ABSTRACT
A final potential site of regulation of vascular growth is at the level of endogenous inhibition of angiogenesis, and this importance is underscored by the low rate of endothelial proliferation in the mature endothelium of the adult, such as in the cerebrovascular tree. Two known endogenous inhibitors of angiogenesis are angiostatin and endostatin (31,32). These proteins were identified based upon their ability to inhibit tumor neovascularization and were subsequently identified as cleavage products of other known proteins; angiostatin from plasminogen and endostatin from collagen XVIII. These proteins inhibit endothelial proliferation and they induce endothelial cell apoptosis (33,34). Angiostatin binds and inhibits ATP synthase on the endothelial cell surface, thereby shutting off the cell’s energy supply (35). Another factor that may play an inhibitory role in angiogenesis is Angiopoietin-2, Ang2 (36). Ang1 activates the Tie2 receptor while Ang2 appears to be a context-dependent inhibitor of Tie2. Ang1 is a potent endothelial cell survival factor that helps stabilize the adult vasculature (21,23). In contrast, Ang2 is thought to facilitate VEGF-mediated angiogenesis by inhibiting the stabilizing actions of Ang1 while in the absence of an appropriate angiogenic stimulus like VEGF, Ang2 may promote endothelial cell apoptosis by blocking the protective effects of Ang1 (23). Thus, from these and other studies, it is clear that a number of factors play important roles in regulating the complex balance that is required to change vascular density and/or to stabilize the vascular tree.
