Ye Yanchen, Huang Lin, Wang Kangjie, Sun Yunhao, Zhou Zhihao, Deng Tang, Liu Yunyan, Wang Rui, Wu Ridong, Yao Chen
Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
J Tissue Eng. 2025 Feb 18;16:20417314251315959. doi: 10.1177/20417314251315959. eCollection 2025 Jan-Dec.
Endothelial injury is a key factor initiating in-stent restenosis (ISR) following peripheral artery stent implantation. Genetically modified endothelial progenitor cells (EPCs) can promote reendothelialization of injured arteries and inhibit neointimal hyperplasia. However, the role of engineered EPCs overexpressing lncRNA H19 in these processes remains unclear. We constructed EPCs overexpressing lncRNA H19 and investigated their effects and mechanisms in promoting reendothelialization and inhibiting neointimal hyperplasia both and . Compared to the normal control group, ISR patients exhibited a significant reduction in circulating EPCs. Engineered EPCs overexpressing lncRNA H19 promoted reendothelialization and inhibited neointimal hyperplasia in injured arteries. Exogenous overexpression of lncRNA H19 significantly upregulated the endothelial repair-related gene S1PR3 in EPCs, while the opposite was also observed. Additionally, engineered EPCs overexpressing S1PR3 promoted reendothelialization and inhibited neointimal hyperplasia in injured arteries. S1PR3 overexpression enhanced EPCs proliferation, migration, and tube formation ; these effects were lost with S1PR3 inhibition. Binding sites for H3K27 acetylation were identified on the S1PR3 promoter. Mechanistically, we found that lncRNA H19 directly interacted with HDAC2, a known H3K27ac deacetylase, disrupting its binding to H3K27 acetylation. Our findings suggest that lncRNA H19 positively regulates S1PR3 expression by disrupting HDAC2 / H3K27ac binding, thereby promoting reendothelialization of injured arteries and inhibiting neointimal hyperplasia.
内皮损伤是外周动脉支架植入术后支架内再狭窄（ISR）发生的关键因素。基因修饰的内皮祖细胞（EPCs）可促进损伤动脉的再内皮化并抑制内膜增生。然而，过表达lncRNA H19的工程化EPCs在这些过程中的作用仍不清楚。我们构建了过表达lncRNA H19的EPCs，并研究了它们在促进再内皮化和抑制内膜增生方面的作用及机制。与正常对照组相比，ISR患者循环EPCs显著减少。过表达lncRNA H19的工程化EPCs促进了损伤动脉的再内皮化并抑制了内膜增生。外源性过表达lncRNA H19显著上调了EPCs中内皮修复相关基因S1PR3的表达，反之亦然。此外，过表达S1PR3的工程化EPCs促进了损伤动脉的再内皮化并抑制了内膜增生。S1PR3过表达增强了EPCs的增殖、迁移和管腔形成；S1PR3抑制后这些作用消失。在S1PR3启动子上鉴定到H3K27乙酰化的结合位点。机制上，我们发现lncRNA H19直接与已知的H3K27ac去乙酰化酶HDAC2相互作用，破坏其与H3K27乙酰化的结合。我们的研究结果表明，lncRNA H19通过破坏HDAC2/H3K27ac结合来正向调节S1PR3表达，从而促进损伤动脉的再内皮化并抑制内膜增生。
