Extracellular Vesicles Derived from Human Umbilical Cord MSC Improve Vascular Endothelial Function in In Vitro and In Vivo Models of Preeclampsia through Activating Arginine Metabolism.
Extracellular Vesicles Derived from Human Umbilical Cord MSC Improve Vascular Endothelial Function in In Vitro and In Vivo Models of Preeclampsia through Activating Arginine Metabolism.
复制标题
来源于人脐带MSC的细胞外囊泡通过激活精氨酸代谢改善先兆子痫体外和体内模型的血管内皮功能。
DOI：
10.1021/acs.molpharmaceut.3c00816
复制
发表时间：
2023-10
影响因子：
4.9
通讯作者：
Zhaoer Yu;Wei Zhang;Yixiao Wang;Mingming Gao;Min Zhang;Dan Yao;Chengping Qiao;Xianwei Cui;Ruizhe Jia
中科院分区：
文献类型：
--
作者：
Zhaoer Yu;Wei Zhang;Yixiao Wang;Mingming Gao;Min Zhang;Dan Yao;Chengping Qiao;Xianwei Cui;Ruizhe Jia
内皮细胞损伤是子痫前期（PE）的重要特征。人脐带间充质干细胞衍生的细胞外囊泡（HUMSC衍生的EV）已被证明对多种疾病和组织损伤具有治疗作用。然而，HUMSC衍生的EV对PE中内皮损伤的治疗作用仍不清楚。本研究探讨了HUMSC衍生的EV治疗内皮细胞损伤的可能机制。使用肿瘤坏死因子α和脂多糖诱导的内皮功能障碍模型来评估HUMSC衍生的EV对内皮损伤的治疗效果。我们进一步构建了PE小鼠模型，以探索HUMSC衍生的EV在体内的功能。通过代谢组学分析HUMSC衍生的EV处理后内皮细胞中代谢产物的变化，并通过细胞实验进一步验证。HUMSC衍生的EV治疗可以减轻PE中的内皮细胞损伤，涉及细胞增殖、迁移、血管生成和抗炎。重要的是，HUMSC衍生的EV的施用改善PE小鼠中的高血压和蛋白尿，减轻肾损伤，并促进胎盘中的血管形成。此外，代谢组学分析发现，精氨酸代谢途径在HUMSC衍生的EV处理后被激活。我们还观察到精氨酸水平、一氧化氮含量和一氧化氮合酶活性增加，进一步的实验证明激活精氨酸代谢途径可以减轻内皮功能障碍。我们的研究结果表明，HUMSC衍生的EV可以通过激活精氨酸代谢途径来改善PE内皮功能障碍，并可能作为治疗PE的治疗方法。
Endothelial cell damage is an important feature of preeclampsia (PE). Human umbilical mesenchymal stem-cell-derived extracellular vesicles (HUMSCs-derived EVs) have been shown to have therapeutic effects on a variety of diseases and tissue damage. However, the therapeutic effect of HUMSCs-derived EVs on endothelial injury in PE remains unclear. This study explored the possible mechanism of HUMSCs-derived EVs in the treatment of endothelial cell injury. Tumor necrosis factor α- and lipopolysaccharide-induced endothelial dysfunction models were used to evaluate the therapeutic effect of HUMSCs-derived EVs on endothelial injury. We further constructed PE mouse models to explore the function of HUMSCs-derived EVs in vivo. The changes of metabolites in endothelial cells after HUMSCs-derived EVs treatment were analyzed by metabolomics analysis and further validated by cell experiments. HUMSCs-derived EVs treatment can alleviate endothelial cell injury in PE, involving cell proliferation, migration, angiogenesis, and anti-inflammatory. Importantly, administration of HUMSCs-derived EVs improves hypertension and proteinuria in PE mice, alleviates kidney damage, and promotes vascularization in the placenta. Furthermore, metabolomics analysis found that the arginine metabolic pathway is activated after HUMSCs-derived EVs treatment. We also observed increased arginine level, nitric oxide content, and nitric oxide synthase activity, and further experiments proved that activating the arginine metabolic pathway could alleviate endothelial dysfunction. Our results reveal that HUMSCs-derived EVs could ameliorate PE endothelial dysfunction by activating the arginine metabolic pathway and may serve as a therapeutic method for treating PE.