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J. Biol. Chem., Vol. 283, Issue 35, 23791-23800, August 29, 2008

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The Foxc2 Transcription Factor Regulates Angiogenesis via Induction of Integrin β3 Expression^*

From the Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6300

Forkhead transcription factor Foxc2 is an essential regulator of the cardiovascular system in development and disease. However, the cellular and molecular functions of Foxc2 in vascular endothelial cells are still not fully understood. Here, through gene expression profiling in endothelial cells, we identified molecules associated with cell-extracellular matrix interactions, integrin β3 (Itgb3), integrin β5 (Itgb5), and fibronectin, as downstream targets of Foxc2. We found that Itgb3 expression is directly regulated by Foxc2 through multiple Forkhead-binding elements within two high homology regions in the Itgb3 promoter. Because Itgb3 is known to regulate angiogenesis, we further tested whether Foxc2 is directly involved in angiogenesis by regulating Itgb3 expression by in vitro experiments. Overexpression of Foxc2 significantly enhanced endothelial cell migration and adhesion, whereas this effect was strongly inhibited by Itgb3 neutralization antibody. In accordance with these results, pulmonary microvascular endothelial cells isolated from Foxc2 heterozygous mutant mice showed a marked reduction in Itgb3 expression and cell migration. Finally, ex vivo aortic ring assay to test the sprouting and microvessel formation revealed enhanced microvessel outgrowth by Foxc2 overexpression. Conversely, microvessel outgrowth from aortas of Foxc2 heterozygous mutant mice was reduced. Taken together, these results suggest that Foxc2 directly induces Itgb3 expression and regulates angiogenesis by Itgb3-mediated endothelial cell adhesion and migration.

Received for publication, January 9, 2008 , and in revised form, June 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL067105, DK068547, and HL074121 (to T. K.). 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 "Materials and Methods," Figs. 1–4, Table 1, and an additional reference.

¹ To whom correspondence should be addressed: Div. of Cardiovascular Medicine, Dept. of Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave., Nashville, TN 37232-6300. Tel.: 615-936-2884; Fax: 615-936-1872; E-mail: tsutomu.kume{at}vanderbilt.edu.

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