Ischemia, the combined lack of oxygen (hypoxia) and nutrients, triggers the production of vascular endothelial growth factor (VEGF) and other angiogenic factors that contribute to neovascularization in the affected tissue, which leads to protection from further damage. Arany et al. investigated a role for the transcriptional coactivator PGC-1α [peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α] in the ischemic response. Real-time quantitative polymerase chain reaction assays and Western blotting analysis showed that the abundance of PGC-1α mRNA and protein was increased in C2C12 myotubes cultured under conditions of ischemia. Ischemia-induced VEGF expression was lower in skeletal muscle cells from PGC-1α–/– mice than in wild-type mice, whereas cells from PGC-1α transgenic mice showed increased expression of VEGF. Ligation of the femoral artery in PGC-1α transgenic mice resulted in neovascularization at a rate higher than that in wild-type mice, which in turn was accelerated compared to the rate in PGC-1α–/– mice. Although the transcription factor hypoxia-inducible factor 1α (HIF-1α) is known to induce increased expression of VEGF under hypoxic conditions, reporter assays showed that PGC-1α-induced VEGF expression was HIF-1α-independent, as was expression of PGC-1α. Instead, the authors showed that PGC-1α increased VEGF expression by coactivating the orphan nuclear receptor, estrogen receptor-related α (ERRα). Adenoviral expression of PGC-1α in embryonic fibroblasts from ERR-α–/– mice failed to increase expression of VEGF. Together, these data suggest an important role for PGC-1α in the HIF-1α-independent, ERR-α-dependent induction of genes encoding angiogenic factors in response to ischemia, which provides a new potential therapeutic target in the treatment of ischemia.
Z. Arany, S.-Y. Foo, Y. Ma, J. L. Ruas, A. Bommi-Reddy, G. Girnun, M. Cooper, D. Laznik, J. Chinsomboon, S. M. Rangwala, K. H. Baek, A. Rosenzweig, B. M. Spiegelman, HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451, 1008-1012 (2008). [PubMed]