Training-induced vascular adaptations to ischemic muscle.

Peripheral arterial insufficiency is a progressive degenerative disease associated with an increased morbidity and mortality. It decreases exercise tolerance and often presents with symptoms of intermittent claudication. Enhanced physical activity is one of the most effective means of improving the life of affected patients. While this occurs for a variety of reasons, vascular remodeling can be an important means for improved oxygen exchange and blood flow delivery. Relevant exercise-induced signals stimulate angiogenesis, within the active muscle (e.g. hypoxia), and arteriogenesis (enlargement of pre-existing vessels via increased shear stress) to increase oxygen exchange and blood flow capacity, respectively. Evidence from pre-clinical studies shows that the increase in collateral blood flow observed with exercise progresses over time of training, is accompanied by significant enlargement of isolated collateral vessels, and enhances the responses observed with angiogenic growth factors (e.g. VEGF, FGF-2). Thus, enhanced physical activity can be an effective means of enlarging the structure and function of the collateral circuit. Interestingly, disrupting normal NO production (via L-NAME) eliminates this increase in collateral blood flow induced by training, but does not disturb the increase in muscle capillarity within the active muscle. Similarly, inhibiting VEGF receptor kinase activity eliminates the increase in collateral-dependent blood flow, and lessens, but does not eliminate, angiogenesis within the calf muscle. These findings illustrate distinctions between the processes influencing angiogenesis and arteriogenesis. Further, sympathetic modulation of the collateral circuit does not eliminate the increase in collateral circuit conductance induced by exercise training. These findings indicate that structural enlargement of the collateral vessels is essential to realize the increase in collateral-dependent blood flow capacity caused by exercise training. This raises the potential that meaningful vascular remodeling can occur in patients with intermittent claudication who actively participate in exercise training.