Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Swansea College of Medicine, Swansea University, Singleton Park, Swansea, Wales SA2 8PP, UK.
Cardiovasc Res. 2017 Dec 1;113(14):1763-1775. doi: 10.1093/cvr/cvx190.
The migration and proliferation of vascular smooth muscle cells (VSMCs) are crucial events in the neointimal formation, a hallmark of atherosclerosis and restenosis. Semaphorin3E (Sema3E) has been found to be a critical regulator of cell migration and proliferation in many scenarios. However, its role on VSMCs migration and proliferation is unclear. This study aimed to investigate the effect of Sema3E on VSMCs migration, proliferation and neointimal formation, and explore possible mechanisms.
We found that the expression of Sema3E was progressively decreased during neointimal formation in a carotid ligation model. H&E-staining showed lentivirus-mediated overexpression of Sema3E in carotid ligation area attenuated neointimal formation. Immunofluorescence staining showed that the receptor (PlexinD1) of Sema3E was expressed in vascular walls. In cultured mouse VSMCs, Sema3E inhibited VSMCs migration and proliferation via plexinD1 receptor. The inhibitory effect was mediated, at least in part, by inactivating Rap1-AKT signalling pathways in VSMCs. Moreover, we found that PDGFBB down-regulated the expression of Sema3E in VSMCs and Sema3E notably inhibited the expression of PDGFB in endothelial cells. In addition, the number of Sema3E-positive VSMCs was diminished in plaques of atherosclerotic patients. Results from a public GEO microarray database showed a negative correlation between Sema3E and PDGFB transcriptional levels in the human plaques examined.
Our study demonstrates that Sema3E/plexinD1 inhibits proliferation and migration of VSMCs via inactivation of Rap1-AKT signalling pathways. The mutual inhibition between PDGF-BB and Sema3E after vascular injury plays a critical role in the process of neointimal formation.
血管平滑肌细胞（VSMCs）的迁移和增殖是新内膜形成的关键事件，也是动脉粥样硬化和再狭窄的标志。在许多情况下，神经信号蛋白 3E（Sema3E）已被发现是细胞迁移和增殖的关键调节因子。然而，其在 VSMCs 迁移和增殖中的作用尚不清楚。本研究旨在探讨 Sema3E 对 VSMCs 迁移、增殖和新内膜形成的影响，并探索可能的机制。
我们发现，在颈动脉结扎模型中，新内膜形成过程中 Sema3E 的表达逐渐降低。H&E 染色显示，慢病毒介导的 Sema3E 过表达可减轻颈动脉结扎区的新内膜形成。免疫荧光染色显示，Sema3E 的受体（PlexinD1）在血管壁中表达。在培养的小鼠 VSMCs 中，Sema3E 通过 PlexinD1 受体抑制 VSMCs 的迁移和增殖。这种抑制作用至少部分是通过使 VSMCs 中的 Rap1-AKT 信号通路失活介导的。此外，我们发现 PDGFBB 下调 VSMCs 中 Sema3E 的表达，而 Sema3E 显著抑制内皮细胞中 PDGFB 的表达。此外，在动脉粥样硬化患者的斑块中，Sema3E 阳性 VSMCs 的数量减少。来自公共 GEO 微阵列数据库的结果表明，在所研究的人类斑块中，Sema3E 和 PDGFB 的转录水平呈负相关。
本研究表明，Sema3E/PlexinD1 通过使 Rap1-AKT 信号通路失活来抑制 VSMCs 的增殖和迁移。血管损伤后 PDGF-BB 和 Sema3E 之间的相互抑制在新内膜形成过程中起着关键作用。
