During angiogenesis, endothelial cells engage components of the extracellular matrix through integrin-mediated adhesion. Endothelial expression of laminin-411 and laminin-511 are known to promote vessel stability. However, little is known about the contribution of these laminins to endothelial morphogenesis. We used two organotypic cell culture angiogenesis assays in conjunction with RNAi approaches to demonstrate that depletion of either the α4 chain of laminin-411 or the α5 chain of laminin-511 from endothelial cells inhibits sprouting and tube formation. Depletion of α6 integrins resulted in similar phenotypes. Gene expression analysis indicated that loss of either laminin-511 or α6 integrins inhibited the expression of CXCR4, a gene previously associated with angiogenic endothelial cells. Pharmacological or RNAi-dependent inhibition of CXCR4 suppressed endothelial sprouting and morphogenesis. Importantly, expression of recombinant CXCR4 rescued endothelial morphogenesis when the α6 integrin expression was inhibited. Additionally, the depletion of α6 integrins from established tubes resulted in the loss of tube integrity and laminin-511. Taken together, our results indicate that α6 integrins and laminin-511 can promote endothelial morphogenesis by regulating the expression of CXCR4 and suggest that the α6-dependent deposition of laminin-511 protects the integrity of established endothelial tubes. Summary statement Endothelial-secreted laminin-511 and α6 integrins promote endothelial morphogenesis by regulating the expression of the chemokine receptor, CXCR4. The depletion of α6 integrins from established tubes results in the loss of tube integrity and laminin-511.
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