modulation will be investigated. We are convinced that the identification of differentially expressed protein(s) by the atheroma-prone populations will provide new insights into our understanding of atherosclerosis and restenosis.The ultimate aim of our work is the development of tools to influence the evolution of atherosclerotic and restenotic lesions.
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