Department of Geriatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Geriatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biomed Pharmacother. 2024 Apr;173:116343. doi: 10.1016/j.biopha.2024.116343. Epub 2024 Feb 29.
Therapeutic neovascularization is a strategy to promote blood vessel growth and improve blood flow, which is critical to tissue repair and regeneration in ischemic diseases. Here, we investigated the role of endothelial progenitor cell - derived exosomes (EPC-Exos) in therapeutic neovascularization and clarified the mechanism of hsa_circ_0093884 in EPC-Exos mediated neovascularization. Injection of EPC-Exos improved mouse ischemic hindlimb perfusion, promoted angiogenesis in Matrigel plugs and mouse skin wound healing. In vitro coculture with EPC-Exos improved HUVEC proliferation, angiogenic and migration ability, while alleviated hypoxia-induced apoptosis. hsa_circ_0093884 was identified from eleven types of circRNA derived from SIRT1 and proved to be enriched in EPC-Exos. Overexpression of hsa_circ_0093884 in EPC-Exos further enhanced the angiogenic capacity, while knockdown of hsa_circ_0093884 abolished the benefits. Mechanistically, EPC-Exos mediated shuttling of hsa_circ_0093884 induced cytoplasmic sponge of miR-145, thereby releasing repression of SIRT1. In vitro co-transfection indicated silence of miR-145 further strengthened the angiogenic effect of hsa_circ_0093884, while overexpression of miR-145 inhibited hsa_circ_0093884 mediated angiogenesis and abolished the beneficial effect of EPC-Exos. Furthermore, in vivo experiments using endothelial specific SIRT1 conditional knockout mice indicated hsa_circ_0093884 overexpressing EPC-Exos failed to promote therapeutic neovascularization in SIRT1 mice. Collectively, our results demonstrated that EPC-Exos promoted therapeutic neovascularization through hsa_circ_0093884/miR-145/SIRT1 axis.
治疗性血管新生是一种促进血管生长和改善血流的策略，这对于缺血性疾病中的组织修复和再生至关重要。在这里，我们研究了内皮祖细胞衍生的外泌体（EPC-Exos）在治疗性血管新生中的作用，并阐明了 hsa_circ_0093884 在 EPC-Exos 介导的血管新生中的作用机制。EPC-Exos 的注射改善了小鼠缺血后肢的灌注，促进了 Matrigel 塞子和小鼠皮肤伤口愈合中的血管生成。体外与 EPC-Exos 的共培养改善了 HUVEC 的增殖、血管生成和迁移能力，同时减轻了缺氧诱导的细胞凋亡。从 SIRT1 衍生的 11 种 circRNA 中鉴定出 hsa_circ_0093884，并证明其在 EPC-Exos 中富集。EPC-Exos 中 hsa_circ_0093884 的过表达进一步增强了血管生成能力，而 hsa_circ_0093884 的敲低则消除了其益处。机制上，EPC-Exos 介导的 hsa_circ_0093884 穿梭诱导细胞质 miR-145 的海绵化，从而释放 SIRT1 的抑制作用。体外共转染表明 miR-145 的沉默进一步增强了 hsa_circ_0093884 的血管生成作用，而过表达 miR-145 则抑制 hsa_circ_0093884 介导的血管生成，并消除了 EPC-Exos 的有益作用。此外，使用内皮特异性 SIRT1 条件性敲除小鼠的体内实验表明，EPC-Exos 过表达 hsa_circ_0093884 未能促进 SIRT1 小鼠的治疗性血管新生。总之，我们的研究结果表明，EPC-Exos 通过 hsa_circ_0093884/miR-145/SIRT1 轴促进了治疗性血管新生。
