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(Circulation. 2009;119:2808-2817.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Microparticles From Ischemic Muscle Promotes Postnatal Vasculogenesis

Aurelie S. Leroyer, PhD; Téni G. Ebrahimian, PhD; Clément Cochain, MSc; Alice Récalde, MSc; Olivier Blanc-Brude, PhD; Barend Mees, MD; José Vilar, PhD; Alain Tedgui, PhD; Bernard I. Levy, MD, PhD; Giovanna Chimini, PhD; Chantal M. Boulanger, PhD; Jean-Sébastien Silvestre, PhD

From the Paris Cardiovascular Research Center, INSERM U970, Hôpital Européen Georges Pompidou, Université Paris-Descartes, Paris, France (A.S.L., T.G.E., C.C., A.R., O.B.-B., J.V., A.T., B.I.L., C.M.B., J.-S.S.); Departments of Vascular Surgery and of Cell Biology and Genetics Erasmus University Medical Center, Rotterdam, the Netherlands (B.M.); and Laboratory of Immunopathology, Faculty of Medicine, Université de la Mediterranee, Marseille, France (G.C.).

Correspondence to Jean-Sébastien Silvestre, PhD, Paris Cardiovascular Research Center, INSERM U970, Hôpital Européen Georges Pompidou, Université Paris-Descartes, 56 Rue Leblanc, 75015 Paris, France. E-mail Jean-Sebastien.Silvestre{at}inserm.fr

Received August 22, 2008; accepted March 27, 2009.

Background— We hypothesized that microparticles (MPs) released after ischemia are endogenous signals leading to postischemic vasculogenesis.

Methods and Results— MPs from mice ischemic hind-limb muscle were detected by electron microscopy 48 hours after unilateral femoral artery ligation as vesicles of 0.1- to 1-µm diameter. After isolation by sequential centrifugation, flow cytometry analyses showed that the annexin V⁺ MP concentration was 3.5-fold higher in ischemic calves than control muscles (1392±406 versus 394±180 annexin V⁺ MPs per 1 mg; P<0.001) and came mainly from endothelial cells (71% of MPs are CD¹⁴⁴⁺). MPs isolated from ischemic muscles induced more potent in vitro bone marrow–mononuclear cell (BM-MNC) differentiation into cells with endothelial phenotype than those isolated from control muscles. MPs isolated from atherosclerotic plaques were ineffective, whereas those isolated from apoptotic or interleukin-1β–activated endothelial cells also promoted BM-MNC differentiation. Interestingly, MPs from ischemic muscles produced more reactive oxygen species and expressed significantly higher levels of NADPH oxidase p47 (6-fold; P<0.05) and p67 subunits (16-fold; P<0.001) than controls, whereas gp91 subunit expression was unchanged. BM-MNC differentiation was reduced by 2-fold with MPs isolated from gp91-deficient animals compared with wild-type mice (P<0.05). MP effects on postischemic revascularization were then examined in an ischemic hind-limb model. MPs isolated from ischemic muscles were injected into ischemic legs in parallel with venous injection of BM-MNCs. MPs increased the proangiogenic effect of BM-MNC transplantation, and this effect was blunted by gp91 deficiency. In parallel, BM-MNC proangiogenic potential also was reduced in ABCA1 knockout mice with impaired vesiculation.

Conclusion— MPs produced during tissue ischemia stimulate progenitor cell differentiation and subsequently promote postnatal neovascularization.

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CLINICAL PERSPECTIVE

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Circulation 2009 119: 2749-2751. [Extract] [Full Text]