While fundamental to recovery from vascular occlusive events such as myocardial infarction, stroke, and peripheral vascular insufficiency, neovascular development also underlies the growth and progression of both benign and malignant tumors. In this proposal, we postulate that that the fibrinolytic receptor complex, known as the annexin 2/p11 system, promotes neoangiogenesis by supporting the development of key protease activities at the surface of vascular cells and their precursors. Specifically, we plan to focus on the role of annexin 2 (A2) in the recruitment and differentiation of vascular mural cells for stabilization of the developing neovessel. A2 belongs to a 60-member family of calcium-regulated, phospholipid-binding proteins expressed throughout the phylogenetic tree. We and others have identified A2 as the major endothelial cell fibrinolytic receptor that binds tissue plasminogen activator and its physiologic substrate, plasminogen. This assembly greatly accelerates plasmin generation, and promotes the dissolution of fibrin. Recently, we demonstrated that mice completely deficient in A2 have markedly impaired neoangiogenesis. New preliminary data substantiate and extend these findings by demonstrating a failure of tumor allograft growth in A2-null mice due to impaired tumor angiogenesis. We note specifically a paucity of neovessels, neovascular dilatation, and a deficiency of mural cells. Tumor-bearing A2-null mice display reduced circulating bone marrow derived VEGFR1+/CD11+ hematopoietic precursors, and tumor growth can be restored upon transplantation of A2-/- mice with A2+/+ marrow. We, therefore, hypothesize that expression of A2 on the surface of vascular cells and vascular precursor cells is essential for effective neoangiogenesis.
Our aims are to  determine whether A2 supports stabilization of new blood vessels by promoting recruitment of mural cells (pericytes and smooth muscle cells) to sites of angiogenesis in tumor-bearing mice and in humans with cancer,  determine whether PDGF-BB recruits mural cells to developing neovessels by stimulating translocation of the A2/p11 complex to the surface of mural cell precursors,  determine whether A2-supported angiogenesis also requires participation of its cofactor, p11, and  determine whether hyperhomocysteinemia impairs the angiogenic response by derivatizing A2 and blocking its protease-inducing activity. It is anticipated that new insights derived from these studies may lead to novel modalities in the diagnosis and treatment of neovascular disorders.
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