Microvascular Adaptations to Exercise: Protective Effect of PGC-1 Alpha

BACKGROUND Sedentary behavior and obesity are major risk factors for cardiovascular disease. Regular physical activity has independent protective effects on the cardiovascular system, but the mechanisms responsible remain elusive. Recent studies suggest that the protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) participates in the response to exercise training. We hypothesized that the arterioles of athletes maintain dilation to flow despite combined inhibition of multiple vasodilators, but loss of PGC-1α renders these vessels susceptible to inhibition of a single vasodilator pathway. In addition, arterioles from overweight and obese individuals will display an an exercise-like phenotype when PGC-1α is activated. METHODS Isolated arterioles from exercise-trained (ET) and from mildly overweight or obese subjects (body mass index >25) were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the absence and presence of compounds that inhibit various endothelium-dependent vasodilators. RESULTS Microvessels of ET subjects displayed robust dilation that could not be inhibited through targeting the combination of nitric oxide, prostaglandins, and hydrogen peroxide, but were inhibited via interference with membrane hyperpolarization. Loss of PGC-1α (siRNA) in the microcirculation of ET subjects eliminates this vasodilatory robustness rendering vessels susceptible to blockade of H2O2 alone. Pharmacological activation of PGC-1α with alpha-lipoic acid in isolated microvessels from sedentary, overweight, and obese subjects increases arteriolar resistance to vasodilator blockade and protects against acute increases in intraluminal pressure. CONCLUSIONS These findings suggest that the microvascular adaptations to exercise training, and the exercise-induced protection against acute vascular stress in overweight/obese subjects, are mediated by PGC-1α.