The regulation of endothelial cell form and function by VE-cadherin

Cell-cell adhesion is critical for the proper formation of the vasculature during development, vessel remodeling, and angiogenesis. An understanding of the mechanism by which cell-cell adhesion regulates endothelial cell structure and fate decisions has remained elusive, however, because of the difficulty of experimentally manipulating this variable independently of other signals. We developed a micropatterning approach to control cell-cell adhesion and cell shape with micrometer precision, and investigated the role of vascular endothelial (VE)-cadherin in the regulation of endothelial cell form and function. We supplemented this approach with adenoviral vectors to manipulate VE-cadherin engagement and signaling molecularly in endothelial cells. We found that VE-cadherin activates the Rho GTPase, RhoA, to increase intracellular tension. Increasing tension within the actin cytoskeleton has different effects on endothelial cell fate depending on the local microenvironment. In unconstrained cells, the VE-cadherin-mediated activation of RhoA decreases cell spreading, cell-matrix adhesion, and cell proliferation. When changes in spreading were prevented, we found that the VE-cadherin-mediated activation of RhoA increases cell-matrix adhesion and proliferation. Our results provide an explanation for the underlying mechanism to contact inhibition of cell spreading and proliferation. Importantly, our results also suggest that cells use changes in the pathways regulating cytoskeletal structure to integrate mechanochemical signals from cell-cell and cell-matrix adhesion and navigate in their physical microenvironment.