ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1548122
Protective Effect of Brain Microvascular Endothelial Cell-Derived Exosomes on Blood-Brain Barrier Induced by Ischemia-Reperfusion Injury in vivo and in vitro
Provisionally accepted
Jin Sun1Meng Wang2Lichen Guo2Yushuang Cao2Linlin Su2
Shaoxia Wang2Lijuan Chai2
Qing Yuan2*
Hulimin Hu2*- 1Jining Medical University, Shandong, China
- 2Tianjin University of Traditional Chinese Medicine, Tianjin, China
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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 in vitro 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 in vivo 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 in vitro. Besides, EC-Exo not only reduces gait abnormalities in MCAO/R-injured mice, attenuates BBB permeability in vivo. 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 in vitro. 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.
Keywords: ischemic stroke, Exosomes, Cerebral microvascular endothelial cells, Pericytes, Blood-Brain Barrier, Middle cerebral artery occlusion/reperfusion
Received: 19 Dec 2024; Accepted: 21 Apr 2025.
Copyright: © 2025 Sun, Wang, Guo, Cao, Su, Wang, Chai, Yuan and Hu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qing Yuan, Tianjin University of Traditional Chinese Medicine, Tianjin, China
Hulimin Hu, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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