Gli3 regulation of myogenesis is necessary for ischemia-induced angiogenesis

Marie Ange Renault*, Soizic Vandierdonck, Candice Chapouly, Yang Yu, Gangjian Qin, Alexandre Metras, Thierry Couffinhal, Douglas W. Losordo, Qinyu Yao, Annabel Reynaud, Béatrice Jaspard-Vinassa, Isabelle Belloc, Claude Desgranges, Alain Pierre Gadeau

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Rationale: 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 crosstalk between angiogenesis and myogenesis in adults. Methods and 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 ischemiainduced myogenesis. Moreover, angiogenesis was also significantly impaired in HSA-CreERT2; Gli3Flox/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. (Circ Res. 2013;113:1148-1158.).

Original languageEnglish (US)
Pages (from-to)1148-1158
Number of pages11
JournalCirculation research
Volume113
Issue number10
DOIs
StatePublished - Oct 25 2013

Keywords

  • Angiogenesis
  • Hedgehogs
  • Ischemia
  • Muscle
  • Pathological
  • Regeneration
  • Skeletal

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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