Tie2 is an endothelial receptor tyrosine kinase (RTK) that is required for both embryonic vascular development and pathological angiogenesis. Tie2 is unique among RTKs in that it has two ligands with apparently opposing actions. Angiopoietin-1 (Ang1) is an activating ligand while Angiopoietin-2 (Ang2) is thought to be a naturally occurring antagonist for Tie2. Mice lacking Tie2 or Ang1 die midway through gestation due to abnormalities of vascular morphogenesis characterized by deficient recruitment of supporting smooth muscle cells and pericytes. Moreover, Ang1 promotes endothelial cell survival and blocks the increases in vascular permeability induced by vascular endothelial growth factor (VEGF), supporting a role for Ang1 in the stabilization and maintenance of the adult vasculature. In contrast, Ang2 is required for VEGF-mediated angiogenesis, and in the absence of endothelial mitogens Ang2 may induce vascular regression. The importance of endothelial damage in the progression of vascular diseases has been well documented. Endothelial injury initiates numerous signals that contribute to thrombosis, atherosclerosis, and neointimal hyperplasia. Based on this information, we hypothesize that the Angiopoietins will have differential effects on vascular remodeling; specifically that Ang1, but not Ang2, will prevent endothelial injury-induced vascular remodeling and neointimal hyperplasia. To investigate this hypothesis, the Specific Aims of this proposal are to: 1. Determine the differences in Ang1- and Ang2-mediated gene expression; 2. Develop and characterize specific inhibitors of Ang1 and Ang2; 3. Determine the effects of Ang1 and Ang2 in a venous bypass grafting model; and 4. Determine the effects of inhibiting Ang1 and Ang2 in a venous bypass grafting model. Accomplishing these Specific Aims will provide important insights into the precise roles of the Angiopoietins during maintenance of the adult vasculature and during vascular remodeling, such as that which occurs after venous bypass grafting. Moreover, these studies may lead to the identification of novel therapeutic targets in a variety of vascular diseases.
