O5	Role of smooth muscle cell progenitors on atherosclerotic plaque development and stability.
1J.Zoll, 1S.Le Ricousse-Roussanne, 2V.Fontaine, 2P.Gourdy, 1I.Lopes-Kam, 1Z.Mallat, 2J-F.Arnal, 3P.Henry, 1G.Tobelem, 1A.Tedgui
1INSERM U689, Paris, FR; 2INSERM U589, Toulouse, FR; 3Service cardiologie, Paris, FR.

The risk of plaque rupture appears to depend critically on the fibrous cap components of an advanced atherosclerotic plaque. Endothelial (EPC) and smooth muscle (SPC) progenitor cells have been implicated in the formation and progression of atherosclerotic lesions. We hypothesized that SPC could play a protective role by promoting atherosclerosis plaque stability. To that end, we conducted experiments in ApoE-/- mice injected with EPC or SPC and we determined plasma levels of SPC in patients with acute coronary syndrome (ACS). Methods and Results Twelve-week-old male ApoE-/-RAG2-/- knockout mice (25±0.4g) received intravenous injection of saline (control group, n=6), 5.105 SPC (SPC group, n=5), or 5.105 EPC (EPC group, n=7), both derived from human umbilical cord blood. Animals fed a high-fat diet beginning 1 week before the first injection, and received 4 successive injections every 2 weeks. Circulating SPCs were quantified from plasmatic bone marrow cells (PBMC) of 10 stable angina and 9 ACS patients. PBMCs were cultured on collagen I coated plaque in the presence of PDGF for 2 weeks. We found that in mice treated with SPC the development of atherosclerosis in the aortic sinus was reduced by 40% compared with control mice (aortic sinus lesion area were 222624±42224µm2 in control vs 128678±27000µm2 in SPC, P<0.1). The macrophage content tended to decrease in the SPC group (-38%, p=0.08). Smooth muscle cell (SMC) and collagen contents were significantly increased in the aortic sinus of SPC group by 245% (P=0.003) and by 76% (P=0.01), respectively compared to control-treated mice. In EPC group, no change in lesion size, macrophage, or SMC contents was observed compared to controls. The numbers of isolated SPC (Myosine Heavy Chain positive cells) were significantly reduced by 73% in ACS patients compared to stable angina patients (P<0.05). Conclusions The present study demonstrates that SPC can limit plaque development and promote substantial changes in plaque composition towards a more stable phenotype in mice. Then, the reduced level of SPCs in ACS patients may represent a mechanism contributing to the plaque destabilization.

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