Endothelial cell adhesion receptors and their role in angiogenesis

The maintainance of vessel wall integrity under quiescent conditions as well as its responsiveness under conditions of vascular injury, inflammation and activation of defence mechanisms largely relies on a variety of adhesive interactions. The intact, undisturbed endothelium provides a non-thrombogenic, anti-adhesive surface and serves as a permeability barrier between the flowing blood and the underlying tissues. Following vascular injury or stimulation by specific cytokines or growth factors, endothelial cells respond with the expression of adhesion proteins and cell surface receptors for proteases that are required for proliferation and cellular motility during the wound healing process. The vitronectin receptor ανβ3 represents a typical integrin expressed on stimulated endothelial cells that have aquired the angiogenic phenotype. In a mouse model of retinal neovascularization subcutaneous injection of a high affinity cyclic RGD-peptide largely inhibited hypoxia-induced angiogenesis in vivo. Endothelial cells exposed to the vitronectin receptor antagonist largely underwent apoptosis. Together with components of the plasminogen activation system, the urokinase receptor on endothelial cells is considered to be an additional key element in pericellular proteolysis during the angiogenesis process. Soluble multimeric vitronectin constitutes a novel high affinity ligand for the urokinase receptor and thereby provides a molecular link that controls the dynamics of endothelial cell function particularly at sites of increased vascular permeability and extravasation. Based on these findings the search for novel angiostatic compounds may prove to be successful in the future.