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. 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

Sonic hedgehog mediates a novel pathway of PDGF-BB–dependent vessel maturation

“…This finding reveals a new effect of Shh on SMCs, in addition to its previously demonstrated role in proliferation of these cells. [16][17][18] Even if Hh proteins are suggested to act on angiogenesis only indirectly, 12,31,32 ECs were shown to respond to Shh by increasing their migration and the impermeability of the brain endothelium. 33 In the context of growing vessels, SMC-derived Shh may not only act on SMCs themselves, but also on the neighborhood ECs by stimulating their migration and consequently by promoting vessel growth.…”

Extracellular Vesicles as Therapeutic Tools in Cardiovascular Diseases

“…Controversy regarding Shh signaling is also present in vivo since Shh-induced angiogenesis is not affected in Gli1 null-mice (74), whereas capillaries morphogenesis is inhibited by the presence of Gli1 inhibitor GANT61 (70). Impaired angiogenesis in ischemic tissue of middle-aged or old mice is associated with a decrease in Gli1 transcription factor mRNA expression (68, 75). These results reflect the complex interplay between canonical and non-canonical Shh pathways, or at least that of the Gli family of transcription factors, in the regulation of tubulogenesis and angiogenesis processes.…”

Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

“…Shh can protect neurons against various stresses, including the amyloid β-peptide, high levels of glutamate, hydrogen peroxide, and rotenone, all are molecules or mediators related to ischemic injury or neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [53]. It is suggested that Shh may function as an anti-aging signal [33,54] based on several lines of evidence; these include the observations that the total Shh activity or inducibility are notably reduced in older animals [55], the age-related process of cellular senescence is blocked by active Shh signaling [56], and Shh-targeting drugs possess the potential to mitigate aging-related pathological conditions [57]. …”