title: Gli3 regulation of myogenesis is necessary for ischemia-induced angiogenesis.
abstract: BACKGROUND
  A better understanding of the mechanism underlying skeletal muscle repair is required to develop therapies that promote tissue regeneration in adults. Hedgehog signaling has been shown previously to be involved in myogenesis and angiogenesis: 2 crucial processes for muscle development and regeneration.
  
  
  OBJECTIVE
  The objective of this study was to identify the role of the hedgehog transcription factor Gli3 in the cross-talk between angiogenesis and myogenesis in adults.
  
  
  RESULTS
  Using conditional knockout mice, we found that Gli3 deficiency in endothelial cells did not affect ischemic muscle repair, whereas in myocytes, Gli3 deficiency resulted in severely delayed ischemia-induced myogenesis. Moreover, angiogenesis was also significantly impaired in HSA-Cre(ERT2); Gli3(Flox/Flox) mice, demonstrating that impaired myogenesis indirectly affects ischemia-induced angiogenesis. The role of Gli3 in myocytes was then further investigated. We found that Gli3 promotes myoblast differentiation through myogenic factor 5 regulation. In addition, we found that Gli3 regulates several proangiogenic factors, including thymidine phosphorylase and angiopoietin-1 both in vitro and in vivo, which indirectly promote endothelial cell proliferation and arteriole formation. In addition, we found that Gli3 is upregulated in proliferating myoblasts by the cell cycle-associated transcription factor E2F1.
  
  
  CONCLUSIONS
  This study shows for the first time that Gli3-regulated postnatal myogenesis is necessary for muscle repair-associated angiogenesis. Most importantly, it implies that myogenesis drives angiogenesis in the setting of skeletal muscle repair and identifies Gli3 as a potential target for regenerative medicine.
authors.affiliation: From the Université de Bordeaux, Adaptation cardiovasculaire à l'ischémie, U1034, Pessac, France.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Renault
authors.forename: Soizic
authors.initials: S
authors.lastname: Vandierdonck
authors.forename: Candice
authors.initials: C
authors.lastname: Chapouly
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Metras
authors.forename: Thierry
authors.initials: T
authors.lastname: Couffinhal
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.forename: Qinyu
authors.initials: Q
authors.lastname: Yao
authors.forename: Annabel
authors.initials: A
authors.lastname: Reynaud
authors.forename: Béatrice
authors.initials: B
authors.lastname: Jaspard-Vinassa
authors.forename: Isabelle
authors.initials: I
authors.lastname: Belloc
authors.forename: Claude
authors.initials: C
authors.lastname: Desgranges
authors.forename: Alain-Pierre
authors.initials: AP
authors.lastname: Gadeau
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D050687:E2F1 Transcription Factor / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D053823:Hedgehog Proteins / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D007511:Ischemia / Q000503:physiopathology*; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000074290:Zinc Finger Protein Gli3
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3; D007334:Insulin-Like Growth Factor I
keywords: angiogenesis, pathological; hedgehogs; ischemia; muscle, skeletal; regeneration
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