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J. Biol. Chem., Vol. 281, Issue 46, 35544-35553, November 17, 2006

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A Novel Class of Vascular Endothelial Growth Factor-responsive Genes That Require Forkhead Activity for Expression^*

Md. Ruhul Abid¹, Shu-Ching Shih, Hasan H. Otu^¶, Katherine C. Spokes, Yoshiaki Okada, David T. Curiel^||, Takashi Minami^**2, and William C. Aird

From the Center for Vascular Biology Research, Department of Medicine, the Divisions of Molecular and Vascular Medicine, Department of Pathology, and ^¶Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, the ^||Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology, Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, and the ^**Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153, Japan

Recently, we have shown that transient phosphorylation and inhibition of the pro-apoptotic transcription factor, forkhead, by vascular endothelial growth factor (VEGF) is essential for endothelial cell (EC) survival and proliferation. The goal of the present study was to determine whether forkhead (FKHR) also plays a positive role in agonist-mediated gene induction. Human coronary artery ECs were transduced with adenovirus overexpressing constitutively active phosphorylation-resistant triple mutant FKHR or transfected with small interference RNA (siRNA) against FKHR. The cells were then treated in the absence or presence of VEGF and assayed for gene expression using quantitative real-time PCR and Northern blots analyses. The data revealed a novel set of VEGF-responsive genes that require FKHR activity for optimal expression in ECs, including bone morphogenic protein 2, cbp/p300-interacting transactivator 2, decay accelerating factor (DAF), vascular cell adhesion molecule-1 (VCAM-1), manganese superoxide dismutase, endothelial-specific molecule-1, RING1 and YY1-binding protein, and matrix metalloproteinase-10. Consistent with a positive role for FKHR in mediating VEGF induction of DAF and VCAM-1 mRNA, siRNA against FKHR attenuated the effect of VEGF on complement-mediated EC lysis and monocyte adhesion, respectively. VEGF induction of the forkhead-dependent genes was down-regulated by the NF-B inhibitor, constitutively active Ad-IB, and in some cases by the nuclear factor of activated T-cells (NF-AT) inhibitor, cyclosporin. Together, these findings suggest that the VEGF-forkhead signaling axis plays an important functional role in ECs beyond the regulation of cell survival/apoptosis and cell cycle.

Received for publication, September 6, 2006

^* This work was supported in part by National Institutes of Health Grant HL077348 (to W. C. A. and M. R. A.) and American Heart Association Grant SDG 0453284N (to M. R. A.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

² Supported by the Science and Technology from Ministry of Education, Culture, Sports, Sciences and Technology, and the Takeda Science Foundation, Japan.

¹ To whom correspondence should be addressed: Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, E/RW-663, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-1025; Fax: 617-667-2913; E-mail: rabid{at}bidmc.harvard.edu.

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