title: Sonic hedgehog regulates angiogenesis and myogenesis during post-natal skeletal muscle regeneration.
abstract: 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.
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Straface
authors.affiliation: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Aprahamian
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Flex
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gaetani
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Biscetti
authors.affiliation: Center of Cardiovascular Research, Department of Medicine, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Roy C
authors.initials: RC
authors.lastname: Smith
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pecorini
authors.affiliation: Department of Orthopedics, Catholic University School of Medicine, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Pola
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, Catholic University School of Medicine, Rome, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Angelini
authors.affiliation: Department of Pathology, Catholic University School of Medicine, Rome, Italy.
authors.forename: Egidio
authors.initials: E
authors.lastname: Stigliano
authors.affiliation: Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Castellot
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.affiliation: 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.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pola
mesh_terms: 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*
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse