INDUCTION OF THE ANGIOGENIC PHENOTYPE BY HOX D3

Angiogenesis is characterized by distinct phenotypic changes in vascul ar endothelial cells (EC). Evidence is provided that the Hox D3 homeob ox gene mediates conversion of endothelium from the resting to the ang iogenic/invasive state. Stimulation of EC with basic fibroblast growth factor (bFGF) resulted in increased expression of Hox D3, integrin al pha v beta 3, and the urokinase plasminogen activator (uPA). Hox D3 an ti-sense blocked the ability of bFGF to induce uPA and integrin alpha v beta 3 expression, yet had no effect on EC cell proliferation or bFG F-mediated cyclin D1 expression. Expression of Hox D3, in the absence of bFGF, resulted in enhanced expression of integrin alpha v beta 3 an d uPA. In fact, sustained expression of Hox D3 in vivo on the chick ch orioallantoic membrane retained EC in this invasive state and prevente d vessel maturation leading to vascular malformations and endothelioma s. Therefore, Hox D3 regulates EC gene expression associated with the invasive stage of angiogenesis.