title: Revascularization of ischemic skeletal muscle by estrogen-related receptor-γ.
abstract: BACKGROUND
  Oxidative myofibers in the skeletal muscles express high levels of angiogenic factors, have dense vasculature, and promptly revascularize during ischemia. Estrogen-related receptor-gamma (ERRγ) activates genes that govern metabolic and vascular features typical to oxidative myofibers. Therefore, ERRγ-dependent remodeling of the myofibers may promote neoangiogenesis and restoration of blood perfusion in skeletal muscle ischemia.
  
  
  OBJECTIVE
  To investigate the muscle fiber type remodeling by ERRγ and its role in the vascular recovery of ischemic muscle.
  
  
  RESULTS
  Using immunohistology, we show that skeletal muscle-specific transgenic overexpression of ERRγ increases the proportions of oxidative and densely vascularized type IIA and IIX myofibers and decreases glycolytic and less vascularized type IIB myofibers. This myofiber remodeling results in a higher basal blood flow in the transgenic skeletal muscle. By applying unilateral hind limb ischemia to transgenic and wild-type mice, we found accelerated revascularization (fluorescent microangiography), restoration of blood perfusion (laser Doppler flowmetry), and muscle repair (Evans blue dye exclusion) in transgenic compared to wild-type ischemic muscles. This ameliorative effect is linked to enhanced neoangiogenesis (CD31 staining and microfil perfusion) by ERRγ. Using cultured muscle cells in which ERRγ is inactivated, we show that the receptor is dispensable for the classical hypoxic response of transcriptional upregulation and secretion of vascular endothelial growth factor A. Rather, the ameliorative effect of ERRγ is linked to the receptor-mediated increase in oxidative myofibers that inherently express and secrete high levels of angiogenic factors.
  
  
  CONCLUSIONS
  The ERRγ is a hypoxia-independent inducer of neoangiogenesis that can promote reparative revascularization.
authors.affiliation: Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, The University of Texas Medical School at Houston, 77030, USA.
authors.forename: Antonios
authors.initials: A
authors.lastname: Matsakas
authors.forename: Vikas
authors.initials: V
authors.lastname: Yadav
authors.forename: Sabina
authors.initials: S
authors.lastname: Lorca
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Vihang A
authors.initials: VA
authors.lastname: Narkar
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity; D015687:Cell Hypoxia; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006614:Hindlimb; D007150:Immunohistochemistry; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D012039:Regional Blood Flow; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C490916:Esrrg protein, mouse; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse