M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p
Abstract Background Extracellular vesicles (EVs) derived from M2 macrophages (M2-EVs) play a protective role in the pathogenesis of acute lung injury. However, their roles and mechanisms in abdominal aortic aneurysm (AAA) are unknown. Methods The effects of M2-EVs in AAA were examined in ApoE−/− mic...
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BMC
2025-08-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-025-00768-w |
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| author | Yang Ma Xiang-jiu Ding Si-yu Lu Xiao-fang Huang Yuan-yuan Hu Han Liu Bin Liu Ke-yin Liu Ming-xiang Zhang Hao Wang Feng Xu Wei-dong Qin |
| author_facet | Yang Ma Xiang-jiu Ding Si-yu Lu Xiao-fang Huang Yuan-yuan Hu Han Liu Bin Liu Ke-yin Liu Ming-xiang Zhang Hao Wang Feng Xu Wei-dong Qin |
| author_sort | Yang Ma |
| collection | DOAJ |
| description | Abstract Background Extracellular vesicles (EVs) derived from M2 macrophages (M2-EVs) play a protective role in the pathogenesis of acute lung injury. However, their roles and mechanisms in abdominal aortic aneurysm (AAA) are unknown. Methods The effects of M2-EVs in AAA were examined in ApoE−/− mice with angiotensin II infusion. After M2 macrophages were stimulated with antisense oligonucleotides of miR221-5p (miR221-5p-ASOs), EVs were extracted and administered to mice via the tail vein. In vitro, the primary bone marrow-derived monocytes (BMDMs) were isolated and co-cultured with human aortic endothelial cells (HAECs) in Transwell chambers. Results M2-EVs significantly reduced AAA incidence and maximal aortic diameters, improved fiber continuity, increased α-SMA, and reduced macrophage infiltration in AAA mice. RNA sequencing revealed that miR221-5p was upregulated in M2-EVs and downregulated in AAA. miR221-5p-ASOs reduced the protection of M2-EVs in AAA mice. M2-EVs induced M2 macrophage polarization, while miR221-5p-ASOs had no effect. Moreover, M2-EVs alleviated oxidative stress and inflammatory responses in HAECs. Mechanistically, miR221-5p bound to poly(ADP-ribose) polymerase 1 (PARP-1) mRNA and reduced PARP-1 expression; PARP-1 was bound to protein phosphatase 1ɑ (PP-1ɑ) and negatively regulated its expression. In vitro experiments showed miR221-5p modulated macrophage polarization through the PARP-1/PP-1ɑ/JNK/c-Jun pathway. Macrophage deletion of PARP-1 inhibited AAA formation and phosphorylation of JNK/c-Jun in mice. Conclusions miR221-5p in M2-EVs plays a critical role in AAA pathophysiology by modulating macrophage polarization through PARP-1/PP-1ɑ/JNK/c-Jun signaling. M2-EVs and miR221-5p represent promising therapeutic options for AAA. |
| format | Article |
| id | doaj-art-ed6c4a5875df4204ba14d7730a03c2d3 |
| institution | DOAJ |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-ed6c4a5875df4204ba14d7730a03c2d32025-08-20T03:05:15ZengBMCCellular & Molecular Biology Letters1689-13922025-08-0130112310.1186/s11658-025-00768-wM2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5pYang Ma0Xiang-jiu Ding1Si-yu Lu2Xiao-fang Huang3Yuan-yuan Hu4Han Liu5Bin Liu6Ke-yin Liu7Ming-xiang Zhang8Hao Wang9Feng Xu10Wei-dong Qin11Department of Critical Care Medicine, Qilu Hospital of Shandong UniversityDepartment of Vascular Surgery, General Surgery, Qilu Hospital of Shandong UniversityDepartment of Critical Care Medicine, Qilu Hospital of Shandong UniversityDepartment of Critical Care Medicine, Qilu Hospital of Shandong UniversityDepartment of Critical Care Medicine, Qilu Hospital of Shandong UniversityDepartment of Critical Care Medicine, Qilu Hospital of Shandong UniversityDepartment of Emergency Medicine, Qilu Hospital of Shandong UniversityState Key Laboratory of Biobased Material and Green Paper Making, Key Laboratory of Pulp & Paper Science and Technology of Shandong Province/Ministry of Education, Qilu University of Technology, Shandong Academy of SciencesDepartment of Cardiology, Qilu Hospital of Shandong UniversityDepartment of Critical Care Medicine, Qilu Hospital of Shandong UniversityDepartment of Emergency Medicine, Qilu Hospital of Shandong UniversityDepartment of Critical Care Medicine, Qilu Hospital of Shandong UniversityAbstract Background Extracellular vesicles (EVs) derived from M2 macrophages (M2-EVs) play a protective role in the pathogenesis of acute lung injury. However, their roles and mechanisms in abdominal aortic aneurysm (AAA) are unknown. Methods The effects of M2-EVs in AAA were examined in ApoE−/− mice with angiotensin II infusion. After M2 macrophages were stimulated with antisense oligonucleotides of miR221-5p (miR221-5p-ASOs), EVs were extracted and administered to mice via the tail vein. In vitro, the primary bone marrow-derived monocytes (BMDMs) were isolated and co-cultured with human aortic endothelial cells (HAECs) in Transwell chambers. Results M2-EVs significantly reduced AAA incidence and maximal aortic diameters, improved fiber continuity, increased α-SMA, and reduced macrophage infiltration in AAA mice. RNA sequencing revealed that miR221-5p was upregulated in M2-EVs and downregulated in AAA. miR221-5p-ASOs reduced the protection of M2-EVs in AAA mice. M2-EVs induced M2 macrophage polarization, while miR221-5p-ASOs had no effect. Moreover, M2-EVs alleviated oxidative stress and inflammatory responses in HAECs. Mechanistically, miR221-5p bound to poly(ADP-ribose) polymerase 1 (PARP-1) mRNA and reduced PARP-1 expression; PARP-1 was bound to protein phosphatase 1ɑ (PP-1ɑ) and negatively regulated its expression. In vitro experiments showed miR221-5p modulated macrophage polarization through the PARP-1/PP-1ɑ/JNK/c-Jun pathway. Macrophage deletion of PARP-1 inhibited AAA formation and phosphorylation of JNK/c-Jun in mice. Conclusions miR221-5p in M2-EVs plays a critical role in AAA pathophysiology by modulating macrophage polarization through PARP-1/PP-1ɑ/JNK/c-Jun signaling. M2-EVs and miR221-5p represent promising therapeutic options for AAA.https://doi.org/10.1186/s11658-025-00768-wAbdominal aortic aneurysmM2 macrophagesExtracellular vesiclesmicroRNA 221-5pMacrophage polarization |
| spellingShingle | Yang Ma Xiang-jiu Ding Si-yu Lu Xiao-fang Huang Yuan-yuan Hu Han Liu Bin Liu Ke-yin Liu Ming-xiang Zhang Hao Wang Feng Xu Wei-dong Qin M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p Cellular & Molecular Biology Letters Abdominal aortic aneurysm M2 macrophages Extracellular vesicles microRNA 221-5p Macrophage polarization |
| title | M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p |
| title_full | M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p |
| title_fullStr | M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p |
| title_full_unstemmed | M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p |
| title_short | M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p |
| title_sort | m2 macrophage derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through mir221 5p |
| topic | Abdominal aortic aneurysm M2 macrophages Extracellular vesicles microRNA 221-5p Macrophage polarization |
| url | https://doi.org/10.1186/s11658-025-00768-w |
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