During angiogenesis, endothelial cells engage components of the extracellular matrix through integrin-mediated adhesion. Endothelial expression of laminin-411 and laminin-511 is 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 (LAMA4) or the α5 chain of laminin-511 (LAMA5) from endothelial cells inhibits sprouting and tube formation. Depletion of α6 (ITGA6) 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 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.

在血管生成过程中，内皮细胞通过整合素介导的粘附与细胞外基质的成分结合。已知层粘连蛋白 411 和层粘连蛋白 511 的内皮表达可促进血管稳定性。然而，人们对这些层粘连蛋白对内皮形态发生的贡献知之甚少。我们使用两种器官型细胞培养血管生成测定，结合 RNAi 方法，证明内皮细胞中层粘连蛋白 411 (LAMA4) 的 α4 链 (LAMA4) 或层粘连蛋白 511 (LAMA5) 的 α5 链的消耗会抑制发芽和管形成。α6 (ITGA6) 整合素的耗尽导致相似的表型。基因表达分析表明，层粘连蛋白 511 或 α6 整合素的缺失会抑制CXCR4的表达，CXCR4 是一种先前与血管生成内皮细胞相关的基因。CXCR4 的药理学或 RNAi 依赖性抑制可抑制内皮萌芽和形态发生。重要的是，当 α6 整合素表达受到抑制时，重组 CXCR4 的表达可以挽救内皮形态发生。此外，已建立的管中 α6 整合素的消耗导致管完整性和层粘连蛋白 511 的丧失。综上所述，我们的结果表明α6整合素和层粘连蛋白511可以通过调节CXCR4的表达促进内皮形态发生，并表明层粘连蛋白511的α6依赖性沉积保护已建立的内皮管的完整性。