Vascular Endothelial Cell Interactions and Signaling

Endothelial cells use cell adhesion molecules, such as integrins and cadherins to attach themselves to each other and to the vascular extracellular matrix. Vascular endothelial (VE)-cadherin mediates the calcium-dependent interactions between neighboring endothelial cells. These adherens junctions are believed to provide a mechanical barrier to interendothelial leakage. The short cytoplasmic tail of VE-cadherin is able to interact with the plakoglobin complex (a-, b-, and g-catenin) and this complex interacts with a-actinin and vinculin to link the VE-cadherin-catenin complex to the actin cytoskeleton. VE-cadherin coordinates with VEGFR-2 (Flk-1) to mediate PI3K/Akt-dependent endothelial cell survival. Additionally, endothelial cells adhere to the extracellular matrix (ECM) through interactions with cell surface heterodimeric integrins (e.g., aVb3). The ECM is a dense network of collagen and elastin contained in a complex of proteoglycans and glycoproteins. The engagement of integrins with the ECM causes the activation of focal adhesion molecules, such as focal adhesion kinase (FAK). Activated FAK recruits Src, which phosphorylates FAK on additional sites allowing for the subsequent recruitment of signaling molecules such as phosphatidylinositol 3-kinase (PI3K), CAS, and paxillin to focal adhesions. In addition to adhesion-dependent cell survival, endothelial cells can also respond to receptor tyrosine kinase-mediated survival signals via VEGF through its receptor VEGFR-2 and via angiopoietin-1 (ANG-1) through its receptor Tie2. Both VEGF and ANG-1 allow endothelial cells to escape apoptosis (anoikis) upon detachment from the ECM.

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