Vascular Remodeling and Regeneration Group, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Cardiovasc Res. 2017 Nov 1;113(13):1653-1663. doi: 10.1093/cvr/cvx158.
Adventitial cells have been suggested to contribute to neointima formation, but the functional relevance and the responsible signalling pathways are largely unknown. Sonic hedgehog (Shh) is a regulator of vasculogenesis and promotes angiogenesis in the adult.
Here we show that proliferation of vascular smooth muscle cells (SMC) after wire-induced injury in C57BL/6 mice is preceded by proliferation of adventitial fibroblasts. Simultaneously, the expression of Shh and its downstream signalling protein smoothened (SMO) were robustly increased within injured arteries. In vitro, combined stimulation with Shh and platelet-derived growth factor (PDGF)-BB strongly induced proliferation and migration of human adventitial fibroblasts. The supernatant of these activated fibroblasts contained high levels of interleukin-6 and -8 and strongly induced proliferation and migration of SMC. Inhibition of SMO selectively prevented fibroblast proliferation, cytokine release, and paracrine SMC activation. Mechanistically, we found that PDGF-BB activates protein kinase A in fibroblasts and thereby induces trafficking of SMO to the plasma membrane, where it can be activated by Shh. In vivo, SMO-inhibition significantly prevented the proliferation of adventitial fibroblasts and neointima formation following wire-induced injury.
The initial activation of adventitial fibroblasts is essential for the subsequent proliferation of SMC and neointima formation. We identified SMO-dependent Shh signalling as a specific process for the activation of adventitial fibroblasts.
已有研究提示外膜细胞可能参与到新生内膜的形成过程中，但对于其功能相关性及相关信号通路仍知之甚少。 sonic hedgehog (Shh) 是血管发生的调控因子，可促进成年个体血管生成。
在这里我们发现，在 C57BL/6 小鼠的血管损伤后，血管平滑肌细胞（SMC）的增殖是在外膜成纤维细胞增殖之后发生的。同时，Shh 及其下游信号蛋白 smoothened (SMO) 的表达在损伤的动脉中显著增加。在体外，Shh 和血小板衍生生长因子（PDGF）-BB 的联合刺激强烈诱导人外膜成纤维细胞的增殖和迁移。这些激活的成纤维细胞的上清液中含有高水平的白细胞介素-6 和白细胞介素-8，并强烈诱导 SMC 的增殖和迁移。SMO 的抑制作用可选择性地阻止成纤维细胞的增殖、细胞因子的释放和旁分泌的 SMC 激活。在机制上，我们发现 PDGF-BB 在成纤维细胞中激活蛋白激酶 A，并由此诱导 SMO 向质膜的运输，在质膜中 Shh 可以激活 SMO。在体内，SMO 抑制显著阻止了血管损伤后外膜成纤维细胞的增殖和新生内膜的形成。
外膜成纤维细胞的初始激活对于随后的 SMC 增殖和新生内膜形成是必需的。我们确定了 SMO 依赖性 Shh 信号作为激活外膜成纤维细胞的特定过程。
