HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α

Ischaemia of the heart, brain and limbs is a leading cause of morbidity and mortality worldwide. Hypoxia stimulates the secretion of vascular endothelial growth factor ( VEGF) and other angiogenic factors, leading to neovascularization and protection against ischaemic injury(1). Here we show that the transcriptional coactivator PGC-1 alpha ( peroxisome- proliferator- activated receptor-gamma coactivator-1 alpha), a potent metabolic sensor and regulator(2), is induced by a lack of nutrients and oxygen, and PGC-1 alpha powerfully regulates VEGF expression and angiogenesis in cultured muscle cells and skeletal muscle in vivo. PGC-1 alpha(-/-) mice show a striking failure to reconstitute blood flow in a normal manner to the limb after an ischaemic insult, whereas transgenic expression of PGC-1 alpha in skeletal muscle is protective. Surprisingly, the induction of VEGF by PGC-1 alpha does not involve the canonical hypoxia response pathway and hypoxia inducible factor ( HIF). Instead, PGC-1 alpha coactivates the orphan nuclear receptor ERR-alpha ( oestrogen- related receptor- alpha) on conserved binding sites found in the promoter and in a cluster within the first intron of the VEGF gene. Thus, PGC-1 alpha and ERR-alpha, major regulators of mitochondrial function in response to exercise and other stimuli, also control a novel angiogenic pathway that delivers needed oxygen and substrates. PGC-1 alpha may provide a novel therapeutic target for treating ischaemic diseases.