Hedgehog-dependent regulation of angiogenesis and myogenesis is impaired in aged mice

Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2858-66. doi: 10.1161/ATVBAHA.113.302494. Epub 2013 Oct 17.

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.

Approach and 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.

Keywords: aging; angiogenesis effect; angiogenesis, pathological; hedgehogs; peripheral arterial disease; regeneration.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genetic Therapy
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Hindlimb
  • Immunoglobulin G / genetics
  • Immunoglobulin G / metabolism
  • Ischemia / genetics
  • Ischemia / metabolism*
  • Ischemia / pathology
  • Ischemia / physiopathology
  • Ischemia / therapy
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Development*
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Neovascularization, Physiologic*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Regeneration
  • Signal Transduction
  • Smoothened Receptor
  • Transfection
  • Zinc Finger Protein GLI1

Substances

  • Boc protein, mouse
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Immunoglobulin G
  • Kruppel-Like Transcription Factors
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Zinc Finger Protein GLI1