The purpose of the present study is to define the role played by fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF) in coronary angiogenesis in the setting of chronic myocardial ischemia. Ischemic coronary disease is the leading cause of morbidity and mortality in the Western world. Most available therapeutic approaches aim either at relieving symptoms by reducing myocardial oxygen demand, preventing further disease progression by modifying risk factors, restoring flow to a localized segment of the arterial tree (angioplasty) or bypassing obstruction (bypass surgery). However, no attempts have been made to restore blood supply to the myocardium by providing new venues for blood flow. Therapeutic angiogenesis may sense this goal. Angiogenesis is a complex process involving endothelial and smooth muscle cell proliferation and migration formation of new capillaries, breakdown of existing extracellular matrix and formation of a new one. Relatively little is known regarding physiological importance and therapeutic potential of this process in chronic myocardial ischemia and molecular cellular events involved in its regulation are poorly understood. The present study, therefore, will examine 3 Specific Aims: I. Angiogenic efficiency of exogenous FGFs and VEGF in chronic myocardial ischemia: Il. Role of endogenous FGFs, VEGF, and their receptors in coronary angiogenesis: III. Heparan sulfate matrix growth factor interaction in angiogenesis. The first part of the study will examine kinetics and efficiency of coronary angiogenesis stimulated by local administration of FGFs (mitogenic for both smooth-muscle and endothelial cells) and VEGF (an endothelial cell mitogen) in a pig coronary ameroid constrictor model. The growth factors will be delivered using implantable polymer delivering systems to the ischemic region of the myocardium and sequential changes in the regional myocardial blood flow, regional and global left ventricular function and the morphological extent of the neovascularization will be determined. The second part will examine kinetics of growth factor and their receptor expression during coronary angiogenesis and will determine the necessity of individual mitogens and their receptors in this process by selective in vivo and in vitro suppression. Finally, the third part will address molecular events involved in modulation of extracellular matrix. Together these interrelated projects comprise a research program that should yield novel information regarding angiogenic function of FGFs and VEGF and may provide fundamental insights into regulation of angiogenesis in myocardial ischemia.
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