Cardiac and skeletal muscle adapt to stimuli such as myocardial ischemia and hypoxia, certain forms of myocardial hypertrophy, and exercise conditioning by increasing blood supply to the muscle. The increase in perfusion comes about not only by an increase in flow through already existent vessels, but also by the growth of new vessels. The objective of the proposed studies is to identify factors that regulate vascular growth in cardiac and skeletal muscle in vivo. The studies focus on the role that four recently characterized angiogenic growth factors (basic fibroblast growth factor, endothelial cell growth factor, transforming growth factor alpha, and angiogenin) play in regulating vascular growth.
The specific aims of the proposal are: 1. To develop intact animal models of myocardial ischemia, myocardial hypertrophy, and chronic skeletal muscle stimulation which induce vascular growth. 2. To examine in these models the in vivo regulation of expression of putative angiogenic growth factors at both the gene and protein level in response to physiologic stimuli known to stimulate vascular growth. 3. To determine if regulation of vascular growth occurs primarily through autocrine, paracrine or endocrine mechanisms, or through a combination of these mechanisms. 4. To assess regulation of angiogenic growth factor expression in vitro culture models that mimick in vivo models of ischemia, hypertrophy, and muscle stimulation. It is anticipated that the knowledge gained from these studies will be relevant to the treatment of pathophysiologic states in cardiac and skeletal muscle. If proteins which induce blood vessel growth in vivo are identified, and their regulation understood, then methods may be developed to stimulate new blood vessel growth in diseased organs, or to increase the capacity for perfusion in nondiseased organs.
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