Hedgehog-dependent regulation of angiogenesis and myogenesis is impaired in aged mice.
Arterioscler Thromb Vasc Biol
; 33(12): 2858-66, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-24135022
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
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Músculo Esquelético
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Neovascularização Fisiológica
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Desenvolvimento Muscular
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Proteínas Hedgehog
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Isquemia
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article