Atherosclerotic lesions in humans and other animal models of the disease are associated with areas of increased vasa vasasorum that proliferate and extend into the intimal layer. Published data suggests these plaque capillaries may be markers of cell proliferation, promote inflammatory cell entry into lesions, or may be involved in plaque hemorrhage and rupture that can initiate a myocardial infarction or stroke. In recent studies, endotheljal cell inhibitors reduced intimal neovascularization and plaque growth in ApoE-deficient mice, which suggest plaque angiogenesis contributes to the progression of atherosclerosis. Due to its association with disease progression and the development of acute ischemic complications, it is relevant to understand the mechanisms and to identify the endogenous factors that regulate plaque angiogenesis. Intimal neovascularization has been documented in advanced lesions of ApoE-/- mice. Atherosclerotic lesions will be tested in a serum-free in vitro assay of plaque-induced sprout formation to characterize the relative biologic activities that stimulate angiogenesis in lesions. ApoE-/- mice will be treated with specific antagonists of these endogenous factors to determine if they regulate plaque angiogenesis and lesion growth in vivo. Endostatin an endogenous inhibitor of angiogenesis is retained in the medial layer of the aorta. ApoE-/- mice will be crossed with mice deficient in collagen XVlll/endostatjn to determine if loss of an endogenous inhibitor of angiogenesis in the aorta will enhance intimal neovascularization and plaque growth. Atherosclerotic lesions treated with different angiogenesis inhibitors will be evaluated to determine the functional consequences of these agents on the cell content and turnover of lesions.
