Survival of the ischemic heart is dependent on the growth of the collateral circulation. However, collateral development is frequently not sufficient to fully meet the blood supply needs of the compromised myocardium. One of the goals of this research team is to develop angiogenic therapies which promote collateral growth. The animal model for these experiments consists of placing an amaroid occluder on the left circumflex coronary artery of pigs to produce gradual coronary occlusion. It will be determined if administration of growth factors (bFGF and VEGF) combined with heparin enhances collateral development. A second goal is to identify the molecular mechanisms which are responsible for angiogenesis in the heart during coronary artery occlusion and thus elucidated potential approaches for stimulating blood vessel growth. The principal investigator's preliminary evidence suggests that VEGF is involved in collateral synthesis. The principal investigator will extend this observation by attempting to establish a cause and effect relationship between expression of VEGF and blood vessel synthesis in the heart. Studies will be performed in both this animal model and in cultured cardiomyocytes. The in vivo studies will involve a use of a flow probe which will permit monitoring the degree of coronary occlusion so that molecular, physiologic, and morphologic events can be correlated. These studies will involve measurements of flow with microspheres, measurement of VEGF and other growth factor expression by in-situ and solution hybridization, morphometric analysis, and immunohistochemistry. The in vitro studies will involve exposure of cells to hypoxic conditions and examining VEGF secretion and angiogenic properties. Lastly, promoter sequences involved in the response will be examined by use of promoter/reporter chimeras in both cultured cells and in intact hearts.
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