title: Hedgehog-dependent regulation of angiogenesis and myogenesis is impaired in aged mice.
abstract: OBJECTIVE
  The purpose of this study is to further document alteration of signal transduction pathways, more particularly of hedgehog (Hh) signaling, causing impaired ischemic muscle repair in old mice.
  
  
  RESULTS
  We used 12-week-old (young mice) and 20- to 24-month-old C57BL/6 mice (old mice) to investigate the activity of Hh signaling in the setting of hindlimb ischemia-induced angiogenesis and skeletal muscle repair. In this model, delayed ischemic muscle repair observed in old mice was associated with an impaired upregulation of Gli1. Sonic Hh expression was not different in old mice compared with young mice, whereas desert Hh (Dhh) expression was downregulated in the skeletal muscle of old mice both in healthy and ischemic conditions. The rescue of Dhh expression by gene therapy in old mice promoted ischemia-induced angiogenesis and increased nerve density; nevertheless, it failed to promote myogenesis or to increase Gli1 mRNA expression. After further investigation, we found that, in addition to Dhh, smoothened expression was significantly downregulated in old mice. We used smoothened haploinsufficient mice to demonstrate that smoothened knockdown by 50% is sufficient to impair activation of Hh signaling and ischemia-induced muscle repair.
  
  
  CONCLUSIONS
  The present study demonstrates that Hh signaling is impaired in aged mice because of Dhh and smoothened downregulation. Moreover, it shows that hegdehog-dependent regulation of angiogenesis and myogenesis involves distinct mechanisms.
authors.affiliation: From the University of Bordeaux, Adaptation cardiovasculaire à l'ischémie, UMR1034, Pessac, France (M.-A.R., F.R., C.C., Q.Y., S.V., A.R., I.B., C.D., A.-P.G.); INSERM, Adaptation cardiovasculaire à l'ischémie, U1034, Pessac, France (M.-A.R., F.R., C.C., Q.Y., S.V., A.R., I.B., C.D., A.-P.G.); CHU de Bordeaux, Pharmacie de l'Hôpital Haut-Lévêque, Bordeaux, France (C.C., S.V.); and CNRS, UPR-3294, Laboratoire de Neurobiologie et Développement, Institut de Neurobiologie Alfred Fessard IFR2118, Gif-sur-Yvette, France (E.T., M.R.).
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Renault
authors.forename: Fanny
authors.initials: F
authors.lastname: Robbesyn
authors.forename: Candice
authors.initials: C
authors.lastname: Chapouly
authors.forename: Qinyu
authors.initials: Q
authors.lastname: Yao
authors.forename: Soizic
authors.initials: S
authors.lastname: Vandierdonck
authors.forename: Annabel
authors.initials: A
authors.lastname: Reynaud
authors.forename: Isabelle
authors.initials: I
authors.lastname: Belloc
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Traiffort
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.forename: Claude
authors.initials: C
authors.lastname: Desgranges
authors.forename: Alain-Pierre
authors.initials: AP
authors.lastname: Gadeau
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000294:innervation / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018919:Neovascularization, Physiologic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014162:Transfection; D000071676:Zinc Finger Protein GLI1
chemical_list: C510745:Boc protein, mouse; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D051741:Kruppel-Like Transcription Factors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1
keywords: aging; angiogenesis effect; angiogenesis, pathological; hedgehogs; peripheral arterial disease; regeneration