Abstract
Endothelial cells engage extracellular matrix and basement membrane components through integrin-mediated adhesion to promote angiogenesis. Angiogenesis involves the sprouting of endothelial cells from pre-existing vessels, their migration into surrounding tissue, the upregulation of angiogenesis-associated genes, and the formation of new endothelial tubes. To determine whether the endothelial laminin-binding integrins, α6β4, and α3β1 contribute to these processes, we employed RNAi technology in organotypic angiogenesis assays, as well in migration assays, in vitro. The endothelial depletion of either α6β4 or α3β1 inhibited endothelial sprouting, indicating that these integrins have non-redundant roles in this process. Interestingly, these phenotypes were accompanied by overlapping and distinct changes in the expression of angiogenesis-associated genes. Lastly, depletion of α6β4, but not α3β1, inhibited migration. Taken together, these results suggest that laminin-binding integrins regulate processes associated with angiogenesis by distinct and overlapping mechanisms.
Highlights
Angiogenesis contributes to both normal and pathological processes, including tissue repair, cancer progression, and inflammation [1,2]
Angiogenesis is a multistep process that involves the sprouting of endothelial cells from the pre-existing vasculature, which form endothelial tubes that anastomose with one another to form new vascular networks
At the onset of angiogenesis, endothelial cells interact with proteins present in the extracellular matrix, some of which are provided by other cell types, such as those present in the provisional matrix during tissue repair [3,4]
Summary
Angiogenesis contributes to both normal and pathological processes, including tissue repair, cancer progression, and inflammation [1,2]. Mouse genetic studies examining the effect of Tie2-dependent deletion of the β4 subunit have not focused on angiogenesis per se; these studies have identified a role for α6β4 in hypoxia-induced vessel remodeling and in promoting endothelial barrier function in the brain vasculature in response to inflammation [20,21]. We employed RNAi technology together with organotypic angiogenesis assays—which model angiogenesis in an ECM environment, similar to that present during tissue repair [24–26]—in addition to transwell migration assays Using these assays, we previously demonstrated that endothelial cells secrete both laminin-411 and laminin-511 during the formation of endothelial tubes [7]. Our study is the first to examine the contribution of laminin-binding integrins to the regulation of a set of previously identified angiogenesis-associated genes
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