Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development

Integrin cell adhesion receptors and fibronectin, one of their extracellular matrix ligands, have been demonstrated to be important for angiogenesis using functional perturbation studies and complete knockout mouse models. Here, we report on the roles of the alpha 5 and alpha v integrins, which are the major endothelial fibronectin receptors, in developmental angiogenesis. We generated an integrin alpha 5-floxed mouse line and ablated alpha 5 integrin in endothelial cells. Unexpectedly, endothelial-specific knockout of integrin alpha 5 has no obvious effect on developmental angiogenesis. We provide evidence for genetic interaction between mutations in integrin alpha 5 and alpha v and for overlapping functions and compensation between these integrins and perhaps others. Nonetheless, in embryos lacking both alpha 5 and alpha v integrins in their endothelial cells, initial vasculogenesis and angiogenesis proceed normally, at least up to E11.5, including the formation of apparently normal embryonic vasculature and development of the branchial arches. However, in the absence of endothelial alpha 5 and alpha v integrins, but not of either alone, there are extensive defects in remodeling of the great vessels and heart resulting in death at similar to E14.5. We also found that fibronectin assembly is somewhat affected in integrin alpha 5 knockout endothelial cells and markedly reduced in integrin alpha 5/alpha v double-knockout endothelial cell lines. Therefore, neither alpha 5 nor alpha v integrins are required in endothelial cells for initial vasculogenesis and angiogenesis, although they are required for remodeling of the heart and great vessels. These integrins on other cells, and/or other integrins on endothelial cells, might contribute to fibronectin assembly and vascular development.