Hypoxic induction of vascular endothelial growth factor (VEGF) and angiogenesis in muscle by truncated peroxisome proliferator-activated receptor γ coactivator (PGC)-1α

J Biol Chem. 2014 Mar 28;289(13):8810-7. doi: 10.1074/jbc.M114.554394. Epub 2014 Feb 6.

Abstract

The transcriptional coactivator peroxisome proliferator-activator receptor γ coactivator (PGC)-1α is required for full hypoxic induction of vascular endothelial growth factor (VEGF) in skeletal muscle cells. Under normoxic conditions, PGC-1α also strongly induces mitochondrial biogenesis, but PGC-1α does not activate this program under hypoxic conditions. How this specificity is achieved is not known. We show here that hypoxia specifically induces alternatively spliced species encoding for truncated forms of PGC-1α: NT-PGC-1α and PGC-1α4. NT-PGC-1α strongly induces VEGF expression, whereas having little effect on mitochondrial genes. Conditioned medium from cells expressing NT-PGC-1α robustly induces endothelial migration and tube formation, hallmarks of angiogenesis. Transgenic expression of PGC-1α4 in skeletal muscle in mice induces angiogenesis in vivo. Finally, knockdown of these PGC-1α isoforms and hypoxia-inducible factor-1α (HIF-1α) abrogates the induction of VEGF in response to hypoxia. NT-PGC-1α and/or PGC-1α4 thus confer angiogenic specificity to the PGC-1α-mediated hypoxic response in skeletal muscle cells.

Keywords: Angiogenesis; Hypoxia; Hypoxia-inducible Factor (HIF); Metabolism; Mitochondria; PGC-1; PGC-1alpha; RNA Splicing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cell Hypoxia
  • Cell Line
  • Exons / genetics
  • Humans
  • Mice
  • Mitochondria / genetics
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / cytology*
  • Muscle, Skeletal / metabolism
  • Neovascularization, Physiologic*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phenotype
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Transcription Factors
  • Vascular Endothelial Growth Factor A