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J. Biol. Chem., Vol. 283, Issue 17, 11435-11444, April 25, 2008

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Induction of Hypoxia-inducible Factor 1 Gene Expression by Vascular Endothelial Growth Factor^*

Juan José P. Deudero, Carlos Caramelo, María Carmen Castellanos, Fernando Neria, Ruth Fernández-Sánchez, Olalla Calabia, Silvia Peñate, and Francisco Román González-Pacheco¹

From the Laboratorio de Nefrología-Hipertensión, Fundación Jiménez Díaz-Capio and Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, 28040 Madrid, Spain

Transcriptional regulation of vascular endothelial growth factor (VEGF) is critically dependent on hypoxia-inducible factor 1 (HIF-1). However, not only hypoxia, but selected growth factors can induce HIF-1. High levels of both VEGF and HIF-1 coexist in certain conditions, e.g. tumors. Nonetheless, the possibility that the stimulatory relationship between HIF-1 and VEGF may be bi-directional has not been addressed up to date. The present study in endothelial cells analyzed whether HIF-1 is regulated by a product of its own transcriptionally activated genes, namely, VEGF. As a main finding, VEGF-A₁₆₅ induced the increase of HIF-1 mRNA and HIF-1 protein and nuclear translocation. Autologous endothelial cell VEGF mRNA and protein were also increased upon exposure to exogenous VEGF. The signaling implication of reactive oxygen species was examined by comparison with H₂O₂ and hypoxanthine/xanthine oxidase and by the superoxide dismutase mimetic, MnTMPyP, the Rac1-NAD(P)H oxidase complex inhibitor, apocynin, transfection of a dominant negative Rac1 mutant, and transfection of a p67phox antisense oligonucleotide. Superoxide anion, largely dependent on Rac1-NAD(P)H oxidase complex activity, was the critical signaling element. The transductional functionality of the pathway was confirmed by means of a reporter gene flanked by a transcription site-related VEGF sequence and by quantitative PCR. In summary, the present results reveal a previously undescribed action of VEGF on the expression of its own transcription factor, HIF-1, and on VEGF itself. This effect is principally mediated by superoxide anion, therefore identifying a new, potentially relevant role of reactive oxygen species in VEGF signaling.

Received for publication, May 10, 2007 , and in revised form, February 19, 2008.

We dedicate this work in memoriam of Dr. Carlos Caramelo.

^* This study has been supported by Red Cardiovascular of Instituto de Salud Carlos III (RECAVA), Fondo de Investigaciones de la Seguridad Social (FIS: PI030888; PI061247), Comunidad Autónoma de Madrid (CM, GR/SAL/0418/2004), CM-Acute Renal Failure Consortium, Fundación Conchita Rábago, Fundación Jiménez Díaz-CAPIO, Sociedad Española de Nefrología, Instituto Reina Sofía de Investigación Nefrológica, Janssen Cilag (Madrid, Spain), and Amgen SA (Barcelona, Spain). 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: Northwestern University, The Feinberg School of Medicine, 303 East Superior, Tarry Bldg. 4-750/752 Chicago, IL 60611. Tel.: 312-503-2923; Fax: 312-503–0622; E-mail: fromanglez{at}gmail.com.

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