α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

The RGD-binding alpha 5 and alpha v integrins have been shown to be key regulators of vascular smooth muscle cell (vSMC) function in vitro. However, their role on vSMCs during vascular development in vivo remains unclear. To address this issue, we have generated mice that lack alpha 5, alpha v or both alpha 5 and alpha v integrins on their vSMCs, using the SM22 alpha-Cre transgenic mouse line. To our surprise, neither alpha 5 nor alpha v mutants displayed any obvious vascular defects during embryonic development. By contrast, mice lacking both alpha 5 and alpha v integrins developed interrupted aortic arches, large brachiocephalic/carotid artery aneurysms and cardiac septation defects, but developed extensive and apparently normal vasculature in the skin. Cardiovascular defects were also found, along with cleft palates and ectopically located thymi, in Wnt1-Cre alpha 5/alpha v mutants, suggesting that alpha 5 and alpha v cooperate on neural crest-derived cells to control the remodelling of the pharyngeal arches and the septation of the heart and outflow tract. Analysis of cultured alpha 5/alpha v-deficient vSMCs suggests that this is achieved, at least in part, through proper assembly of RGD-containing extracellular matrix proteins and the correct incorporation and activation of latent TGF-beta.