Published Online
on July 17, 2006

A more recent version of this article appeared on July 25, 2006

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Submitted on September 19, 2005
Revised on May 18, 2006
Accepted on May 18, 2006

Increase in Vascular Permeability and Vasodilation Are Critical for Proangiogenic Effects of Stem Cell Therapy

Dong You MSc, Ludovic Waeckel MSc, Téni G. Ebrahimian MSc, Olivier Blanc-Brude PhD, Philippe Foubert MSc, Véronique Barateau , Micheline Duriez , Sophie LeRicousse-Roussanne PhD, José Vilar PhD, Elisabetta Dejana PhD, Gérard Tobelem MD, PhD, Bernard I. Lévy MD, PhD, and Jean-Sébastien Silvestre PhD^*

From the Cardiovascular Research Center, INSERM U689, Hôpital Lariboisière, Paris, France (D.Y., L.W., T.G.E., O.B.-B., M.D., J.V., B.I.L., J.S.); Institut des vaisseaux et du sang, Hôpital Lariboisière, Paris, France (P.F., V.B., S.L.-R., G.T.); and FIRC Institute of Molecular Oncology, Milan, Italy (E.D.).

^* To whom correspondence should be addressed. E-mail: Jean-Sebastien.Silvestre{at}larib.inserm.fr.

Background--Proangiogenic cell therapy based on administration of bone marrow-derived mononuclear cells (BMCs) or endothelial progenitor cells (EPCs) is now under investigation in humans for the treatment of ischemic diseases. However, mechanisms leading to the beneficial effects of BMCs and EPCs remain unclear.

Methods and Results--BMC- and CD34⁺-derived progenitor cells interacted with ischemic femoral arteries through SDF-1 and CXCR4 signaling and released nitric oxide (NO) via an endothelial nitric oxide synthase (eNOS)-dependent pathway. BMC-induced NO production promoted a marked vasodilation and disrupted vascular endothelial-cadherin/-catenin complexes, leading to increased vascular permeability. NO-dependent vasodilation and hyperpermeability were critical for BMC infiltration in ischemic tissues and their proangiogenic potential in a model of hindlimb ischemia in mice.

Conclusions--Our results propose a new concept that proangiogenic progenitor cell activity does not rely only on their ability to differentiate into endothelial cells but rather on their capacity to modulate the function of preexisting vessels.

Key words: angiogenesis • ischemia • nitric oxide • stem cells

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