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Alpha 6 Integrins Regulate the Expression of Laminin-511 and CXCR4 to Promote Endothelial Tubular Morphogenesis

During angiogenesis, endothelial cells engage components of the extracellular matrix through integrin-mediated adhesion. Endothelial cells express laminin-411 and laminin-511 that bind to integrins, including the α6 integrins, α6β1 and α6β4. However, little is known about the contribution of these laminins to endothelial tubular morphogenesis and stability. We used two organotypic angiogenesis assays in conjunction with RNAi approaches to demonstrate that endothelial depletion of either the α4 chain of laminin-411 or the α5 chain of laminin-511 inhibited sprouting and tube formation. Depletion of α6 integrins resulted in similar phenotypes. Interestingly, depletion of α6 integrins also inhibited the expression of laminin-511, which correlated with the loss of tubular stability. Loss of either α6 integrins or laminin-511 resulted in the inhibition of the expression of CXCR4, a gene previously associated with sprouting endothelial cells. Pharmacological inhibition of CXCR4 signaling suppressed endothelial sprouting and morphogenesis, suggesting that α6 integrins and laminin-511 promotes endothelial tubular morphogenesis in part by regulating the expression of CXCR4. Taken together, our results suggest that α6 integrins regulate gene expression to promote both early events in tubular morphogenesis, as well as the stability of established endothelial tubes. Summary statement Endothelial-secreted laminin-511 and its receptors, α6 integrins promote tubular morphogenesis by regulating the expression of the chemokine receptor, CXCR4. Additionally, the depletion of α6 integrins from established tubes results in the loss of tubular integrity and laminin-511 expression.