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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1093.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Preconditioning by Mitochondrial Reactive Oxygen Species Improves the Proangiogenic Potential of Adipose-Derived Cells-Based Therapy

Audrey Carrière; Téni G. Ebrahimian; Stéphanie Dehez; Nathalie Augé; Carine Joffre; Mireille André; Samuel Arnal; Micheline Duriez; Corinne Barreau; Emmanuelle Arnaud; Yvette Fernandez; Valérie Planat-Benard; Bernard Lévy; Luc Pénicaud; Jean-Sébastien Silvestre; Louis Casteilla

From the Université de Toulouse (A.C., S.D., C.J., M.A., S.A., M.D., C.B., E.A., Y.F., V.P.-B., L.P., L.C.) UPS, UMR 5241 Métabolisme, Plasticité et Mitochondrie, Toulouse Cedex 4, France; CNRS (A.C., S.D., C.J., M.A., S.A., M.D., C.B., E.A., U.F., V.P.-B., L.P., L.C.) UMR 5241 Métabolisme, Plasticité et Mitochondrie, Toulouse, France; Paris-Cardiovascular Research Center (T.G.E., B.L., J.-S.S.), INSERM U970, Hôpital Européen Georges Pompidou, Université Paris 5, France; and Inserm U858 - I2MR (N.A.), team 10, CHU Rangueil, Toulouse Cedex 4, France.

Correspondence to Louis Casteilla, UMR 5241 UPS CNRS, IFR31, IFR109, CHU Rangueil, BP 84225, 31432 Toulouse Cedex 4, France. E-mail louis.casteilla{at}inserm.fr

Objective— Transplantation of adipose-derived stroma cells (ADSCs) stimulates neovascularization after experimental ischemic injury. ADSC proangiogenic potential is likely mediated by their ability to differentiate into endothelial cells and produce a wide array of angiogenic and antiapoptotic factors. Mitochondrial reactive oxygen species (ROS) have been shown to control ADSC differentiation. We therefore hypothesized that mitochondrial ROS production may change the ADSC proangiogenic properties.

Methods and Results— The use of pharmacological strategies (mitochondrial inhibitors, antimycin, and rotenone, with or without antioxidants) allowed us to specifically and precisely modulate mitochondrial ROS generation in ADSCs. We showed that transient stimulation of mitochondrial ROS generation in ADSCs before their injection in ischemic hindlimb strongly improved revascularization and the number of ADSC-derived CD31-positive cells in ischemic area. Mitochondrial ROS generation increased the secretion of the proangiogenic and antiapoptotic factors, VEGF and HGF, but did not affect ADSC ability to differentiate into endothelial cells, in vitro. Moreover, mitochondrial ROS-induced ADSC preconditioning greatly protect ADSCs against oxidative stress-induced cell death.

Conclusion— Our study demonstrates that in vitro preconditioning by moderate mitochondrial ROS generation strongly increases in vivo ADSC proangiogenic properties and emphasizes the crucial role of mitochondrial ROS in ADSC fate.

Adipose-derived stroma cells possess a great potential to promote neovascularization in ischemic hindlimb. We demonstrated herein that in vitro preconditioning by moderate and transient mitochondrial ROS generation strongly enhanced adipose-derived cells proangiogenic properties in vivo, this being associated with an increase in angiogenic factors release and protection against oxidative stress-induced apoptosis.

Key Words: adipose tissue • stem cells • angiogenesis • oxidative stress • mitochondria