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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 146790
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 01.04.2013 - 30.06.2016
Approved amount 343'960.00
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Keywords (7)

Apelin; Macrophages; S100A4; Restenosis; Smooth muscle cells; Calmodulin; Atherosclerosis

Lay Summary (French)

Lead
Lors de la formation de la plaque d’athérome et de la lésion resténotique, les cellules musculaires lisses (CMLs), normalement présentent dans un phénotype différencié dans la media, s’accumulent dans l’intima. L’hypothèse qu’une sous-population de CMLs de la média soit responsable de ce processus implique qu’elles soient hétérogènes.
Lay summary

Nous avons isolé deux populations différentes de CMLs de la coronaire du porc in vitro, les CMLs fusiformes et rhomboïdes. Les CMLs rhomboïdes se caractérisent par une prolifération et une migration accrues et un phénotype dédifférencié par rapport aux CMLs fusiformes; elles sont retrouvées en plus grande proportion dans l’intima. Nous avons identifié la S100A4 comme marqueur des CMLs rhomboïdes in vitro et des CMLs intimales in vivo, chez le porc comme chez l’homme.

La forme extracellulaire de la S100A4 joue un rôle primordial dans le développement du phénotype rhomboïde. Nous planifions d’utiliser la technique de microarray pour identifier les gènes cibles activés et les récepteurs impliqués dans ce processus.

L’apeline, dont le rôle dans l’athérosclérose n’est pas démontré, est exprimée dans le noyau des CMLs rhomboïdes. Nous aimerions étudier le rôle de l’apeline dans le changement phénotypique des CMLs.

Nous avons isolé deux populations distinctes de CMLs de la carotide humaine : les CMLs petites et grandes. La coculture de la media avec les macrophages de la plaque induit la migration des CMLs petites, qui sont similaires aux CMLs rhomboïdes de porc. La calmoduline est surexprimée dans les CMLs petites et joue un rôle dans le changement phénotypique de ces cellules. Afin d’identifier les cytokines/facteurs de croissance relachés par les macrophages, nous utilserons la technique de « cytokine array ».

L’étude de ces marqueurs devrait permettre d’élucider certains mécanismes d’accumulation des CMLs dans l’intima. Notre but ultime est le développement d’outils influençant l’évolution des lésions athérosclérotiques et resténotiques.

Direct link to Lay Summary Last update: 11.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The myofibroblast in wound healing and fibrosis: answered and unanswered questions.
Bochaton-Piallat Marie-Luce, Gabbiani Giulio, Hinz Boris (2016), The myofibroblast in wound healing and fibrosis: answered and unanswered questions., in F1000Research, 5, 1-6.
Extracellular S100A4 induces smooth muscle cell phenotypic transition mediated by RAGE.
Chaabane Chiraz, Heizmann Claus W, Bochaton-Piallat Marie-Luce (2015), Extracellular S100A4 induces smooth muscle cell phenotypic transition mediated by RAGE., in Biochimica et biophysica acta, 1853(9), 2144-57.
Lymphatic vessels: an emerging actor in atherosclerotic plaque development.
Kutkut Issa, Meens Merlijn J, McKee Thomas A, Bochaton-Piallat Marie-Luce, Kwak Brenda R (2015), Lymphatic vessels: an emerging actor in atherosclerotic plaque development., in European journal of clinical investigation, 45(1), 100-8.
Stable incorporation of α-smooth muscle actin into stress fibers is dependent on specific tropomyosin isoforms.
Prunotto Marco, Bruschi Maurizio, Gunning Peter, Gabbiani Giulio, Weibel Franziska, Ghiggeri Gian Marco, Petretto Andrea, Scaloni Andrea, Bonello Teresa, Schevzov Galina, Alieva Irina, Bochaton-Piallat Marie-Luce, Candiano Giovanni, Dugina Vera, Chaponnier Christine (2015), Stable incorporation of α-smooth muscle actin into stress fibers is dependent on specific tropomyosin isoforms., in Cytoskeleton (Hoboken, N.J.), 72(6), 257-67.
Smooth muscle cell phenotypic switch: implications for foam cell formation.
Chaabane Chiraz, Coen Matteo, Bochaton-Piallat Marie-Luce (2014), Smooth muscle cell phenotypic switch: implications for foam cell formation., in Current opinion in lipidology, 25(5), 374-9.
Biological responses in stented arteries.
Chaabane Chiraz, Otsuka Fumiyuki, Virmani Renu, Bochaton-Piallat Marie-Luce (2013), Biological responses in stented arteries., in Cardiovascular research, 99(2), 353-63.
Calmodulin expression distinguishes the smooth muscle cell population of human carotid plaque.
Coen Matteo, Marchetti Giovanna, Palagi Patricia M, Zerbinati Carlotta, Guastella Giuseppe, Gagliano Teresa, Bernardi Francesco, Mascoli Francesco, Bochaton-Piallat Marie-Luce (2013), Calmodulin expression distinguishes the smooth muscle cell population of human carotid plaque., in The American journal of pathology, 183(3), 996-1009.

Collaboration

Group / person Country
Types of collaboration
Prof. R. Virmani, CVPath Insitute, Gaithersburg, MD United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. C. Chaponnier, Department of Pathology and Immunology, University of Geneva, Geneva Switzerland (Europe)
- Publication
Prof. G. Thiene, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua Italy (Europe)
- Publication
Dr H. Hao, Hyogo College of Medicine, Hyogo Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
Dr Y. Audigier, CRCT, Université Toulouse III, CHU Rangueil, Toulouse France (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
6th Annual Meeting of the International Society for Neurovascular Disease Talk given at a conference Structural changes in extra-CNS blood vessels in neurodegeneration 29.04.2016 New York, NY, United States of America Bochaton-Piallat Marie-Luce;
Cardiovascular & Metabolic Research Conference 2016 Poster S100A4 is a key player of smooth muscle cell phenotypic transition: implications in atherosclerosis 14.01.2016 Fribourg, Switzerland Bochaton-Piallat Marie-Luce; Sakic Antonija;
Colloque de Diabétologie, HUG Individual talk S100A4, marqueur des cellules musculaires lisses de la plaque d’athérome: quelle fonction? 29.10.2015 Geneva, Switzerland Bochaton-Piallat Marie-Luce;
81st European Atherosclerosis Society Congress Poster Extracellular S100A4 promotes arterial smooth muscle cell phenotypic transition: implication in atherosclerosis and restenosis 02.06.2015 Lyon, France Chaabane Chiraz; Bochaton-Piallat Marie-Luce;
19th International Symposium on Calcium Binding Proteins and Calcium Function in Health and Disease Talk given at a conference S100A4 promotes smooth muscle cell phenotypic transition: implications in atherosclerosis 30.05.2015 Nashville, TN, United States of America Bochaton-Piallat Marie-Luce;
Angiogenesis and Leukocytes in Atherosclerosis Talk given at a conference Calcium-binding proteins in arterial smooth muscle cell phenotypic changes 30.01.2015 Geneva, Switzerland Bochaton-Piallat Marie-Luce;
Cardiovascular & Metabolic Research Conference 2015 Talk given at a conference Extracellular S100A4 induces smooth muscle cell transition mediated by RAGE 22.01.2015 Fribourg, Switzerland Bochaton-Piallat Marie-Luce; Chaabane Chiraz;
13th International Meeting of the European Calcium Society Talk given at a conference S100A4 and calmodulin promote smooth muscle cell phenotypic transition: implications in atherosclerosis 13.09.2014 Aix-en-Provence, France Bochaton-Piallat Marie-Luce;
European Society of Cardiology Congress 2014 Talk given at a conference Molecular basis of restenosis in the stent era 30.08.2014 Barcelona, Spain Bochaton-Piallat Marie-Luce;
Frontiers in CardioVascular Biology 2014 Poster Extracellular S100A4 induces arterial smooth muscle cell activation in a RAGE-dependent manner 04.07.2014 Barcelona, Spain Chaabane Chiraz; Bochaton-Piallat Marie-Luce;
Frontiers in CardioVascular Biology 2014 Talk given at a conference Role of nuclear targeting apelin induces phenotypic transition of vascular smooth muscle cells 04.07.2014 Barcelona, Spain Bochaton-Piallat Marie-Luce; Chaabane Chiraz;
Special lecture for the graduate students of Hyogo College of Medicine Individual talk Exploring smooth muscle cell heterogeneity in pig and human: discovery of novel biomarkers relevant for atherosclerosis 18.04.2014 Hyogo, Japan Bochaton-Piallat Marie-Luce;
18th International Vascular Biology Meeting Poster Extracellular and not intracellular S100A4 is a key modulator of arterial smooth muscle cell phenotypic changes 14.04.2014 Kyoto, Japan Chaabane Chiraz; Bochaton-Piallat Marie-Luce;
18th International Vascular Biology Meeting Poster Role of nuclear targeting apelin in vascular smooth muscle cell phenotypic changes: Implications in atherosclerotic plaque formation 14.04.2014 Kyoto, Japan Bochaton-Piallat Marie-Luce; Chaabane Chiraz;
Aneurysm/Endothelium and Smooth Muscle Cell Individual talk Calcium-binding proteins in arterial smooth muscle cell phenotypic changes 06.02.2014 Verona, Italy Bochaton-Piallat Marie-Luce;
Angiogenesis and Leukocytes in Atherosclerosis Poster Calmodulin expression distinguishes the smooth muscle cell population of the human carotid plaque 30.01.2014 Geneva, Switzerland Bochaton-Piallat Marie-Luce;
Angiogenesis and Leukocytes in Atherosclerosis Poster Role of nuclear targeting apelin in vascular smooth muscle cell phenotypic changes: Implications in atherosclerotic plaque formation. 30.01.2014 Geneva, Switzerland Bochaton-Piallat Marie-Luce; Chaabane Chiraz;
Cardiovascular & Metabolic Research Conference 2014 Poster Calmodulin expression distinguishes the smooth muscle cell population of the human carotid plaque 16.01.2014 Fribourg, Switzerland Bochaton-Piallat Marie-Luce;
Cardiovascular & Metabolic Research Conference 2014 Talk given at a conference Role of nuclear targeting apelin in vascular smooth muscle cell phenotypic changes: Implications in atherosclerotic plaque formation 16.01.2014 Fribourg, Switzerland Bochaton-Piallat Marie-Luce; Chaabane Chiraz;
Cardiovascular & Metabolic Research Conference 2014 Poster Extracellular and not intracellular S100A4 is a key modulator of arterial smooth muscle cell phenotypic changes 16.01.2014 Fribourg, Switzerland Chaabane Chiraz; Bochaton-Piallat Marie-Luce;
2013 International Society for Eye Research Sarasota Symposium Talk given at a conference Biological properties of the myofibroblast in health and disease 29.09.2013 Sarasota, FL, United States of America Bochaton-Piallat Marie-Luce;
European Society of Cardiology Congress 2013 Talk given at a conference Calcium binding proteins in smooth muscle cell differentiation 31.08.2013 Amsterdam, Netherlands Bochaton-Piallat Marie-Luce;
81st European Atherosclerosis Society Congress Poster Calmodulin expression distinguishes the smooth muscle cell population of the human carotid plaque 02.06.2013 Lyon, France Bochaton-Piallat Marie-Luce;
81st European Atherosclerosis Society Congress Poster Nuclear targeting of apelin in vascular smooth muscle cells: Implications in cell proliferation and atherosclerotic plaque formation? 02.06.2013 Lyon, France Chaabane Chiraz; Bochaton-Piallat Marie-Luce;
Course in Cardiovascular Science Individual talk Exploring smooth muscle cell heterogeneity in pig and human: discovery of novel biomarkers relevant for atherosclerosis 09.04.2013 University of Verona Medical School, Italy Bochaton-Piallat Marie-Luce;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Journée portes ouvertes Diabète & Obésité Western Switzerland 2015

Associated projects

Number Title Start Funding scheme
166357 S100A4 is a key player of smooth muscle cell phenotypic transition: implications for atherosclerosis 01.07.2016 Project funding
130700 Hétérogénéité des cellules musculaires lisses artérielles: implications dans l'athérosclérose et la resténose 01.04.2010 Project funding

Abstract

During atherosclerosis and restenosis, smooth muscle cells (SMCs) accumulate into the intima 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 display the features of an atheroma-prone phenotype. We have identified S100A4, a calcium-binding protein, as being a marker of the R-SMC population in vitro and of intimal SMCs, both in pig and man.Aim 1. We have demonstrated that the extracellular form of S100A4 is essential for the establishment of the R-phenotype and acts, to some extent, through the receptor for advanced glycation end products RAGE. In the frame of this grant application, we will characterize signaling pathways and genes involved in SMC phenotypic transition by means of microarray analysis comparing S-SMCs treated with conditioned medium containing or not extracellular S100A4. Our preliminary results show that 23 genes exhibit more than 10-fold increase. We will first focus our studies on the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) and on its role in SMC phenotypic changes. Codependence between RAGE/LOX-1 will be also explored. We have developed the tools to study and modulate SMC phenotypic changes, S100A4 and RAGE expression.Aim 2. Apelin is a small peptide hitherto poorly studied in SMCs. We have observed a nuclear expression of apelin in R-SMCs. Transfection of a plasmid containing nuclear-targeting apelin in S-SMCs (devoid of apelin) induces a phenotypic transition toward a R-phenotype, which is associated with increased nuclear expression of intracellular S100A4. We will confirm these unexpected results by thoroughly characterizing the SMC phenotypic changes induced by nuclear apelin overexpression and to clearly define whether apelin acts upstream S100A4. In parallel, we will explore the effect of secreted apelin in SMC phenotypic changes. Actin isoforms reveal a diverse organization in both SMC phenotypes. Therefore we will explore the relocalization of intracellular S100A4, from a stress-fiber like organization to a more diffuse pattern, by means of double immunofluorescence staining followed by confocal analysis using specific actin isoform antibodies and anti-S100A4.Aim 3. We have isolated two distinct SMC populations, small and large, from the media of human carotid arteries and observed that atherosclerotic plaque-derived macrophages promote selective migration of small SMCs, which represent an atheroma-prone phenotype. Moreover plaque-derived macrophages induce the large to small phenotypic transition. Calmodulin is overexpressed in small SMCs and plays a role in SMC phenotypic changes. In the frame of this grant, by using cytokine arrays, we plan to identify cytokine(s)/growth factor(s) released by plaque-derived macrophages, which are involved in the selective recruitment of small SMCs from the media and/or the large-to-small phenotypic transition. Once identified, the role of different cytokine(s) on SMC phenotypic modulation will be investigated.Aim 4. The relevance of molecules studied and identified in aims 1, 2 3 will be tested on human tissue specimens thanks to our network of collaboration with expert cardiovascular pathologist.Taken together, our results suggest that a better understanding of S100A4 expression, release and regulation in SMCs will help to shed light on the mechanisms of SMC accumulation in the intima. The identification of cytokines released by plaque-derived macrophages should help in dissecting the mechanisms of the crosstalk between macrophages and SMCs. The ultimate aim of our work is the development of tools to influence the evolution of atherosclerotic and restenotic lesions.
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