Biology of Cardiovascular Diseases, Univ. Bordeaux, Inserm, CHU de Bordeaux, F-33604 Pessac, France.
Cardiovasc Res. 2018 Apr 1;114(5):759-770. doi: 10.1093/cvr/cvy017.
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.
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.
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.
已有研究表明 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。在缺血骨骼肌中，Sonic Hedgehog（Shh）的表达上调超过 80 倍，但 Shh 在缺血诱导的血管生成中的具体作用尚未得到充分研究。本研究旨在探讨内源性 Shh 在缺血诱导的血管生成中的作用。
为此，我们使用诱导型 Shh 敲除（KO）小鼠，出乎意料的是，在诱导后肢缺血 5 天后，Shh 缺陷小鼠的再生肌肉中的毛细血管密度显著增加，这表明内源性 Shh 不会促进血管生成，而是可能限制其生成。Shh 缺陷小鼠和对照组小鼠的肌球蛋白和 MyoD 表达相当，表明内源性 Shh 不是缺血诱导的成肌所必需的。此外，我们观察到 Shh 缺陷小鼠缺血肌肉中的巨噬细胞浸润明显增加。我们的数据表明，这是由于在 Hh 信号受损的情况下，成肌细胞中趋化因子表达增加所致，这是通过组织特异性 Smoothened 条件性 KO 小鼠观察到的。在缺乏 Hh 信号的小鼠中，巨噬细胞浸润增加与 VEGFA 表达增加和短暂的血管生成增加有关，这表明 Shh 通过向肌细胞发出信号间接限制炎症和血管生成。
尽管先前已表明外源性 Shh 可促进缺血诱导的血管生成，但本研究揭示内源性 Shh 并不促进缺血诱导的血管生成。相反，缺乏 Shh 会导致缺血组织炎症异常和短暂的血管生成增加。
