REGULATION OF MACROPHAGE ANGIOGENIC ACTIVITY

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Macrophages (Mphi) play a central role in the induction of neovascularization in several pathophysiological processes yet the mechanisms which regulate expression of this trait are still poorly understood. We have evidence that macrophage (Mphi) activation results in the inactivation of a suppressor gene(s) that functions to: 1) up-regulate production of an inhibitor of neovascularization that is biochemically and immunologically related if not identical to a portion of the multifunctional thrombospondin (TSP) molecule and 2) down-regulate expression of Mphi-derived mediators of angiogenesis. Having defined these controls phenotypically we now plan to turn our attention to the mechanisms by which they operate and their functional significance in vivo. The proposal is designed to: 1) evaluate the anti-angiogenic effects of TSP and several of its peptide fragments following their introduction into experimental wounds. 2) identify the distribution and specific cellular sources of TSP in experimental wounds and determine the relationship between the level of TSP and the time course and magnitude of neovascularization using in situ hybridization, immunohistochemistry, and tritiated thymidine autoradiography. This relationship will be further evaluated in 2 angiogenesis-depended human diseases: rheumatoid arthritis and chronic periodontitis. 3) determine the effects of increased TSP production on the angiogenic activity of tumor cells and activated Mphi after transfection with a human TSP cDNA, and evaluate the effect of continuous endogenous TSP production on neovascularization after introducing these transfected cells into experimental wounds. 4) determine if the activation-linked suppressor that controls expression of TSP and Mphi-derived angiogenic factors functions at the level of transcription. Anti-angiogenesis has long been envisioned as a possible approach in the treatment of angiogenesis-depended disorders such as solid tumor growth and chronic inflammatory disease. Further characterization of the in vivo significance of this inhibitor and the mechanism underlying suppressor gene-control of Mphi angiogenic activity should permit the development of novel strategies for the treatment of disease processes characterized by deregulated angiogenesis.