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(Circulation Research. 2009;105:537.)
© 2009 American Heart Association, Inc.

Cellular Biology

NADPH Oxidase Nox2 Is Required for Hypoxia-Induced Mobilization of Endothelial Progenitor Cells

Katrin Schröder, Andreas Kohnen, Alexandra Aicher, Elisa A. Liehn, Tom Büchse, Stefan Stein, Christian Weber, Stefanie Dimmeler, Ralf P. Brandes

From the Institut für Kardiovaskuläre Physiologie (K.S., A.K., R.P.B.) and the Institut für kardiovaskuläre Regeneration (S.D., A.A.), Goethe-Universität, Frankfurt am Main, Germany; the Interdisciplinary Biomedical Research Centre (A.A.), School of Science and Technology, Nottingham Trent University, UK; the Institute for Molecular Cardiovascular Research (E.A.L., C.W.), RWTH Aachen University, Germany; the Institut für Medizinische Biochemie und Molekularbiologie (T.B.), Universität Rostock, Germany; and Georg-Speyer-Haus (S.S.), Frankfurt am Main, Germany.

Correspondence to Ralf P. Brandes, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail r.brandes{at}em.uni-frankfurt.de

Rationale: Endothelial progenitor cells (EPCs, defined as sca-1⁺flk-1⁺lin^– mononuclear blood cells) contribute to vascular repair. The role of hypoxia and reactive oxygen species (ROS) in mobilization and function of these cells is incompletely understood.

Objective: We studied the contribution of the NADPH oxidase Nox2, an important vascular source of ROS in this context.

Methods and Results: Hypoxia (10% oxygen) induced the mobilization of EPCs in wild-type (WT) and Nox1 but not in Nox2 knockout (Nox2^y/–) mice. As erythropoietin (EPO) is known to induce EPC mobilization, we focused on this hormone. EPO induced the mobilization of EPCs in WT and Nox1^y/– but not Nox2^y/– animals. Transplantation of bone marrow from Nox2^y/– mice into WT-mice blocked mobilization in response to hypoxia and EPO, whereas transplantation of WT bone marrow into Nox2^y/– mice restored mobilization. Reendothelialization of the injured mouse carotid artery was enhanced by hypoxia as well as by EPO, and this effect was not observed in Nox2^y/– mice or after transplantation of Nox2^y/– bone marrow. In cultured EPCs from WT but not Nox2^y/– mice, EPO induced ROS production, migration, and proliferation. EPO signaling involves the STAT5 transcription factor. EPO-induced STAT5-dependent reporter gene expression was absent in Nox2-deficient cells. siRNA against the redox-sensitive phosphatase SHP-2 restored EPO-mediated STAT5 induction and inhibition of SHP-2 restored EPO-induced migration in Nox2-deficient cells

Conclusions: We conclude that Nox2-derived ROS inactivate SHP-2 and thereby facilitate EPO signaling in EPCs to promote hypoxia-induced mobilization and vascular repair by these cells.

Key Words: oxidative stress • superoxide • NADPH oxidase