The study investigates the role of the transcriptional coactivator PGC-1α in regulating vascular endothelial growth factor (VEGF) expression and angiogenesis under hypoxic conditions. PGC-1α is induced by nutrient and oxygen deprivation, and it significantly enhances VEGF expression and angiogenesis in cultured muscle cells and in vivo. PGC-1α−/− mice show impaired blood flow recovery after ischemic injury, while transgenic expression of PGC-1α in skeletal muscle is protective. Surprisingly, PGC-1α's induction of VEGF does not involve the canonical hypoxia response pathway or hypoxia-inducible factor (HIF). Instead, PGC-1α coactivates the orphan nuclear receptor ERR-α on conserved binding sites within the VEGF gene promoter and intron. This novel pathway, independent of HIF, provides a potential therapeutic target for treating ischemic diseases.The study investigates the role of the transcriptional coactivator PGC-1α in regulating vascular endothelial growth factor (VEGF) expression and angiogenesis under hypoxic conditions. PGC-1α is induced by nutrient and oxygen deprivation, and it significantly enhances VEGF expression and angiogenesis in cultured muscle cells and in vivo. PGC-1α−/− mice show impaired blood flow recovery after ischemic injury, while transgenic expression of PGC-1α in skeletal muscle is protective. Surprisingly, PGC-1α's induction of VEGF does not involve the canonical hypoxia response pathway or hypoxia-inducible factor (HIF). Instead, PGC-1α coactivates the orphan nuclear receptor ERR-α on conserved binding sites within the VEGF gene promoter and intron. This novel pathway, independent of HIF, provides a potential therapeutic target for treating ischemic diseases.