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Skeletal Myofiber VEGF Is Essential for the Vascular Response to Exercise Training in Adult Mice /


Exercise training stimulates angiogenesis in locomotor muscles. We hypothesize that skeletal myofiber expressed vascular endothelial growth factor is necessary for this angiogenic response to exercise training and overall improvements in exercise capacity. A conditional skeletal myofiber-specific VEGF gene deletion adult mouse model (HSA-Cre-ERT² X VEGFLoxP), in which skeletal muscle VEGF levels are reduced by >80%, was used to test this hypothesis. After 8 weeks of exercise training, skmVEGF-/- mice were unable to improve maximal speed or endurance. Wild-type littermates showed 18% and 99% increases in speed and endurance, respectively (p < 0.01). Capillary measurements revealed the angiogenic response (C:F) to training was attenuated in the plantaris of skmVEGF-/- mice (VEGF +/+ EX, 38%; skmVEGF-/- EX, 18%; p < 0.01), and completely inhibited in the gastrocnemius (VEGF +/+ EX, 43%, p < 0.01; skmVEGF-/- 7%, n.s.). Capillarity was unaffected under sedentary conditions. SkmVEGF-/- mice displayed increased BrdU+ cells (total cell proliferation), vimentin+ cells (fibroblast proliferation) and [alpha]- smooth muscle actin (arterial remodeling), which was amplified with training. Contraction-induced blood flow, measured by optical imaging of near-infrared fluorescent nanospheres, was inhibited in skmVEGF-/- mice. Contractile function of isolated soleus and extensor digitorum longus remained unchanged. SkmVEGF-/- mice had increased sedentary [Beta]-hydroxyacyl-CoA dehydrogenase activity, but training-induced augmentation was completely blocked. Improvements in citrate synthase and phosphofructokinase activity was inhibited and unaltered, respectively. These data suggest VEGF is necessary to augment capillary number and improve exercise capacity in response to exercise training, and plays an essential role in maintaining the vascular system in adult mice

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