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Importantly, propranolol had no effect on the ability or willingness of mice to run on voluntarywheels.Hence, adrenergic stimulation mediates a large part of the induction of PGC and VEGF by exercise.Next, to investigate if PGC mediates adrenergic induction of VEGF, PGC mice were injected with clenbuterol, and hlater quadriceps were isolated.fold in wildtype animals, the induction of VEGF was abrogated in PGC mice. The same was true in PGCMKO mice, indicating that the defect in signaling is intrinsic to the myocyte compartment. Together, these data demonstrate that exercise and adrenergic signaling induces VEGF expression in skeletal myocytes via PGC.To test if the induction of VEGF by PGC in skeletal muscle cells was entirely dependent on this ERR pathway, primaryskeletal muscle cells were isolated from ERR animals and wildtype controls.The cells were made to differentiate into myotubes in cell culture, and were infected with adenovirus encoding for PGC, or GFP control.Infection of wildtype myotubes with PGC virus induced expression of VEGF fold, compared to control virus. To test the role of ERR in adrenergicmediated induction of VEGF invivo, ERR mice andwildtype controls were injectedwith either PBS or clenbuterol.Af ter h, VEGF expression was measured in quadriceps by qPCR.Hence, adrenergic signaling acts through PGC to induce VEGF.Hence PGC coactivates ERR to induce the VEGF enhancer.To test this, ERR mice and wildtype controls were placed in cages containing voluntaryrunning wheels.After days, quadriceps were removed, and capillarydensity was Fluorouracil quantified by immunohistochemistr y, as above.In sharp contrast, almost no changes in capillarydensity were seen in ERR mice.Hence, endurance exerciseinduced angiogenesis requires ERR.The prevailing paradigm to explain exerciseinduced angiogenesis has been that increased metabolic demands in exercising muscle cause a supplydemand mismatch.This mismatch causes hypox ia andor ATP deficiency, leading to activation of HIF andor AMPK, respectively. However, recent data do not entirely support this notion.In this scenario, angiogenesis is triggered by the anticipated need for higher metabolic efficiency heralded by repetitive nerve stimulation.It is likely that this pathway also interacts with metabolic perturbations wrought by exercise.It will now be of interest to better understand how upstream signals are controlled locally, and how metabolic status integrates into the PGC pathway.The role of adrenergic signaling in angiogenesis has not been studied extensively.alanine Anecdotal evidence and small trials have suggested that the use of blocking agents can worsen symptoms and function in patients with PAD. Recent trials have suggested that the use of blockers is safe, but these trials were small and, more importantly, of short duration. The data presented demonstrate a key role for PGC in exerciseinduced angiogenesis, a normal physiological process.Angiogenesis is highly complex, involving multiple cells types and signals that must be coordinated in both space and time.The mechanisms by which angiogenesis occurs have been studied extensively in pathologic contexts, rangingfrom tumor neovascularization to proliferative retinopathy.Physiologic angiogenesis, however, has been studied much less extensively.It is likely that these two processes are not identical.It will also be of interest to investigate the precise cascade of events triggered by PGC that leads to the formation of new and functional blood vessels, and how that sequence of events differs from that initiated in pathologic contexts, such as HIF activation in tumor cells.

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