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J. Biol. Chem., Vol. 279, Issue 6, 4862-4868, February 6, 2004

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The Homeobox Transcription Factor Hox D3 Promotes Integrin ₅₁ Expression and Function during Angiogenesis^*

Nancy J. Boudreau and Judith A. Varner¶

From the Department of Surgery, University of California, San Francisco, California 94143 and the Department of Medicine and Comprehensive Cancer Center, University of California, San Diego, California 92093

Neovascularization promotes wound healing, tumor growth, and arthritis. Endothelial cell migration and survival during neovascularization are regulated by adhesion proteins, including integrin ₅₁. Integrin ₅₁ is poorly expressed on normal quiescent blood vessels, but its expression is induced on tumor blood vessels and in response to angiogenic factors such as basic fibroblast growth factor, interleukin-8, tumor necrosis factor-, and the angiomatrix protein Del-1. We show here that ₅₁ expression, and hence function, during angiogenesis is regulated by the transcription factor Hox D3, a homeobox gene that also controls the expression of endothelial cell integrin _v3 and urokinase-type plasminogen activator. Hox D3 expression in endothelial cells enhances integrin ₅ protein and message expression, whereas Hox D3 antisense inhibits its expression. Hox D3 promotes ₅expression during angiogenesis in vivo, whereas inhibition of ₅ expression by Hox D3 antisense suppresses angiogenesis. Hox D3 binds directly to the promoters of the integrin ₅ and ₃ subunits, inducing subunit expression. As Hox D3, integrin _v3, and integrin ₅₁ are expressed on tumor blood vessels but not on normal quiescent vessels, these studies suggest that Hox D3 coordinately regulates the expression of integrin ₅₁ and integrin _v3 during angiogenesis in vivo. These studies also suggest that Hox D3 inhibition could be a useful approach to inhibit tumor angiogenesis.

Received for publication, May 17, 2003 , and in revised form, November 7, 2003.

^* This work was supported by National Institutes of Health Grants CA83133 (to J. A. V.) and CA85249 (to N. J. B.). 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: 9500 Gilman Dr., La Jolla, CA 92093-0912. Tel.: 858-822-0086; Fax: 858-822-1325; E-mail: jvarner{at}ucsd.edu.

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