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J. Biol. Chem., Vol. 283, Issue 37, 25404-25413, September 12, 2008

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Activation of the VEGFR1 Chromatin Domain

AN ANGIOGENIC SIGNAL-ETS1/HIF-2 REGULATORY AXIS^*

From the Institute of Maternal-Fetal Biology and the Division of Cancer and Developmental Biology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160

Angiogenesis is induced by multiple growth factors including vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). In vascular endothelium VEGF signals through two receptor-tyrosine kinases, VEGFR1 and VEGFR2. The VEGFR1 gene encodes both a receptor-tyrosine kinase and a secreted splice variant, soluble VEGFR1. Whereas VEGFR1 is essential for vascular development, mechanisms that regulate VEGFR1 expression in endothelial cells are poorly understood. We demonstrate here that in endothelial cells, FGF2 and epidermal growth factor (EGF) signaling induce VEGFR1 mRNA expression in a combinatorial fashion. EGF/FGF2-mediated VEGFR1 induction is mediated via functional interaction of transcription factors ETS1 and HIF-2. Mechanistic analyses revealed that in endothelial cells EGF/FGF2 signaling induces ETS1 expression, increases HIF-2 protein level in absence of hypoxia, and recruits both ETS1 and HIF-2 to the VEGFR1 chromatin domain. Knockdown of ETS1 and HIF-2 by RNA interference inhibits EGF/FGF2-induced VEGFR1 expression, and loss of expression is associated with impaired RNA-polymerase II recruitment and histone modifications at the VEGFR1 promoter region. In addition, using a mouse embryonic stem cell in vitro differentiation system, we found that induction of VEGFR1 in embryoid bodies is also associated with ETS1 and HIF-2 recruitment to the VEGFR1 locus. These results establish an angiogenic signal-ETS1/HIF-2 axis that regulates the VEGFR1 chromatin domain to induce VEGFR1 transcription in endothelial cells and in differentiating embryonic stem cells.

Received for publication, June 5, 2008 , and in revised form, July 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant P20 RR16475 (Kansas INBRE). This work was also supported by the University of Kansas Cancer Center. 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.

¹ To whom correspondence should be addressed: Institute of Maternal-Fetal Biology, Dept. of Pathology and Laboratory Medicine, University of Kansas Medical Center, KS City, KS 66160. Tel.: 913-588-7236; Fax: 913-588-8287; E-mail: spaul2{at}kumc.edu.

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