Stem cell-derived extracellular vesicles mitigate ageing-associated arterial stiffness and hypertension
Stem cell-derived extracellular vesicles mitigate ageing-associated arterial stiffness and hypertension
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DOI：
10.1080/20013078.2020.1783869
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发表时间：
2020-01-01
影响因子：
16
通讯作者：
Sun, Zhongjie
中科院分区：
文献类型：
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作者：
Feng, Rui;Ullah, Mujib;Sun, Zhongjie
动脉硬化和高血压的患病率随着年龄的增长而增加。本研究探讨了诱导多能间充质干细胞衍生的细胞外囊泡（EV）对年龄相关的动脉僵硬度和高血压的影响。从诱导的多能干细胞衍生的间充质干细胞（iPS-MSC）收集并纯化EV。使用年轻和年老的雄性C57BU6小鼠。EV组中的小鼠每周一次通过尾静脉注射，持续四周（18 X 10（6）EV/小鼠/注射）。采用尾袖法测量血压（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）。老年小鼠PWV和BP显著增加，提示动脉硬化和高血压。静脉注射EV显著减弱了年龄相关的动脉僵硬度和高血压，同时增强了老年EV小鼠的内皮依赖性血管舒张和动脉顺应性。在老年小鼠的动脉中，弹性蛋白降解和胶原蛋白I沉积（纤维化）增加，但EV大大改善了与衰老相关的结构重塑。从机制上讲，EV取消了老年小鼠睾丸中sirtuin 1型（SIRT 1）和内皮型一氧化氮合酶（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（AMPKa）和eNOS的表达。总之，iPS-MSC衍生的EV可能通过激活SIRT1-AMPK α-eNOS通路和抑制MMP和弹性蛋白酶来减轻衰老相关的血管内皮功能障碍、动脉僵硬和高血压。因此，EV缓解动脉老化。这一发现也揭示了电动汽车对衰老相关血管疾病的治疗潜力。
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 C57BU6 mice were used. Mice in the EVs group were injected via tail vein once a week for four weeks (18 x 10(6) 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 (AMPKa), and eNOS. In conclusion, iPS-MSC-derived EVs attenuated ageing-associated vascular endothelial dysfunction, arterial stiffness, and hypertension, likely via activation of the SIRT1-AMPK alpha-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.