title: PGC-1β regulates angiogenesis in skeletal muscle.
abstract: Aerobic metabolism requires oxygen and carbon sources brought to tissues via the vasculature. Metabolically active tissues such as skeletal muscle can regulate blood vessel density to match metabolic needs; however, the molecular cues that coordinate these processes remain poorly understood. Here we report that the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β), a potent regulator of mitochondrial biology, induces angiogenesis in skeletal muscle. PGC-1β induces the expression of vascular endothelial growth factor (VEGF) in cell culture and in vivo. The induction of VEGF by PGC-1β requires coactivation of the orphan nuclear receptor estrogen-related receptor-α (ERRα) and is independent of the hypoxia-inducible factor (HIF) pathway. In coculture experiments, overexpression of PGC-1β in skeletal myotubes increases the migration of adjacent endothelial cells, and this depends on VEGF signaling. Transgenic expression of PGC-1β in skeletal myocytes dramatically increases muscular vessel density. Taken together, these data indicate that PGC-1β is a potent regulator of angiogenesis, thus providing a novel link between the regulations of oxidative metabolism and vascular density.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.forename: Cholsoon
authors.initials: C
authors.lastname: Jang
authors.forename: Ian S
authors.initials: IS
authors.lastname: Patten
authors.forename: Zolt
authors.initials: Z
authors.lastname: Arany
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D002352:Carrier Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D000097983:ERRalpha Estrogen-Related Receptor; C497442:HIF1A protein, human; C455622:PPARGC1B protein, human; C467484:VEGFA protein, human