内皮功能障碍驱动动脉粥样硬化斑块巨噬细胞依赖性腹主动脉瘤形成，这一成果由加拿大多伦多大学Clinton S. Robbins研究团队经过不懈努力而取得。该研究于2025年4月22日发表于国际一流学术期刊《自然—免疫学》杂志上。

通过结合香烟烟雾暴露和高胆固醇血症的motheme模型，该课题组人员证明了香烟烟雾加剧动脉粥样硬化，导致弹性蛋白碎裂、动脉瘤形成、破裂和死亡。动脉损伤是由积聚在动脉粥样硬化斑块内的巨噬细胞驱动的，并在体内表现出组织降解的蛋白水解活性（这一过程依赖于内皮细胞源性巨噬细胞生长因子CSF-1）。单核RNA测序显示，香烟烟雾诱导的内皮细胞功能障碍促进单核细胞募集和炎症信号传导，并放大血管损伤。

此外，单细胞转录组学分析发现，巨噬细胞在motheme和人腹主动脉瘤中有保守的反应，包括TREM2⁺巨噬细胞，它们是动脉损伤的关键介质。这些发现证实了动脉粥样硬化斑块巨噬细胞是动脉瘤病理的关键驱动因素，并为动脉瘤进展和破裂的机制提供了关键见解。

据介绍，目前还没有有效的药物治疗方法来防止腹主动脉瘤的生长和破裂。

附：英文原文

Title: Endothelial dysfunction drives atherosclerotic plaque macrophage-dependent abdominal aortic aneurysm formation

Author: Thayaparan, Danya, Emoto, Takuo, Khan, Aniqa B., Besla, Rickvinder, Hamidzada, Homaira, El-Maklizi, Mahmoud, Sivasubramaniyam, Tharini, Vohra, Shabana, Hagerman, Ash, Nejat, Sara, Needham-Robbins, Charlotte E., Wang, Tao, Lindquist, Moritz, Botts, Steven R., Schroer, Stephanie A., Taniguchi, Masayuki, Inoue, Taishi, Yamanaka, Katsuhiro, Cui, Haotian, Al-Chami, Edouard, Zhang, Hangjun, Althagafi, Marwan G., Michalski, Aja, McGrath, Joshua J. C., Cass, Steven P., Luong, David, Suzuki, Yuya, Li, Angela, Abow, Amina, Heo, Rachel, Pacheco, Shaun, Chen, Emily, Chiu, Felix, Byrne, John, Furuyashiki, Tomoyuki, Husain, Mansoor, Libby, Peter, Okada, Kenji, Howe, Kathryn L., Heximer, Scott P., Yamashita, Tomoya, Wang, Bo, Rubin, Barry B., Cybulsky, Myron I., Roy, Joy, Williams, Jesse W., Crome, Sarah Q., Epelman, Slava, Hirata, Ken-ichi, Stampfli, Martin R., Robbins, Clinton S.

Issue&Volume: 2025-04-22

Abstract: Currently there is no effective pharmacotherapy to prevent the growth and rupture of abdominal aortic aneurysms. Using a mouse model that combines cigarette smoke exposure and hypercholesterolemia, we demonstrated that cigarette smoke exacerbated atherosclerosis, leading to elastin fragmentation, aneurysm formation, rupture and death. Arterial injury was driven by macrophages that accumulated within atherosclerotic plaques and exhibited tissue-degrading proteolytic activity in vivo (a process dependent on the endothelial cell-derived macrophage growth factor CSF-1). Single-nucleus RNA sequencing revealed that cigarette smoke-induced endothelial cell dysfunction promoted monocyte recruitment and inflammatory signaling and amplified vascular injury. Furthermore, single-cell transcriptomic analysis identified conserved macrophage responses across mouse and human abdominal aortic aneurysm, including TREM2+ macrophages, which were key mediators of arterial damage. These findings established atherosclerotic plaque macrophages as critical drivers of aneurysm pathology and provide key insights into the mechanisms underlying aneurysm progression and rupture.

DOI: 10.1038/s41590-025-02132-8

Source: https://www.nature.com/articles/s41590-025-02132-8