title: Hypoxic induction of vascular endothelial growth factor (VEGF) and angiogenesis in muscle by truncated peroxisome proliferator-activated receptor γ coactivator (PGC)-1α.
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.
authors: From the Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115.
authors: Robyn
authors: R
authors: Thom
authors: Glenn C
authors: GC
authors: Rowe
authors: Cholsoon
authors: C
authors: Jang
authors: Adeel
authors: A
authors: Safdar
authors: Zoltan
authors: Z
authors: Arany
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D005091:Exons / Q000235:genetics; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000166:cytology* / Q000378:metabolism; D018919:Neovascularization, Physiologic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; Hypoxia; Hypoxia-inducible Factor (HIF); Metabolism; Mitochondria; PGC-1; PGC-1alpha; RNA Splicing