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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2321.)
© 2005 American Heart Association, Inc.

Vascular Biology

PAR-1 Activation on Human Late Endothelial Progenitor Cells Enhances Angiogenesis In Vitro With Upregulation of the SDF-1/CXCR4 System

David M. Smadja; Ivan Bièche; Georges Uzan; Heidi Bompais; Laurent Muller; Catherine Boisson-Vidal; Michel Vidaud; Martine Aiach; Pascale Gaussem

From INSERM Unité 428 and Hôpital Européen Georges Pompidou (AP-HP) (D.S., C.B.-V., M.A., P.G.), Université Paris V, Paris; Laboratoire de Génétique Moléculaire (I.B., M.V.), UPRES-EA 3618, Université Paris V, Paris; INSERM Unité 602 (G.U., H.B.), Hôpital Paul Brousse, Villejuif; INSERM Unité 36 (L.M.), Collège de France, Paris, France.

Correspondence to Pascale Gaussem, INSERM U 428, Service d’Hématologie Biologique A, Hôpital Européen Georges Pompidou, 20 rue Leblanc, F-75908 Paris Cedex 15, France. E-mail pascale.gaussem{at}egp.aphp.fr

Objectives— The importance of PAR-1 in blood vessel development has been demonstrated in knockout mice. As endothelial progenitor cells (EPCs) are involved in postnatal vasculogenesis, we examined whether they express PAR-1 and whether stimulation by the peptide SFLLRN modulates their angiogenic properties.

Methods and Results— EPC expanded from human CD34+ cord blood cells expressed PAR-1. PAR-1 activation induced EPC proliferation in a concentration-dependent manner far more potently than that of human umbilical vein endothelial cells. PAR-1 activation also enhanced actin reorganization, promoting both spontaneous migration in a Boyden chamber assay and migration toward SDF-1 and VEGF. As shown by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR), EPC stimulation by SFLLRN significantly enhanced the mRNA expression of SDF-1 and its receptor CXCR-4. PAR-1 activation also increased CXCR4 expression on EPC and induced SDF-1 secretion, leading to autocrine stimulation. PAR-1 stimulation by SFLLRN also increased the formation of capillary-like structures by EPC in Matrigel, and this effect was abrogated by anti-CXCR-4, anti-SDF-1, and MEK inhibitor pretreatment.

Conclusions— Human EPCs express functional PAR-1. PAR-1 activation promotes cell proliferation and CXCR4-dependent migration and differentiation, leading to a proangiogenic effect.

We provide evidence that human late endothelial progenitor cells express PAR-1, and that PAR-1 activation induces proliferation, migration and increased capillary-like structure formation in Matrigel. Analysis of this phenomenon showed that enhancement of the CXCR-4/SDF-1 pathway is a key mechanism underlying PAR-1-induced EPC angiogenesis.

Key Words: endothelial progenitor cell • PAR-1 • SFLLRN peptide • CXCR4/SDF1 pathway • cell therapy

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