Peripheral arterial insufficiency, often apparent as intermittent claudication, is a common debilitating cardiovascular disease. Enhanced physical activity represents an important treatment and leads to significant adaptations that increase exercise tolerance. These adaptations include neovascular development to improve a) blood/tissue exchange properties (increased muscle capillarity) and b) flow capacity to active muscle (collateral vessel expansion). Our results, showing that daily heparin injections enhance the exercise-induced increase in collateral-dependent blood flow of claudicant rats, implicates the actions of the angiogenic heparin-binding growth factors (aFGF, bFGF, VEGF). These potent cytokines stimulate neovascularization in experimental ischemia in vivo. Our working hypothesis is that neovascularization occurs in response to tissue 'need' established by flow deficits (ischemia) and/or by increased demand for vascular support (exercise). We will evaluate: 1) the interactions between ischemia, exercise and exogenously infused recombinant bFGF, VEGF, and aFGF; 2) the functional significance of the vascular adaptations; and 3) probe the tissue events related to neovascularization. Bilateral ligation of the femoral artery is used to limit flow capacity, sufficient to produce hindlimb ischemia during exercise, but not infringe upon resting needs. Adult rats are exercised by treadmill running. Ischemia and exercise should shift the dose-response to angiogenic growth factors to the left, as evidenced in: a) the collateral network of the upper hindlimb, by an expansion of existing conduit vessels; b) de novo proliferation of new vessels; and c) the capillary network of muscle. Collateral- dependent blood flow to the distal hindlimb muscles is determined during treadmill running in vivo and using an isolated perfused hind-quarter preparation in situ. The collateral vessel network will be imaged and evaluated morphologically to identify the nature and extent of changes. Physiological and morphometric evaluation of capillary changes will be made. Neovascular adaptations should be self-limiting, influenced by local control, except where flow deficits remain and are experimentally managed. Interactions between heparin and the extracellular matrix of the endothelium will be evaluated. Retention of the bFGF induced collateral vessel enrichment will be determined. Our unique studies evaluating the interactions between exercise and angiogenic growth factors in vivo will provide essential information to help realize an important treatment that could significantly impact the care of patients with intermittent claudication.
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