Department of Vascular Surgery, 1st Hospital of China Medical University, Shenyang, China.
Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1787-94. doi: 10.1161/ATVBAHA.110.208520.
Proliferation of vascular smooth muscle cells (VSMCs) is a crucial event in the pathogenesis of intimal hyperplasia, the main cause of restenosis following vascular reconstruction. Here, the impact of sonic hedgehog (Shh)/Gli family zinc finger 2 (Gli2) signaling on VSMC proliferation was assessed.
Increased Shh signaling was detected in VSMCs in the neointima of vein grafts obtained from mice undergoing restenosis. Comparable results were found in primary cultured human VSMCs (hVSMCs) obtained from patients undergoing coronary bypass surgery, which were used to further assess the impacts of Shh signaling on VSMC proliferation. Inhibition of Shh signaling in hVSMCs through treatment with cyclopamine or knockdown of Gli2 results in G(1) arrest and reduced cyclin D1, cyclin E, and phosphorylated retinoblastoma (pRB) levels. In contrast, activation of Shh/Gli2 signaling in hVSMCs results in increased levels of G(1) cyclins and promotes G(1)-S transition. Stimulation of hVSMC proliferation by Shh is abolished by cyclin D1 knockdown.
Combined, these results demonstrate that Shh/Gli2 signaling stimulates VSMC proliferation via regulation of the G(1) cyclin-retinoblastoma axis and suggest that antagonists that target the Shh pathway may be therapeutically beneficial in the prevention of intimal hyperplasia.
血管平滑肌细胞（VSMC）的增殖是内膜增生发病机制中的一个关键事件，也是血管重建后再狭窄的主要原因。在这里，评估了 sonic hedgehog（Shh）/Gli 家族锌指蛋白 2（Gli2）信号对 VSMC 增殖的影响。
在经历再狭窄的小鼠静脉移植物的新生内膜中检测到 Shh 信号增加。在从接受冠状动脉旁路手术的患者中获得的原代培养的人血管平滑肌细胞（hVSMCs）中也发现了类似的结果，这些细胞被用于进一步评估 Shh 信号对 VSMC 增殖的影响。通过用 cyclopamine 处理或敲低 Gli2 抑制 hVSMCs 中的 Shh 信号会导致 G1 期停滞和降低 cyclin D1、cyclin E 和磷酸化视网膜母细胞瘤（pRB）水平。相比之下，激活 hVSMCs 中的 Shh/Gli2 信号会增加 G1 期细胞周期蛋白水平并促进 G1-S 过渡。Shh 刺激 hVSMC 增殖被 cyclin D1 敲低所阻断。
综上所述，这些结果表明 Shh/Gli2 信号通过调节 G1 细胞周期蛋白-视网膜母细胞瘤轴刺激 VSMC 增殖，并表明靶向 Shh 途径的拮抗剂可能在预防内膜增生方面具有治疗益处。
