Angiogenesis: PGC-1α provides a breath of fresh air

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The transcriptional coactivator PGC-1α and transcription factor ERR-α stimulate angiogenesis in hypoxic conditions by directly upregulating VEGF expression.

Ischemia can be countered by neovascularization at the oxygen-deprived site. It has long been known that hypoxia inducible factor (HIF) promotes angiogenesis under hypoxic conditions by upregulating vascular endothelial growth factor (VEGF) and other pro-angiogenic factors. In Nature, Spiegelman and colleagues now document a novel HIF-independent angiogenic pathway where the transcriptional coactivator PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) upregulates expression of VEGF and other angiogenic factors by stimulating the transcription factor ERR-α (estrogen-related receptor-α).

PGC-1α regulates cellular energy metabolism in muscle by promoting fatty acid oxidation. The authors chose to study PGC-1α activity during the ischemic response because of its known role in cellular respiration. Hypoxic, nutrient-deprived conditions caused a robust upregulation of PGC-1α mRNA and protein in cultured cells. Furthermore, PGC-1α overexpression increased the amount of VEGF, PDGF-BB (platelet-derived growth factor) and angiopoietin 2 mRNA and secreted VEGF protein in hypoxic conditions in cell culture. Depletion of PGC-1α blunted VEGF accumulation of in these conditions.

The link between PGC-1α and pro-angiogenic factors suggested a potential role for PGC-1α in angiogenesis, which was assessed in a mouse model of ischemia. Wild-type mice recover from induced muscle ischemia by inducing angiogenesis. Muscle neovascularization was severely impaired in PGC-1α-deficient mice, but greatly accelerated in mice with targeted overexpression of PGC-1α in skeletal muscle. PGC-1α overexpression in vivo was also accompanied by a marked increase in expression of VEGF, PDGF-BB and angiopoietin 2, suggesting that PGC-1α may mediate angiogenesis in ischemic conditions by upregulating angiogenic factors.

Intriguingly, PGC-1α-mediated induction of VEGF in ischemic conditions appears to be independent of HIF. Exogenous PGC-1α had no effect on HIF-1α transcriptional activity, nor was the promoter of PGC-1α a target for HIF-1α-mediated transcription. However, overexpression of ERR-α, a known effector of PGC-1α, led to a three-fold increase in VEGF mRNA in primary skeletal muscle cells. In addition, ERR-α was required for PGC-1α-mediated induction of VEGF. PGC-1α and ERR-α strongly upregulated transcription of a synthetic VEGF gene construct encompassing five of the 11 predicted ERR-α response elements and could directly bind to these elements in vitro, strongly suggesting that ERR-α can upregulate VEGF in vivo.

These data describe a new pathway for hypoxia-induced angiogenesis in which PGC-1α stimulates ERR-α to induce VEGF transcription. The mechanism by which PGC-1α is induced during hypoxia, and whether PGC-1α can directly upregulate PDGF-BB and angiopoeitin 2 in ischemic conditions is not yet known. Additional studies will be necessary to determine if PGC-1α is important for the vascularization of another well-known hypoxic environment: tumors.

Emily J. Chenette
Signaling Gateway

Reference

Arany Z. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451, 1008-1012 (2008) | Article | PubMed |