Zuo Jia-Chen, Liang Jun, Hu Nan, Yao Bin, Zhang Qi-Jian, Zeng Xiao-Li, Zhang Ling-Jie, Zhang Xu, Chang Zhe-Han, Chen Chong, Yan Xin-Jian, Shao Wen-Wei, Zhu Ping, Li Xiao-Hong
Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China.
Department of Rehabilitation, General Hospital of Tianjin Medical University, Tianjin, 300074, China.
Bioact Mater. 2025 Jun 18;52:541-563. doi: 10.1016/j.bioactmat.2025.06.018. eCollection 2025 Oct.
Vasogenic edema, caused by the disruption of the blood-brain barrier (BBB), is a significant pathological factor in high-altitude cerebral edema (HACE). Due to the rapid progression and high mortality rate of HACE, prophylactic treatment is important. Mesenchymal stem cell exosomes (MSC-EXO) are increasingly being used in tissue injury repair, and research suggests that appropriate conditioning can enhance the targeted efficacy of exosome therapy. Our experiments revealed that hypoxia preconditioned MSC-EXO (H-EXO) significantly outperformed normoxic MSC-EXO (N-EXO) in multiple protective aspects. Specifically, H-EXO demonstrated enhanced capacity to mitigate hypoxia-induced aberrant angiogenesis, maintain vascular endothelial cell viability, and suppress ROS accumulation and apoptotic signaling under hypoxic stress. Mechanistic investigation identified miR-125a-5p cargo in H-EXO as a key mediator of RTEF-1 targeted inhibition during hypoxic exposure. In corresponding studies, H-EXO administration effectively attenuated HACE-induced pathological angiogenesis while maintaining crucial vascular homeostasis markers. The therapeutic effects manifested through three principal aspects: 1) downregulation of RTEF-1/VEGF hyperexpression, 2) modulation of VE-cadherin, SMA, and PDGFRα + β expression to preserve BBB integrity, and 3) concurrent protection of neurovascular functions against HACE-induced damage. This investigation elucidates the miR-125a-5p/RTEF-1 axis as the central mechanism through which hypoxic preconditioning enhances MSC-EXO's endothelial protective properties. Our findings establish H-EXO's multimodal therapeutic potential, demonstrating its capacity to simultaneously inhibit pathological angiogenesis, restore BBB function, and protect neural tissue under hypoxic stress conditions. The study elucidates key mechanisms underlying clinical prevention and management of HACE by delineating H-EXO's preventive mechanisms against hypoxia-induced cerebrovascular injury.
血管源性水肿由血脑屏障（BBB）破坏引起，是高原脑水肿（HACE）的一个重要病理因素。由于HACE进展迅速且死亡率高，预防性治疗很重要。间充质干细胞外泌体（MSC-EXO）越来越多地用于组织损伤修复，研究表明适当的预处理可以提高外泌体治疗的靶向疗效。我们的实验表明，缺氧预处理的MSC-EXO（H-EXO）在多个保护方面明显优于常氧MSC-EXO（N-EXO）。具体而言，H-EXO在减轻缺氧诱导的异常血管生成、维持血管内皮细胞活力以及抑制缺氧应激下的ROS积累和凋亡信号方面表现出更强的能力。机制研究确定H-EXO中的miR-125a-5p是缺氧暴露期间RTEF-1靶向抑制的关键介质。在相应研究中，给予H-EXO可有效减轻HACE诱导的病理性血管生成，同时维持关键的血管稳态标志物。治疗效果通过三个主要方面体现：1）下调RTEF-1/VEGF的过度表达；2）调节VE-钙黏蛋白、平滑肌肌动蛋白和血小板衍生生长因子受体α+β的表达以维持BBB完整性；3）同时保护神经血管功能免受HACE诱导的损伤。本研究阐明了miR-125a-5p/RTEF-1轴是缺氧预处理增强MSC-EXO内皮保护特性的核心机制。我们的研究结果确立了H-EXO的多模式治疗潜力，证明其在缺氧应激条件下同时抑制病理性血管生成、恢复BBB功能和保护神经组织的能力。该研究通过描述H-EXO对缺氧诱导的脑血管损伤的预防机制，阐明了HACE临床预防和管理的关键机制。
