Mechanisms of PAI-1 Induced Anti-Angiogenesis

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DESCRIPTION (provided by applicant): Endothelial cells lining the vascular wall are normally maintained in a differentiated, quiescent state by anti-angiogenic molecules. Pro-angiogneic molecules destabilize the quiescent endothelium into migratory, proliferative endothelial cells that form new capillary blood vessels. The steady turn over rate of the vascular endothelium is maintained by a tightly controlled balance of pro- and anti-angiogenic molecules that have cell survival and death functions, respectively. A shift in the balance can alter the turn over rate of the endothetium and disrupt vascular homeostasis. It has been shown that vascular endothelial growth factor (VEGF) has a role in atherosclerotic plaque development. This is supported by studies which show that angiogenesis is associated with increases in plasmin and metalloproteinase activity which increases plaque susceptibility to acute rupture or plaque destabilization. Several animal studies have shown a reduction in atherosclerotic plaque neovascularization and plaque growth after treatment with angiogenesis inhibitors. Plasminogen activator inhibitor-1 (PAl-1) is over expressed in the intimal layer in the atherosclerotic vessel wall in human coronary artery disease. This has led to one hypothesis that PAl-1 expression is a means of controlling localized plasminogen activators that contribute to extracellular matrix degradation and smooth muscle cell migration. We have constructed recombinant truncated PAl-1 (rPAI-1) proteins to examine the anti-angiogenic activity of PAl-1 in "inactive" conformations (absence of reactive center loop). One rPAI-1 protein, rPAI-123, has potent anti-angiogenic activity. The activity of rPAI-123 induces cleavage of plasmin into angiostatin and inhibits the bioavailability of VEGF. In this study, we will utilize rPAI-123 to: Aim I: Clarify the rPAI-123 interactions that induce cleavage of plasmin into angiostatin; Aim II: Determine if rPAI-123 inhibits VEGF release from heparan sulfate; and Aim Ill: Define the anti-angiogenic/pro-apoptotic signaling pathways in rPAI-123 treated aortic endothelial cells. Due to the potent anti-angiogenic activity of rPAI-123 protein, it may ultimately play a useful role in the treatment of diiseases characterized by excessive angiogenesis, such as progression and stabilization of atherosclerotic plaques, diabetic retinopathy, and certain types of cancer.