PGC-1β regulates angiogenesis in skeletal muscle

Rowe GC, Jang C, Patten IS, Arany Z. PGC-1 beta regulates angiogenesis in skeletal muscle. Am J Physiol Endocrinol Metab 301: E155-E163, 2011. First published March 1, 2011; doi: 10.1152/ajpendo.00681.2010.-Aerobic metabolism requires oxygen and carbon sources brought to tissues via the vasculature. Metabolically active tissues such as skeletal muscle can regulate blood vessel density to match metabolic needs; however, the molecular cues that coordinate these processes remain poorly understood. Here we report that the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1 beta (PGC-1 beta), a potent regulator of mitochondrial biology, induces angiogenesis in skeletal muscle. PGC-1 beta induces the expression of vascular endothelial growth factor (VEGF) in cell culture and in vivo. The induction of VEGF by PGC-1 beta requires coactivation of the orphan nuclear receptor estrogen-related receptor-alpha (ERR alpha) and is independent of the hypoxia-inducible factor (HIF) pathway. In coculture experiments, overexpression of PGC-1 beta in skeletal myotubes increases the migration of adjacent endothelial cells, and this depends on VEGF signaling. Transgenic expression of PGC-1 beta in skeletal myocytes dramatically increases muscular vessel density. Taken together, these data indicate that PGC-1 beta is a potent regulator of angiogenesis, thus providing a novel link between the regulations of oxidative metabolism and vascular density.