Department of Cardiology, Ishikawa, Japan; Department of System Biology, Ishikawa, Japan.
Department of Cardiology, Ishikawa, Japan; Department of System Biology, Ishikawa, Japan.
Biochem Biophys Res Commun. 2019 Mar 26;511(1):179-184. doi: 10.1016/j.bbrc.2019.02.047. Epub 2019 Feb 15.
Vascular remodeling, resulting from proliferation and migration of vascular smooth muscle cells (VSMCs), is a major cause of atherosclerosis and restenosis. The lysophospholipid mediator sphingosine-1-phosphate (S1P) regulates proliferation and migration of VSMCs via S1P-specific G protein-coupled receptors, including S1P receptor 1 (S1PR1) to S1PR3. However, the role of S1PR1 in vascular remodeling is not well understood. Therefore, in this study, we aimed to investigate the effect of S1PR1 on neointimal hyperplasia in a carotid artery ligation mouse model using transgenic C57Bl/6 mice that overexpressed S1PR1 (Tg-S1PR1) under the control of α-smooth muscle actin promoter. We found that S1PR1 expression in carotid artery was upregulated after carotid artery ligation in non-transgenic (nTg) mice. Tg-S1PR1 mice showed enhanced ligation-induced neointimal hyperplasia with increased neointimal cell proliferation, compared with control nTg mice. VSMCs isolated from Tg-S1PR1 mice showed enhanced proliferation and migration in response to S1P stimulation. VSMCs from Tg-S1PR1 mice showed greater expression of interleukin-6 (IL-6) compared with nTg mouse-derived VSMCs, and administration of IL-6-neutralizing antibody into Tg-S1PR1 mice suppressed neointimal hyperplasia. These results suggest that S1P-S1PR1 signaling plays an important role in neointimal hyperplasia after vascular injury via IL-6 production.
血管重构是动脉粥样硬化和再狭窄的主要原因，其源于血管平滑肌细胞（VSMC）的增殖和迁移。溶血磷脂介质 1-磷酸鞘氨醇（S1P）通过 S1P 特异性 G 蛋白偶联受体（包括 S1P 受体 1（S1PR1）到 S1PR3）来调节 VSMC 的增殖和迁移。然而，S1PR1 在血管重构中的作用尚不清楚。因此，在这项研究中，我们旨在使用在α-平滑肌肌动蛋白启动子控制下过表达 S1PR1 的转基因 C57Bl/6 小鼠（Tg-S1PR1）研究 S1PR1 在颈动脉结扎小鼠模型中的血管重构中的作用。我们发现，在非转基因（nTg）小鼠的颈动脉结扎后，颈动脉中的 S1PR1 表达上调。与对照 nTg 小鼠相比，Tg-S1PR1 小鼠表现出增强的结扎诱导性新生内膜增生，伴有新生内膜细胞增殖增加。与 nTg 鼠来源的 VSMC 相比，从 Tg-S1PR1 小鼠分离出的 VSMC 在 S1P 刺激下显示出增强的增殖和迁移。与 nTg 鼠来源的 VSMC 相比，Tg-S1PR1 小鼠来源的 VSMC 表达更高水平的白细胞介素 6（IL-6），并且向 Tg-S1PR1 小鼠中给予 IL-6 中和抗体可抑制新生内膜增生。这些结果表明，S1P-S1PR1 信号通过 IL-6 的产生在血管损伤后的新生内膜增生中起重要作用。
