Gli3-Regulation of Myogenesis is Necessary for Ischemia-Induced Angiogenesis
Rationale: A better understanding of mechanism underlying skeletal muscle repair is required to develop therapies that promote tissue regeneration in adults. Hedgehog (Hh) signaling has previously been shown to be involved in myogenesis and angiogenesis, two crucial processes for muscle development and regeneration.
Objective: The objective of this study was to identify the role of the Hh transcription factor Gli3 in the cross-talk between angiogenesis and myogenesis in adults.
Methods and Results: By using conditional KO mice, we found that Gli3 deficiency in endothelial cells (ECs) did not affect ischemic muscle repair, while in myocytes, Gli3 deficiency resulted in severely delayed ischemia-induced 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 Myf5 regulation; In addition, we found that Gli3 regulates several proangiogenic factors including Thymidine phosphorylase and Angiopoietin1 both in vitro and in vivo, which indirectly promote EC proliferation and arteriole formation. Additionally we found that Gli3 is up-regulated 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.
- muscle regeneration
- animal model cardiovascular disease
- myocyte regeneration
- transcription factors
- Received April 9, 2013.
- Revision received September 13, 2013.
- Accepted September 16, 2013.