Apelin; Macrophages; Atherosclerosis; Smooth muscle cells; S100A4; Restenosis
Rizzo Stefania, Coen Matteo, Sakic Antonija, De Gaspari Monica, Thiene Gaetano, Gabbiani Giulio, Basso Cristina, Bochaton-Piallat Marie-Luce (2018), Sudden coronary death in the young: Evidence of contractile phenotype of smooth muscle cells in the culprit atherosclerotic plaque, in International Journal of Cardiology
, 264, 1-6.
Dorotheou Domna, Bochaton-Piallat Marie-Luce, Giannopoulou Catherine, Kiliaridis Stavros (2018), Expression of α-smooth muscle actin in the periodontal ligament during post-emergent tooth eruption, in Journal of International Medical Research
, 46(6), 2423-2435.
Bochaton-Piallat Marie-Luce, Bäck Magnus (2018), Novel concepts for the role of smooth muscle cells in vascular disease: towards a new smooth muscle cell classification
, 114(4), 477-480, Oxford University Press, Oxford 114(4), 477-480.
Allahverdian Sima, Chaabane Chiraz, Boukais Kamel, Francis Gordon A, Bochaton-Piallat Marie-Luce (2018), Smooth muscle cell fate and plasticity in atherosclerosis, in Cardiovascular Research
, 114(4), 540-550.
Bochaton-Piallat Marie-Luce, Kindler Vincent, Lecarpentier Yves, Schussler Olivier, Sakic Antonija, Rincon-Garriz José Maria, Soulie Priscilla (2018), Human Bone Marrow Contains Mesenchymal Stromal Stem Cells That Differentiate In Vitro into Contractile Myofibroblasts Controlling T Lymphocyte Proliferation, in Stem Cells International
, 2018, 1-15.
Ridger Victoria C., Boulanger Chantal M., Angelillo-Scherrer Anne, Badimon Lina, Blanc-Brude Olivier, Bochaton-Piallat Marie-Luce, Boilard Eric, Buzas Edit I., Caporali Andreas, Dignat-George Francoise, Evans Paul C., Lacroix Romaric, Lutgens Esther, Ketelhuth Daniel F. J., Nieuwland Rienk, Toti Florence, Tuñon Jose, Weber Christian, Hoefer Imo E. (2017), Microvesicles in vascular homeostasis and diseasesPosition Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology, in Thrombosis and Haemostasis
, 117(07), 1296-1316.
Vasileva Ekaterina, Sluysmans Sophie, Bochaton-Piallat Marie-Luce, Citi Sandra (2017), Cell-specific diversity in the expression and organization of cytoplasmic plaque proteins of apical junctionsCytoplasmic plaque proteins of apical junctions, in Annals of the New York Academy of Sciences
, 1405(1), 160-176.
During atherosclerosis and restenosis, smooth muscle cells (SMCs) are known to accumulate into the intima and to switch from a contractile to a synthetic phenotype. In our model, we isolated two distinct SMC populations, spindle-shaped (S-) and rhomboid (R-) SMCs from the porcine coronary artery; the R-phenotype represents the synthetic phenotype. We further identified S100A4 as a marker of R-SMCs in vitro and of intimal SMCs in both pigs and humans. Recently we have shown 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). Remarkably, S-SMCs treated with S100A4-rich conditioned medium (CM, collected from S100A4-transfected SMCs) acquire pro-inflammatory properties. In the frame of this grant, we will continue our studies on the role of S100A4 in porcine SMC phenotypic transition and atherosclerotic plaque formation.Aim 1. We have preliminary shown that multimeric recombinant S100A4 induces a transition from S- to R-phenotype. We will confirm that the multimeric recombinant S100A4 is exclusively responsible for this phenotypic transition and whether it recapitulates the pro-inflammatory properties observed after treatment of S-SMCs with S100A4-rich CM. The SMC phenotype will be characterized using SMC differentiation marker expression, proliferation, apoptosis, and migration assays. The pro-inflammatory profile of SMCs will be characterized by matrix metalloproteinase (MMP) and their inhibitor (TIMP) expression. These results will be strengthen by treating S-SMCs with S100A4-rich CM containing neutralizing S100A4 antibody. To decipher the signaling pathways induced by the multimeric recombinant S100A4, we will first explore the possible implication of RAGE. Based on a microarray assay data comparing S-SMCs treated with CM containing or not extracellular S100A4 and bio-informatics analysis, we will investigate the role of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) and Toll-like receptor-4 (TLR4) in SMC phenotypic transition. Codependence between RAGE/LOX-1 and RAGE/TLR4 will be also explored. The unexpected upregulation of granulocyte macrophage-colony stimulating factors (GM-CSF) gene, detected by microarray assay, provides new perspectives on the possible activation of monocytes by SMCs. We will examine whether extracellular S100A4-treated SMCs yield GM-CSF secretion and further induce monocyte activation. Finally, we will perform a cytokine array to identify additional factor(s) present in S100A4-rich CM, possibly involved in the S- to R-phenotypic transition.Aim 2. We will investigate whether altered S100A4 expression is causally related to the formation of restenotic and atherosclerotic lesions. For this purpose we will perform balloon catheter injury in carotid arteries (a model of restenosis) of S100A4-/-ApoE-/- mice as well as of ApoE-/- mice simultaneously treated with a neutralizing S100A4 antibody. In addition S100A4-/-ApoE-/- mice, fed with a high-cholesterol diet, will be studied for atherosclerotic plaque development. The size and composition of the lesions will be further analyzed.Aim 3. We have preliminarily observed that apelin, a small peptide hitherto poorly studied in SMCs, is involved in SMC phenotypic transition and we will hence study its relationship with intra and extracellular S100A4. 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 expression of S100A4. We will confirm these unexpected results by thoroughly characterizing the SMC phenotypic transition induced by nuclear apelin overexpression and to clearly define whether apelin acts upstream or downstream of S100A4. In parallel, we will explore the effects of secreted apelin in SMC phenotypic transition. 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 ultimate aim of our work is the development of tools to influence the evolution of atherosclerotic and restenotic lesions.