Angiogenesis occurs in skeletal muscle in response to exercise training. To gain insight into the regulation of this process, we evaluated the mRNA expression of factors implicated in angiogenesis over the course of a training program. We studied sedentary control (n = 17) rats and both sedentary (n = 18) and exercise-trained (n = 48) rats with bilateral femoral artery ligation. Training consisted of treadmill exercise (4 times/day, 1-24 days). Basal mRNA expression in sedentary control muscle was inversely related to muscle vascularity. Angiogenesis was histologically evident in trained white gastrocnemius muscle by day 12. Training produced initial three- to sixfold increases in VEGF, VEGF receptors (KDR and Flt), the angiopoietin receptor (Tie-2), and endothelial nitric oxide synthase mRNA, which dissipated before the increase in capillarity, and a substantial (30- to 50-fold) but transient upregulation of monocyte chemoattractant protein 1 mRNA. These results emphasize the importance of early events in regulating angiogenesis. However, we observed a sustained elevation of the angiopoietin 2-to-angiopoietin 1 ratio, suggesting continued vascular destabilization. The response to exercise was (in general) tempered in high-oxidative muscles. These findings place importance on cellular events coupled to the onset of angiogenesis.
Exercise produces a powerful angiogenic stimulus within the active muscle that leads to a functionally important increase in capillarity. Further, exercise can increase flow capacity by enlarging the caliber of arterial supply vessels. These adaptations are achieved by the processes of angiogenesis and arteriogenesis, respectively.
Nitric oxide (NO) has been implicated in both collateral expansion (arteriogenesis) and capillary growth (angiogenesis). Exercise training increases collateral-dependent blood flow to tissues at risk of ischemia and enhances capillarity in active skeletal muscle. Exercise also acutely elevates NO. Thus we assessed the role of NO in training-induced arteriogenesis and angiogenesis. These studies utilized a rat model of peripheral vascular disease (bilateral femoral artery ligation). Untreated rats (control) and rats treated with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 65-70 mg x kg(-1) x day(-1), via drinking water) were divided into sedentary or exercise-trained subgroups. After approximately 3 wk, L-NAME treatment had elevated preexercise mean arterial pressure approximately 39-58%, confirming NO synthesis inhibition. The training program (treadmill exercise twice per day, 20-25 m/min, 15% grade, approximately 18 days) increased collateral-dependent blood flow to the distal hindlimb, with the greatest increase (approximately 59%) in the calf (P < 0.001). This increase was inhibited by L-NAME. In contrast, the training-induced increase in muscle capillarity was not blocked by L-NAME. Thus arteriogenesis and angiogenesis appear to differ in their requirement for NO.
Peripheral arterial disease (PAD) is a common vascular disease that reduces blood flow capacity to the legs of patients. PAD leads to exercise intolerance that can progress in severity to greatly limit mobility, and in advanced cases leads to frank ischemia with pain at rest. It is estimated that 12–15 million people in the United States are diagnosed with PAD, with a much larger population that is undiagnosed. The presence of PAD predicts a 50–1500% increase in morbidity and mortality, depending on severity. Treatment of patients with PAD is limited to modification of cardiovascular disease risk factors, pharmacological intervention, surgery, and exercise therapy. Extended exercise programs that involve walking ~5 times/wk, at a significant intensity that requires frequent rest periods, are most significant. Pre-clinical studies and virtually all clinical trials demonstrate the benefits of exercise therapy, including: improved walking tolerance, modified inflammatory/hemostatic markers, enhanced vasoresponsiveness, adaptations within the limb (angiogenesis, arteriogenesis, mitochondrial synthesis) that enhance oxygen delivery and metabolic responses, potentially delayed progression of the disease, enhanced quality of life indices, and extended longevity. A synthesis is provided as to how these adaptations can develop in the context of our current state of knowledge and events known to be orchestrated by exercise. The benefits are so compelling that exercise prescription should be an essential option presented to patients with PAD in the absence of contraindications. Obviously, selecting for a life style pattern, that includes enhanced physical activity prior to the advance of PAD limitations, is the most desirable and beneficial.
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