on September 1, 2005
Published online before print September 1, 2005, doi: 10.1161/01.ATV.0000184762.63888.bd
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Submitted on April 29, 2005
Accepted on August 5, 2005
PAR-1 Activation on Human Late Endothelial Progenitor Cells Enhances Angiogenesis In Vitro With Upregulation of the SDF-1/CXCR4 System
David Smadja ;
From INSERM Unité 428 and Hôpital Européen Georges Pompidou (AP-HP) (D.S., C.B.-V., M.A., P.G.), Université Paris V, Paris, France; Laboratoire de Génétique Moléculaire (I.B., M.V.), UPRES-EA 3618, Université Paris V, Paris, France; INSERM Unité 602 (G.U., H.B.), Hôpital Paul Brousse, Villejuif, France; INSERM Unité 36 (L.M.), Collège de France, Paris.
* To whom correspondence should be addressed. 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.
Key words: endothelial progenitor cell • PAR-1 • SFLLRN peptide • CXCR4/SDF1 pathway • cell therapy
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