Homeobox B3 promotes capillary morphogenesis and angiogenesis

Endothelial cells (EC) express several members of the Homeobox (Hox) gene f amily, suggesting a role for these morphoregulatory mediators during angiog enesis, We have previously established that Hox D3 is required for expressi on of integrin alpha v beta 3 and urokinase plasminogen activator (uPA), wh ich contribute to EC adhesion, invasion, and migration during angiogenesis. We now report that the paralogous gene, Hox B3, influences angiogenic beha vior in a manner that is distinct from Hox D3. Antisense against Hox B3 imp aired capillary morphogenesis of dermal microvascular EC cultured on baseme nt membrane extracellular matrices. Although levels of Hox D3-dependent gen es were maintained in these cells, levels of the ephrin A1 ligand were mark edly attenuated. Capillary morphogenesis could be restored, however, by add ition of recombinant ephrin A1/Fc fusion proteins. To test the impact of Ho x B3 on angiogenesis in vivo, we constitutively expressed Hox B3 in the chi ck chorioallantoic membrane using avian retroviruses that resulted in an in crease in vascular density and angiogenesis. Thus, while Hox D3 promotes th e invasive or migratory behavior of EC, Hox B3 is required for the subseque nt capillary morphogenesis of these new vascular sprouts and, together, the se results support the hypothesis that paralogous Hox genes perform complem entary functions within a particular tissue type.