ABSTRACT

The prevalence of arterial stiffness and hypertension increases with age. This study investigates the effect of induced pluripotent mesenchymal stem cell-derived extracellular vesicles (EVs) on ageing-associated arterial stiffness and hypertension. EVs were collected and purified from induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs). Young and old male C57BL/6 mice were used. Mice in the EVs group were injected via tail vein once a week for four weeks (18 x 10⁶ EVs/mouse/injection). Blood pressure (BP) was measured using the tail-cuff method and validated by direct cannulation. Pulse wave velocity (PWV) was measured using a Doppler workstation. PWV and BP were increased significantly in the old mice, indicating arterial stiffness and hypertension. Intravenous administration of EVs significantly attenuated ageing-related arterial stiffness and hypertension, while enhancing endothelium-dependent vascular relaxation and arterial compliance in the old EVs mice. Elastin degradation and collagen I deposition (fibrosis) were increased in aortas of the old mice, but EVs substantially improved ageing-associated structural remodelling. Mechanistically, EVs abolished downregulation of sirtuin type 1 (SIRT1), and endothelial nitric oxide synthase (eNOS) protein expression in aortas of the older mice. In cultured human aortic endothelial cells, EVs promoted the expression of SIRT1, AMP-activated protein kinase alpha (AMPKα), and eNOS. In conclusion, iPS-MSC-derived EVs attenuated ageing-associated vascular endothelial dysfunction, arterial stiffness, and hypertension, likely via activation of the SIRT1-AMPKα-eNOS pathway and inhibition of MMPs and elastase. Thus, EVs mitigate arterial ageing. This finding also sheds light into the therapeutic potential of EVs for ageing-related vascular diseases.

Abbreviations

EV: Extracellular vesicles; iPS: induced pluripotent stem cell; MSC: mesenchymal stem cell; AMPKα: AMP activated protein kinase α; eNOS: endothelial nitric oxide synthase; Sirt1: sirtuin 1; JNC7: Seventh Report of the Joint National Committee; CVD: cardiovascular disease; PWV: pulse wave velocity; BP: blood pressure; SNP: sodium nitroprusside

中文翻译：

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干细胞衍生的细胞外囊泡可减轻与衰老相关的动脉僵硬度和高血压。

 抽象的

动脉硬化和高血压的患病率随着年龄的增长而增加。本研究探讨诱导多能间充质干细胞来源的细胞外囊泡 (EV) 对衰老相关动脉僵硬度和高血压的影响。从诱导多能干细胞衍生的间充质干细胞 (iPS-MSC) 中收集和纯化 EV。使用年轻和年老的雄性C57BL/6小鼠。 EV 组中的小鼠每周一次通过尾静脉注射，持续四个星期（18 x 10 ⁶ EV/小鼠/注射）。使用尾套法测量血压（BP），并通过直接插管进行验证。使用多普勒工作站测量脉搏波速度（PWV）。年老小鼠的 PWV 和 BP 显着升高，表明动脉硬化和高血压。静脉注射 EV 可显着减轻衰老相关的动脉僵硬度和高血压，同时增强老年 EV 小鼠的内皮依赖性血管舒张和动脉顺应性。年老小鼠的主动脉中弹性蛋白降解和 I 型胶原蛋白沉积（纤维化）增加，但 EV 显着改善了与衰老相关的结构重塑。从机制上讲，EVs 消除了老年小鼠主动脉中 1 型去乙酰化酶 (SIRT1) 和内皮一氧化氮合酶 (eNOS) 蛋白表达的下调。在培养的人主动脉内皮细胞中，EV 促进 SIRT1、AMP 激活蛋白激酶 α (AMPKα) 和 eNOS 的表达。总之，iPS-MSC 衍生的 EV 可能通过激活 SIRT1-AMPKα-eNOS 通路以及抑制 MMP 和弹性蛋白酶来减轻衰老相关的血管内皮功能障碍、动脉僵硬度和高血压。因此，电动汽车可以减轻动脉老化。 这一发现还揭示了电动汽车治疗衰老相关血管疾病的潜力。

 缩写

EV：细胞外囊泡； iPS：诱导多能干细胞； MSC：间充质干细胞； AMPKα：AMP 激活的蛋白激酶 α； eNOS：内皮一氧化氮合酶； Sirt1：去乙酰化酶1； JNC7：国家联合委员会第七次报告； CVD：心血管疾病； PWV：脉搏波速度； BP：血压； SNP：硝普钠