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

Nature volume 451, pages 1008–1012 (2008)Cite this article

Abstract

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 injury1. Here we show that the transcriptional coactivator PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α), a potent metabolic sensor and regulator2, is induced by a lack of nutrients and oxygen, and PGC-1α powerfully regulates VEGF expression and angiogenesis in cultured muscle cells and skeletal muscle in vivo. PGC-1α-/- 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-1α in skeletal muscle is protective. Surprisingly, the induction of VEGF by PGC-1α does not involve the canonical hypoxia response pathway and hypoxia inducible factor (HIF). Instead, PGC-1α coactivates the orphan nuclear receptor ERR-α (oestrogen-related receptor-α) on conserved binding sites found in the promoter and in a cluster within the first intron of the VEGF gene. Thus, PGC-1α and ERR-α, 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-1α may provide a novel therapeutic target for treating ischaemic diseases.

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Figure 1: PGC-1α regulates VEGF in response to deprivation of nutrients and oxygen.
Figure 2: PGC-1α regulates angiogenesis and blood flow recovery after ischaemia in vivo.
Figure 3: PGC-1α is induced by nutrient/oxygen deprivation and regulates VEGF independently of the HIF pathway.
Figure 4: PGC-1α regulates expression of VEGF through coactivation of ERR-α.

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Acknowledgements

We thank E. Smith for assistance with graphics. This work was supported by grants from the National Institutes of Health (Z.A. and B.M.S.), the Wenner–Gren Foundation (J.L.R.) and the Leducq Foundation (A.R. and B.M.S.).

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Authors and Affiliations

  1. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Zoltan Arany, Yanhong Ma, Jorge L. Ruas, Archana Bommi-Reddy, Geoffrey Girnun, Marcus Cooper, Dina Laznik, Jessica Chinsomboon & Bruce M. Spiegelman

  2. Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Stem Cell Institute, Boston, Massachusetts 02215, USA,

    Zoltan Arany, Shi-Yin Foo & Anthony Rosenzweig

  3. Novartis Institutes for Biomedical Research, Diabetes and Metabolism, Cambridge, Massachusetts 02139, USA,

    Shamina M. Rangwala

  4. Department of Surgery, Vascular Biology Program, Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Kwan Hyuck Baek

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  1. Zoltan Arany
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Correspondence to Zoltan Arany or Bruce M. Spiegelman.

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Arany, Z., Foo, SY., Ma, Y. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451, 1008–1012 (2008). https://doi.org/10.1038/nature06613

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