Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Neurology, the People's Hospital of China Three Gorges University, Institute of Translational Neuroscience, Three Gorges University College of Medicine, Yichang 443002, China.
EBioMedicine. 2019 Jan;39:95-108. doi: 10.1016/j.ebiom.2018.12.023. Epub 2018 Dec 19.
Neointimal hyperplasia is a prominent pathological event during in-stent restenosis. Phenotype switching of vascular smooth muscle cells (VSMCs) from a differentiated/contractile to a dedifferentiated/synthetic phenotype, accompanied by migration and proliferation of VSMCs play an important role in neointimal hyperplasia. However, the molecular mechanisms underlying phenotype switching of VSMCs have yet to be fully understood.
The mouse carotid artery ligation model was established to evaluate Sema3A expression and its role during neointimal hyperplasia in vivo. Bioinformatics analysis, chromatin immunoprecipitation (ChIP) assays and promoter-luciferase reporter assays were used to examine regulatory mechanism of Sema3A expression. SiRNA transfection and lentivirus infection were performed to regulate Sema3A expression. EdU assays, Wound-healing scratch experiments and Transwell migration assays were used to assess VSMC proliferation and migration.
In this study, we found that semaphorin-3A (Sema3A) was significantly downregulated in VSMCs during neointimal hyperplasia after vascular injury in mice and in human atherosclerotic plaques. Meanwhile, Sema3A was transcriptionally downregulated by PDGF-BB via p53 in VSMCs. Furthermore, we found that overexpression of Sema3A inhibited VSMC proliferation and migration, as well as increasing differentiated gene expression. Mechanistically, Sema3A increased the NRP1-plexin-A1 complex and decreased the NRP1-PDGFRβ complex, thus inhibiting phosphorylation of PDGFRβ. Moreover, we found that overexpression of Sema3A suppressed neointimal hyperplasia after vascular injury in vivo.
These results suggest that local delivery of Sema3A may act as a novel therapeutic option to prevent in-stent restenosis.
血管平滑肌细胞（VSMC）向去分化/合成表型的表型转换，伴随着 VSMC 的迁移和增殖，是支架内再狭窄过程中新生内膜增生的一个突出的病理事件。然而，VSMC 表型转换的分子机制尚未完全阐明。
建立小鼠颈总动脉结扎模型，评估 Sema3A 在体内新生内膜增生过程中的表达及其作用。采用生物信息学分析、染色质免疫沉淀（ChIP）实验和启动子-荧光素酶报告基因实验检测 Sema3A 表达的调控机制。通过 siRNA 转染和慢病毒感染来调节 Sema3A 的表达。EdU 检测、划痕实验和 Transwell 迁移实验用于评估 VSMC 的增殖和迁移。
在这项研究中，我们发现，在小鼠血管损伤后新生内膜增生过程中和人动脉粥样硬化斑块中，信号素 3A（Sema3A）在 VSMC 中显著下调。同时，PDGF-BB 通过 p53 在 VSMC 中转录下调 Sema3A 的表达。此外，我们发现过表达 Sema3A 抑制 VSMC 的增殖和迁移，并增加分化基因的表达。机制上，Sema3A 增加了 NRP1- 神经纤毛蛋白 1（plexin-A1）复合物，减少了 NRP1-血小板衍生生长因子受体β（PDGFRβ）复合物，从而抑制 PDGFRβ 的磷酸化。此外，我们发现过表达 Sema3A 抑制了体内血管损伤后的新生内膜增生。
这些结果表明，局部递送 Sema3A 可能成为预防支架内再狭窄的一种新的治疗选择。
Zotero 插件
