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脑微血管内皮细胞衍生的外泌体对缺血再灌注损伤诱导的血脑屏障的保护作用及……（原文结尾不完整）

Protective effect of brain microvascular endothelial cell-derived exosomes on blood-brain barrier induced by ischemia-reperfusion injury and .

作者信息

Sun Jin, Wang Meng, Guo Lichen, Cao Yushuang, Su Linlin, Wang Shaoxia, Chai Lijuan, Yuan Qing, Hu Limin

机构信息

State Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Tianjin Key Laboratory of Traditional Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

出版信息

Front Pharmacol. 2025 Apr 29;16:1548122. doi: 10.3389/fphar.2025.1548122. eCollection 2025.

DOI:10.3389/fphar.2025.1548122
PMID:40365318
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12069432/
Abstract

BACKGROUND

Enhanced blood-brain barrier (BBB) permeability exacerbates clinical symptoms and long-term disability after ischemic stroke. Exosomes derived from cerebral microvascular endothelial cells (EC-Exo) can enhance neural function recovery in MCAO/R mice. However, it remains unclear whether the brain protective effects of EC-Exo are associated with improved BBB structure and functionality.

METHODS

This study developed an BBB model by co-culturing endothelial cells (bEnd.3) with pericytes (MBVP) to examine the effects of EC-Exo on BBB integrity. The neurobehavioral function of EC-Exo was evaluated using the rotarod test and gait assessment. The permeability of BBB was evaluated using the Evans blue penetration test and IgG leakage test. The integrity of the BBB structure was assessed using immunofluorescence and Western blot analysis. Mechanistic investigations aimed to elucidate the regulatory role of PDGF-PDGFRβ and Ang1/Ang2-Tie2 pathways in maintaining BBB integrity.

RESULTS

EC-Exo improves BBB integrity by increasing TEER values and decreasing Papp . Besides, EC-Exo not only reduces gait abnormalities in MCAO/R-injured mice, attenuates BBB permeability . EC-Exo enhances the expression of tight junction and basement membrane proteins. Mechanistic studies have demonstrated that EC-Exo can effectively activate the PDGF-PDGFRβ and Ang1/Ang2-Tie2 signaling pathways, thereby facilitating the maintenance of BBB integrity, and these effects were verified with PDGFRβ inhibitor and Tie2 inhibitor .

CONCLUSION

In conclusion, EC-Exo enhances BBB integrity by activating PDGF-PDGFRβ and Ang1/Ang2-Tie2 signaling pathways, promoting communication between endothelial cells and pericytes. This introduces an innovative adjuvant therapy for treating ischemic stroke.

摘要

背景

血脑屏障（BBB）通透性增强会加剧缺血性中风后的临床症状和长期残疾。源自脑微血管内皮细胞的外泌体（EC-Exo）可促进大脑中动脉闭塞/再灌注（MCAO/R）小鼠的神经功能恢复。然而，EC-Exo的脑保护作用是否与改善BBB结构和功能相关仍不清楚。

方法

本研究通过将内皮细胞（bEnd.3）与周细胞（MBVP）共培养建立BBB模型，以研究EC-Exo对BBB完整性的影响。使用转棒试验和步态评估来评估EC-Exo的神经行为功能。使用伊文思蓝渗透试验和免疫球蛋白G（IgG）渗漏试验评估BBB的通透性。使用免疫荧光和蛋白质印迹分析评估BBB结构的完整性。机制研究旨在阐明血小板衍生生长因子（PDGF）-血小板衍生生长因子受体β（PDGFRβ）和血管生成素1/血管生成素2-酪氨酸激酶受体2（Ang1/Ang2-Tie2）通路在维持BBB完整性中的调节作用。

结果

EC-Exo通过增加跨上皮电阻（TEER）值和降低表观渗透系数（Papp）来改善BBB完整性。此外，EC-Exo不仅减少了MCAO/R损伤小鼠的步态异常，还减弱了BBB通透性。EC-Exo增强了紧密连接和基底膜蛋白的表达。机制研究表明，EC-Exo可有效激活PDGF-PDGFRβ和Ang1/Ang2-Tie2信号通路，从而促进BBB完整性的维持，并且这些作用通过PDGFRβ抑制剂和Tie2抑制剂得到了验证。

结论

总之，EC-Exo通过激活PDGF-PDGFRβ和Ang1/Ang2-Tie2信号通路来增强BBB完整性，促进内皮细胞与周细胞之间的通讯。这为治疗缺血性中风引入了一种创新的辅助治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0ee/12069432/585b78ca441c/fphar-16-1548122-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0ee/12069432/585b78ca441c/fphar-16-1548122-g007.jpg

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本文引用的文献

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Stem Cell Res Ther. 2024 May 20;15(1):143. doi: 10.1186/s13287-024-03758-5.
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Recent advances in tissue repair of the blood-brain barrier after stroke.中风后血脑屏障组织修复的最新进展
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Damage mechanism and therapy progress of the blood-brain barrier after ischemic stroke.
缺血性脑卒中后血脑屏障的损伤机制与治疗进展
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A new insight into the role of pericytes in ischemic stroke.对周细胞在缺血性卒中中作用的新见解。
Acta Neurol Belg. 2024 Jun;124(3):767-774. doi: 10.1007/s13760-023-02391-y. Epub 2023 Oct 7.
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Endothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood-brain barrier integrity.内皮细胞中 Eph 受体 A4 的缺失改变了单个细胞的特征，并改变了 Tie2/Akap12 信号，以维持血脑屏障的完整性。
Proc Natl Acad Sci U S A. 2023 Oct 10;120(41):e2204700120. doi: 10.1073/pnas.2204700120. Epub 2023 Oct 5.
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