Adhesion Proteins & Angiogenesis:
Substantial changes in the adhesive interactions between cells and the extracellular matrix (ECM) take place to permit endothelial cell migration during angiogenesis. These interactions are mediated by Integrins. Integrins are transmembrane, heterodimeric receptors that bind to ligands in the ECM to either promote endothelial cell motility and proliferation, or to inhibit endothelial cell activities. Interactions between specific Integrins and growth factor receptors such as FGF R, VEGF R2, and PDGF R enhance FGF-, VEGF-, and PDGF-mediated pro-angiogenic effects on endothelial cells. Many of the Integrins that mediate physiological angiogenesis are also involved in regulating angiogenesis under pathological conditions including Integrins alpha 1 beta 1, alpha 2 beta 1, alpha 5 beta 1, alpha V beta 3, and alpha V beta 5. Inhibition of either Integrin alpha V beta 3 or Integrin alpha V beta 5 has been shown to prevent angiogenesis and tumor growth in animal models.
Endothelial cell-cell interactions are important for the maintenance of vascular integrity. Adherens and tight junctions seal adjacent endothelial cells together through specific protein-protein interactions. Tight junctions are mediated by Claudins, Occludin, JAM family proteins, and ESAM (endothelial cell specific adhesion molecule), while adherens junctions are primarily regulated by VE-Cadherin. Homophilic interactions between VE-Cadherin molecules on adjacent endothelial cells promote contact inhibition of endothelial cell growth, inhibit endothelial cell apoptosis, maintain the endothelial cell barrier, and protect the integrity of vessel walls. These adhesive functions require the intracellular association of Cadherins with Catenins, which are linked to the actin cytoskeleton. Abnormal increases in vascular permeability are associated with pathological angiogenesis. This can be caused by the loss of VE-Cadherin at the cell surface, phosphorylation-induced disruption of VE-Cadherin/Ca