GENE THERAPY TO INDUCE THERAPEUTIC ANGIOGENESIS

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These studies are divided into tissue culture experiments and preclinical animal studies. The in vitro experiments have the following objectives: (1) to characterize the effect of insulin-like growth factor 1 (IGF-1) on endothelial cell function and the interaction of IGF-1 with other angiogenic growth factors. The results show that IGF-1 alone or in combination with vascular endothelial growth factor has no effect on human microvascular endothelial cell proliferation. In contrast IGF-1 and basic fibroblast growth factor have a significant synergistic effect on endothelial cell proliferation. (2) to elucidate the effect of acidification on endothelial cell function. The result show that hypercarbic acidosis inhibits endothelial cell proliferation despite an increased endothelial mitogen secretion from the endothelial cells grown in acidotic conditions. (3) to determine the effect of hypoxia on integrin expression in endothelial cells. The results show that hypoxia has a significant effect to decrease alphavbeta5 expression, in contrast neither alphavbeta5 nor beta 1 expression were modulated by hypoxia. The in vivo experiments have the following objectives: (1) to determine whether the development of collateral blood flow in response to acute hindlimb ischemia is age-dependent. The results show that gastrocnemius muscle bioenergetic recovery evaluated by 31p NMR in 2 and 20 month old rats 1 and 7 days after femoral artery dissection is impaired in old vs young animals. (2) to determine whether adenovirus-mediated recombinant, secreted acidic fibroblast growth factor (AdCMV.sp+aFGF1-154) gene transfer has a tumorigenic potential. The results show that NIH 3T3 cells infected with AdCMV.sp+aFGF1-154 exhibit a transient growth advantage but not a stable transformation. (3) to determine whether AdCMV.sp+aFGF1-154 has a therapeutic potential in the treatment of acute myocardial ischemia. The results show that the intramyocardial injection of AdCMV.sp+aFGF1-154 in the absence of chronic ischemia induces angiogenesis and decreases the risk region for myocardial infarction upon acute coronary artery ligation.