The transcriptional coactivator PGC-1α mediates exercise-induced angiogenesis in skeletal muscle

Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPAR gamma coactivator (PGC)-1 alpha is a potent transcriptional coactivator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1 alpha mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1 alpha in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1 alpha from an alternate promoter. The induction of PGC-1 alpha depended on beta-adrenergic signaling. beta-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1 alpha. The orphan nuclear receptor ERR alpha mediated the induction of VEGF by PGC-1 alpha, and mice lacking ERR alpha also failed to increase vascular density after exercise. These data demonstrate that beta-adrenergic stimulation of a PGC-1 alpha/ERR alpha/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.