The excessive proliferation and migration of vascular smooth muscle cells (VSMCs) play vital roles in neointimal hyperplasia and vascular restenosis. In the present study, we aimed to investigate the function and mechanism of octamer‐binding transcription factor 4 (OCT4, a key transcription factor for maintaining stem cells in de‐differentiated state) on neointima formation in response to vascular injury. Quantitative reverse‐transcription polymerase chain reaction and western blot results displayed a significant increase of OCT4 levels in injured carotid arteries. Immunohistochemistry and immunofluorescence assays confirmed that the increased OCT4 expression was primarily localized in α‐SMA‐positive VSMCs from neointima, and colocalized with PCNA in the nuclei of VSMCs. Adenovirus‐mediated OCT4 overexpression in injured carotid arteries exacerbated intimal thickening, while OCT4 knockdown significantly inhibited intimal thickening. In‐vitro experiments confirmed that the increased OCT4 expression in VMSCs could be induced by platelet‐derived growth factor‐BB (PDGF‐BB) in a time‐dependent manner. Overexpression of OCT4 greatly promoted VSMCs proliferation and migration, while OCT4 knockdown significantly retarded the PDGF‐BB‐induced excessive proliferation and migration of VSMCs. Bioinformatics analysis, dual‐luciferase reporter assay, and chromatin immunoprecipitation assay confirmed that OCT4 could upregulate matrix metalloproteinases 2 (MMP2) expression through promoting its transcription. Moreover, knockdown of MMP2 significantly attenuated OCT4‐mediated VSMCs proliferation and migration. These results indicated that OCT4 facilitated neointimal formation in response to vascular injury by MMP2‐mediated VSMCs proliferation and migration, and targeting OCT4 in VSMCs might be a novel therapeutic strategy for vascular restenosis.

中文翻译：

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OCT4 通过基质金属蛋白酶 2 介导的平滑肌细胞增殖和迁移调节受损小鼠动脉中的新内膜形成

血管平滑肌细胞 (VSMC) 的过度增殖和迁移在新生内膜增生和血管再狭窄中起重要作用。在本研究中，我们旨在研究八聚体结合转录因子 4（OCT4，一种维持干细胞处于去分化状态的关键转录因子）对血管损伤后新生内膜形成的作用和机制。定量逆转录聚合酶链反应和蛋白质印迹结果显示受损颈动脉中 OCT4 水平显着增加。免疫组织化学和免疫荧光分析证实，OCT4 表达的增加主要定位于来自新内膜的 α-SMA 阳性 VSMC，并与 VSMC 细胞核中的 PCNA 共定位。受损颈动脉中腺病毒介导的 OCT4 过表达加剧了内膜增厚，而 OCT4 敲低显着抑制了内膜增厚。体外实验证实，血小板衍生生长因子-BB (PDGF-BB) 可以以时间依赖性方式诱导 VMSCs 中 OCT4 表达的增加。OCT4 的过表达极大地促进了 VSMCs 的增殖和迁移，而 OCT4 敲低显着延缓了 PDGF-BB 诱导的 VSMCs 的过度增殖和迁移。生物信息学分析、双荧光素酶报告基因分析和染色质免疫沉淀分析证实 OCT4 可以通过促进其转录来上调基质金属蛋白酶 2 (MMP2) 的表达。此外，MMP2 的敲低显着减弱了 OCT4 介导的 VSMC 增殖和迁移。