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Endogenous Sonic Hedgehog limits inflammation and angiogenesis in the ischaemic skeletal muscle of mice.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2018 Apr 01; Vol. 114 (5), pp. 759-770. - Publication Year :
- 2018
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Abstract
- Aims: Hedgehog (Hh) signalling has been shown to be re-activated in ischaemic tissues and participate in ischaemia-induced angiogenesis. Sonic Hedgehog (Shh) is upregulated by more than 80-fold in the ischaemic skeletal muscle, however its specific role in ischaemia-induced angiogenesis has not yet been fully investigated. The purpose of the present study was to investigate the role of endogenous Shh in ischaemia-induced angiogenesis.<br />Methods and Results: To this aim, we used inducible Shh knock-out (KO) mice and unexpectedly found that capillary density was significantly increased in re-generating muscle of Shh deficient mice 5 days after hind limb ischaemia was induced, demonstrating that endogenous Shh does not promote angiogenesis but more likely limits it. Myosin and MyoD expression were equivalent in Shh deficient mice and control mice, indicating that endogenous Shh is not required for ischaemia-induced myogenesis. Additionally, we observed a significant increase in macrophage infiltration in the ischaemic muscle of Shh deficient mice. Our data indicate that this was due to an increase in chemokine expression by myoblasts in the setting of impaired Hh signalling, using tissue specific Smoothened conditional KO mice. The increased macrophage infiltration in mice deficient for Hh signalling in myocytes was associated with increased VEGFA expression and a transiently increased angiogenesis, demonstrating that Shh limits inflammation and angiogenesis indirectly by signalling to myocytes.<br />Conclusion: Although ectopic administration of Shh has previously been shown to promote ischaemia-induced angiogenesis, the present study reveals that endogenous Shh does not promote ischaemia-induced angiogenesis. On the contrary, the absence of Shh leads to aberrant ischaemic tissue inflammation and a transiently increased angiogenesis.
- Subjects :
- Animals
Blood Flow Velocity
Chemokines metabolism
Chemotaxis
Disease Models, Animal
Hedgehog Proteins deficiency
Hedgehog Proteins genetics
Hindlimb
Inflammation genetics
Inflammation physiopathology
Inflammation prevention & control
Ischemia genetics
Ischemia physiopathology
Macrophages metabolism
Mice, Knockout
Myoblasts, Skeletal metabolism
Regional Blood Flow
Signal Transduction
Time Factors
Vascular Endothelial Growth Factor A metabolism
Hedgehog Proteins metabolism
Inflammation metabolism
Ischemia metabolism
Muscle, Skeletal blood supply
Muscle, Skeletal metabolism
Neovascularization, Physiologic
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 114
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 29365079
- Full Text :
- https://doi.org/10.1093/cvr/cvy017