Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke
Yiyang Li,1,* Jiali Chen,1,* Xingping Quan,1 Ying Chen,2 Yan Han,1 Jinfen Chen,1 Li Yang,1 Youhua Xu,3 Xu Shen,4 Ruibing Wang,1,5 Yonghua Zhao1,5 1Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SA...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2024-02-01
|
| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/extracellular-vesicles-maintain-blood-brain-barrier-integrity-by-the-s-peer-reviewed-fulltext-article-IJN |
| _version_ | 1797311725808123904 |
|---|---|
| author | Li Y Chen J Quan X Chen Y Han Y Chen J Yang L Xu Y Shen X Wang R Zhao Y |
| author_facet | Li Y Chen J Quan X Chen Y Han Y Chen J Yang L Xu Y Shen X Wang R Zhao Y |
| author_sort | Li Y |
| collection | DOAJ |
| description | Yiyang Li,1,* Jiali Chen,1,* Xingping Quan,1 Ying Chen,2 Yan Han,1 Jinfen Chen,1 Li Yang,1 Youhua Xu,3 Xu Shen,4 Ruibing Wang,1,5 Yonghua Zhao1,5 1Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, People’s Republic of China; 2School of Health Economics and Management, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 3Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, People’s Republic of China; 4Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 5Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yonghua Zhao, Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao SAR, People’s Republic of China, Tel +853-88224877, Fax +853-28841358, Email yonghuazhao@um.edu.moBackground: Ischemic stroke (IS) causes tragic death and disability worldwide. However, effective therapeutic interventions are finite. After IS, blood–brain barrier (BBB) integrity is disrupted, resulting in deteriorating neurological function. As a novel therapeutic, extracellular vesicles (EVs) have shown ideal restorative effects on BBB integrity post-stroke; however, the definite mechanisms remain ambiguous. In the present study, we investigated the curative effects and the mechanisms of EVs derived from bone marrow mesenchymal stem cells and brain endothelial cells (BMSC-EVs and BEC-EVs) on BBB integrity after acute IS.Methods: EVs were isolated from BMSCs and BECs, and we investigated the therapeutic effect in vitro oxygen-glucose deprivation (OGD) insulted BECs model and in vivo rat middle cerebral artery occlusion (MCAo) model. The cell monolayer leakage, tight junction expression, and metalloproteinase (MMP) activity were evaluated, and rat brain infarct volume and neurological function were also analyzed.Results: The administration of two kinds of EVs not only enhanced ZO-1 and Occludin expressions but also reduced the permeability and the activity of MMP-2/9 in OGD-insulted BECs. The amelioration of the cerebral infarction, BBB leakage, neurological function deficits, and the increasing ZO-1 and Occludin levels, as well as MMP activity inhibition was observed in MCAo rats. Additionally, the increased levels of Caveolin-1, CD147, vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor A (VEGFA) in isolated brain microvessels were downregulated after EVs treatment. In vitro, the employment of Caveolin-1 and CD147 siRNA partly suppressed the expressions of VEGFR2, VEGFA and MMP-2/9 activity and reduced the leakage of OGD insulted BECs and enhanced ZO-1 and Occludin expressions.Conclusion: Our study firstly demonstrates that BEC and BMSC-EVs administrations maintain BBB integrity via the suppression of Caveolin-1/CD147/VEGFR2/MMP pathway after IS, and the efficacy of BMSC-EVs is superior to that of BEC-EVs. Keywords: extracellular vesicles, ischemic stroke, Caveolin-1, CD147, matrix metalloproteinase, VEGFR2, blood-brain barrier |
| first_indexed | 2024-03-08T02:03:48Z |
| format | Article |
| id | doaj.art-866138c5a6ce4803ba366057f27ce139 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-03-08T02:03:48Z |
| publishDate | 2024-02-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-866138c5a6ce4803ba366057f27ce1392024-02-13T19:43:10ZengDove Medical PressInternational Journal of Nanomedicine1178-20132024-02-01Volume 191451146790448Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic StrokeLi YChen JQuan XChen YHan YChen JYang LXu YShen XWang RZhao YYiyang Li,1,* Jiali Chen,1,* Xingping Quan,1 Ying Chen,2 Yan Han,1 Jinfen Chen,1 Li Yang,1 Youhua Xu,3 Xu Shen,4 Ruibing Wang,1,5 Yonghua Zhao1,5 1Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, People’s Republic of China; 2School of Health Economics and Management, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 3Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, People’s Republic of China; 4Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 5Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yonghua Zhao, Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao SAR, People’s Republic of China, Tel +853-88224877, Fax +853-28841358, Email yonghuazhao@um.edu.moBackground: Ischemic stroke (IS) causes tragic death and disability worldwide. However, effective therapeutic interventions are finite. After IS, blood–brain barrier (BBB) integrity is disrupted, resulting in deteriorating neurological function. As a novel therapeutic, extracellular vesicles (EVs) have shown ideal restorative effects on BBB integrity post-stroke; however, the definite mechanisms remain ambiguous. In the present study, we investigated the curative effects and the mechanisms of EVs derived from bone marrow mesenchymal stem cells and brain endothelial cells (BMSC-EVs and BEC-EVs) on BBB integrity after acute IS.Methods: EVs were isolated from BMSCs and BECs, and we investigated the therapeutic effect in vitro oxygen-glucose deprivation (OGD) insulted BECs model and in vivo rat middle cerebral artery occlusion (MCAo) model. The cell monolayer leakage, tight junction expression, and metalloproteinase (MMP) activity were evaluated, and rat brain infarct volume and neurological function were also analyzed.Results: The administration of two kinds of EVs not only enhanced ZO-1 and Occludin expressions but also reduced the permeability and the activity of MMP-2/9 in OGD-insulted BECs. The amelioration of the cerebral infarction, BBB leakage, neurological function deficits, and the increasing ZO-1 and Occludin levels, as well as MMP activity inhibition was observed in MCAo rats. Additionally, the increased levels of Caveolin-1, CD147, vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor A (VEGFA) in isolated brain microvessels were downregulated after EVs treatment. In vitro, the employment of Caveolin-1 and CD147 siRNA partly suppressed the expressions of VEGFR2, VEGFA and MMP-2/9 activity and reduced the leakage of OGD insulted BECs and enhanced ZO-1 and Occludin expressions.Conclusion: Our study firstly demonstrates that BEC and BMSC-EVs administrations maintain BBB integrity via the suppression of Caveolin-1/CD147/VEGFR2/MMP pathway after IS, and the efficacy of BMSC-EVs is superior to that of BEC-EVs. Keywords: extracellular vesicles, ischemic stroke, Caveolin-1, CD147, matrix metalloproteinase, VEGFR2, blood-brain barrierhttps://www.dovepress.com/extracellular-vesicles-maintain-blood-brain-barrier-integrity-by-the-s-peer-reviewed-fulltext-article-IJNextracellular vesiclesischemic strokecaveolin-1cd147matrix metalloproteinasevegfr2blood-brain barrier |
| spellingShingle | Li Y Chen J Quan X Chen Y Han Y Chen J Yang L Xu Y Shen X Wang R Zhao Y Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke International Journal of Nanomedicine extracellular vesicles ischemic stroke caveolin-1 cd147 matrix metalloproteinase vegfr2 blood-brain barrier |
| title | Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke |
| title_full | Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke |
| title_fullStr | Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke |
| title_full_unstemmed | Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke |
| title_short | Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke |
| title_sort | extracellular vesicles maintain blood brain barrier integrity by the suppression of caveolin 1 cd147 vegfr2 mmp pathway after ischemic stroke |
| topic | extracellular vesicles ischemic stroke caveolin-1 cd147 matrix metalloproteinase vegfr2 blood-brain barrier |
| url | https://www.dovepress.com/extracellular-vesicles-maintain-blood-brain-barrier-integrity-by-the-s-peer-reviewed-fulltext-article-IJN |
| work_keys_str_mv | AT liy extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT chenj extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT quanx extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT cheny extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT hany extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT chenj extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT yangl extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT xuy extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT shenx extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT wangr extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke AT zhaoy extracellularvesiclesmaintainbloodbrainbarrierintegritybythesuppressionofcaveolin1cd147vegfr2mmppathwayafterischemicstroke |