Sonic hedgehog regulates angiogenesis and myogenesis during post-natal skeletal muscle regeneration.
Sonic hedgehog (Shh) is a morphogen-regulating crucial epithelial-mesenchymal interactions during embryonic development, but its signalling pathway is considered generally silent in post-natal life. In this study, we demonstrate that Shh is de novo expressed after injury and during regeneration of the adult skeletal muscle. Shh expression is followed by significant up-regulation of its receptor and target gene Ptc1 in injured and regenerating muscles. The reactivation of the Shh signalling pathway has an important regulatory role on injury-induced angiogenesis, as inhibition of Shh function results in impaired up-regulation of prototypical angiogenic agents, such as vascular endothelial growth factor (VEGF) and stromal-derived factor (SDF)-1alpha, decreased muscle blood flow and reduced capillary density after injury. In addition, Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors Myf-5 and MyoD, decreases the up-regulation of insulin-like growth factor (IGF)-1 and reduces the number of myogenic satellite cells at injured site. Finally, Shh inhibition results in muscle fibrosis, increased inflammatory reaction and compromised motor functional recovery after injury. These data demonstrate that the Shh pathway is functionally important for adult skeletal muscle regeneration and displays pleiotropic angiogenic and myogenic potentials in post-natal life. These findings might constitute the foundation for new therapeutic approaches for muscular diseases in humans.
Straface
Giuseppe
G
Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
Aprahamian
Tamar
T
Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
Flex
Andrea
A
Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
Gaetani
Eleonora
E
Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
Biscetti
Federico
F
Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
Smith
Roy C
RC
Center of Cardiovascular Research, Department of Medicine, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Pecorini
Giovanni
G
Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
Pola
Enrico
E
Department of Orthopedics, Catholic University School of Medicine, Rome, Italy.
Angelini
Flavia
F
Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
Stigliano
Egidio
E
Department of Pathology, Catholic University School of Medicine, Rome, Italy.
Castellot
John J
JJ
Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, MA, USA.
Losordo
Douglas W
DW
Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL, USA.
Pola
Roberto
R
Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.|Center of Cardiovascular Research, Department of Medicine, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.|IRCCS OASI, Troina, Italy.
D000818:Animals; D053823:Hedgehog Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012038:Regeneration / Q000502:physiology*
D053823:Hedgehog Proteins; C465570:Shh protein, mouse