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J. Biol. Chem., Vol. 280, Issue 5, 3493-3499, February 4, 2005

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A Novel Role for Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Embryonic Stem Cells during Hypoxia^*

Koen Brusselmans, Françoise Bono, Désiré Collen, Jean-Marc Herbert, Peter Carmeliet, and Mieke Dewerchin¶

From the Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), KULeuven, Leuven, B-3000, Belgium andSanofiAventis Recherche, Cardiovascular/Thrombosis Research Department, Toulouse Cedex F31036, France

Vascular endothelial growth factor (VEGF) is best known for its angiogenic activity on endothelial cells, but it also affects neurons, pneumocytes, and other mature cell types as well as endothelial, neural, and hematopoietic progenitors. Here, we examined its effect on pluripotential embryonic stem (ES) cells under hypoxic stress. ES cells were found to produce VEGF and to express VEGF receptor-2 and neuropilin-1 (Nrp-1), a VEGF₁₆₅ isoform-specific receptor. During hypoxia, expression levels of VEGF, Flk-1, and Nrp-1 were elevated. Inhibition or targeted gene inactivation of VEGF increased ES cell apoptosis during prolonged hypoxia (48 h) by about 10-fold. The survival activity of VEGF was specific since inhibition of other growth factors (including basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor, platelet-derived growth factor, and placental growth factor) had no effect. Neuropilin-1 was involved in the VEGF-survival activity since overexpression of Nrp-1 decreased hypoxia-induced apoptosis about 3-fold. The hypoxia-response element, via which hypoxia-inducible transcription factors up-regulate VEGF expression under hypoxic conditions, was critical since targeted deletion of this element in the VEGF promoter enhanced hypoxia-induced ES cell apoptosis to the same extent as VEGF inhibition or gene inactivation. Thus, VEGF plays a critical role in survival of ES cells during prolonged hypoxia.

Received for publication, June 14, 2004 , and in revised form, November 22, 2004.

^* This work was supported by a postdoctoral fellowship from the Fund for Scientific Research-Flanders (Belgium) (FWO) (to K. B.) and European Union Grant BIOMED BMH4-CT98-3380 (to P. C. and D. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Center for Transgene Technology and Gene Therapy, VIB, KULeuven, Campus Gasthuisberg, Herestraat 49 bus 912, B-3000, Leuven, Belgium. Tel.: 32-16-34-57-75; Fax: 32-16-34-59-90; E-mail: mieke.dewerchin{at}med.kuleuven.ac.be.

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