He Jiang, Zhang Bin, Zhang Hufei, Tu Qiang, Chen Xi, Qiu Yumin, Liu Zhefu, Xia Wenhao, Wu Xing, Tao Jun
Department of Hypertension and Vascular Disease, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Key Laboratory of Assisted Circulation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Cardiovascular Disease and Clinical Experimental Center, Jiangmen Central Hospital, Jiangmen, Guangdong, China.
Hum Mutat. 2025 May 30;2025:6771390. doi: 10.1155/humu/6771390. eCollection 2025.
Age-related proinflammatory microenvironment induced by infiltration of M1 macrophages promotes endothelial senescence-mediated vascular diseases. Macrophages exert their immunomodulatory effects by releasing exosomes. However, the underlying mechanisms governing endothelial cell senescence induced by exosomes derived from M1 macrophages (M1-Exo) remain elusive. In this study, we delved into the intricate interplay between endothelial function and M1 macrophage abundance in the aortas and explored the pivotal role of M1-Exo in endothelial cell senescence and its associated molecular pathways. Our results unveiled a compelling correlation between the infiltration of M1 macrophages in the aortas of aged mice and impaired endothelium-dependent dilatation. Coculturing endothelial cells with M1-Exo engendered the acquisition of a senescent phenotype, marked by increased senescence-associated beta-galactosidase level and a distinct senescence-associated secretory profile. Endothelial cells cocultured with M1-Exo exhibited pronounced signs of cell cycle arrest, accompanied by mitochondrial oxidative damage and dysfunction. Bioinformatics analysis and subsequent validation identified high expression of miR-155 in M1-Exo. The transfer of miR-155 contributed to the prosenescence effect of M1-Exo by targeting SOCS1, subsequently activating JAK2/STAT3 signaling. The administration of M1-Exo into young mice instigated endothelial dysfunction and increased ROS production. Notably, the reduction of miR-155 in M1-Exo partially mitigated such deleterious effects. Our findings demonstrate that exosomal miR-155, originating from M1 macrophages, elicits endothelial cell senescence. The present study brings a groundbreaking insight into the communication between M1 macrophages and endothelial cells as a mediator of vascular aging, providing a promising target for interventions in age-related vascular diseases.
由M1巨噬细胞浸润诱导的与年龄相关的促炎微环境促进了内皮细胞衰老介导的血管疾病。巨噬细胞通过释放外泌体发挥其免疫调节作用。然而，由M1巨噬细胞来源的外泌体（M1-Exo）诱导内皮细胞衰老的潜在机制仍不清楚。在本研究中，我们深入研究了主动脉中内皮功能与M1巨噬细胞丰度之间的复杂相互作用，并探讨了M1-Exo在内皮细胞衰老及其相关分子途径中的关键作用。我们的结果揭示了老年小鼠主动脉中M1巨噬细胞浸润与内皮依赖性舒张受损之间存在显著相关性。将内皮细胞与M1-Exo共培养会导致衰老表型的出现，其特征是衰老相关β-半乳糖苷酶水平升高以及独特的衰老相关分泌谱。与M1-Exo共培养的内皮细胞表现出明显的细胞周期停滞迹象，同时伴有线粒体氧化损伤和功能障碍。生物信息学分析及后续验证确定了M1-Exo中miR-155的高表达。miR-155的转移通过靶向SOCS1促进了M1-Exo的促衰老作用，随后激活JAK2/STAT3信号通路。向年轻小鼠体内注射M1-Exo会引发内皮功能障碍并增加活性氧的产生。值得注意的是，M1-Exo中miR-155的减少部分减轻了这种有害影响。我们发现，源自M1巨噬细胞的外泌体miR-155可引发内皮细胞衰老。本研究为M1巨噬细胞与内皮细胞之间作为血管衰老介质的通讯提供了开创性的见解，为干预与年龄相关的血管疾病提供了一个有前景的靶点。
