Endogenous Sonic Hedgehog limits inflammation and angiogenesis in the ischaemic skeletal muscle of mice
Endogenous Sonic Hedgehog limits inflammation and angiogenesis in the ischaemic skeletal muscle of mice
复制标题
DOI：
10.1093/cvr/cvy017
复制
发表时间：
2018-04-01
影响因子：
10.8
通讯作者：
Renault, Marie-Ange
中科院分区：
文献类型：
--
作者：
Caradu, Caroline;Guy, Alexandre;Renault, Marie-Ange
Hedgehog（Hh）信号在缺血组织中被重新激活并参与缺血诱导的血管生成。Sonic Hedgehog（Shh）在缺血骨骼肌中上调超过80倍，但其在缺血诱导的血管生成中的具体作用尚未得到充分研究。本研究的目的是研究内源性Shh在缺血诱导的血管生成中的作用。方法和结果为此目的，我们使用诱导性Shh敲除（KO）小鼠，意外地发现在诱导后肢缺血后5天，Shh缺陷小鼠的再生肌肉中毛细血管密度显著增加，肌球蛋白和MyoD表达在Shh缺陷小鼠和对照小鼠中是等同的，表明内源性Shh对于缺血诱导的肌生成不是必需的。此外，我们观察到Shh缺陷小鼠缺血肌肉中巨噬细胞浸润显著增加。我们的数据表明，这是由于使用组织特异性Smoothened条件性KO小鼠，在Hh信号传导受损的情况下，成肌细胞的趋化因子表达增加。增加巨噬细胞浸润的小鼠缺乏Hh信号在肌细胞中与VEGFA表达增加和短暂增加血管生成，表明Shh限制炎症和血管生成间接通过信号到myocytes.Conclusion虽然异位管理的Shh以前已被证明促进缺血诱导的血管生成，本研究表明，内源性Shh不促进缺血诱导的血管生成。相反，Shh的缺乏导致异常的缺血性组织炎症和短暂增加的血管生成。
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.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.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.