The homeobox transcription factor Hox D3 promotes integrin α5β1 expression and function during angiogenesis

Neovascularization promotes wound healing, tumor growth, and arthritis. Endothelial cell migration and survival during neovascularization are regulated by adhesion proteins, including integrin alpha(5)beta(1). Integrin alpha(5)beta(1) 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-a, and the angiomatrix protein Del-1. We show here that alpha(5)beta(1) 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 alpha(v)beta(3) and urokinase-type plasminogen activator. Hox D3 expression in endothelial cells enhances integrin alpha(5) protein and message expression, whereas Hox D3 antisense inhibits its expression. Hox D3 promotes alpha(5) expression during angiogenesis in vivo, whereas inhibition of a5 expression by Hox D3 antisense suppresses angiogenesis. Hox D3 binds directly to the promoters of the integrin alpha(5) and beta(3) subunits, inducing subunit expression. As Hox D3, integrin alpha(v)beta(3), and integrin alpha(5)beta(1) are expressed on tumor blood vessels but not on normal quiescent vessels, these studies suggest that Hox D3 coordinately regulates the expression of integrin alpha(5)beta(1) and integrin alpha(v)beta(3) during angiogenesis in vivo. These studies also suggest that Hox D3 inhibition could be a useful approach to inhibit tumor angiogenesis.