M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p

作者：Yang Ma, Xiangjiu Ding, Siyu Lu, Xiaofang Huang, Yuanyuan Hu, Han Liu, Bin Liu, Keyin Liu, Mingxiang Zhang, Hao Wang, Feng Xu, Weidong Qin · 发表于：Cellular & Molecular Biology Letters · 年份：2025 · DOI：10.1186/s11658-025-00768-w · 被引用次数：8 · 研究领域：Aortic aneurysm repair treatments、Extracellular vesicles in disease、Immune cells in cancer

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: 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. CONCLU...