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(Circulation. 2006;114:328-338.)
© 2006 American Heart Association, Inc.

Vascular Medicine

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; 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.).

Correspondence to Jean-Sebastien Silvestre, PhD, INSERM U689, Hopital Lariboisière, 41 boulevard de la chapelle, 75475 Paris Cedex 10, France. E-mail Jean-Sebastien.Silvestre{at}larib.inserm.fr

Received September 19, 2005; revision received May 18, 2006; accepted May 18, 2006.

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/ß-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.

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