Atherosclerotic Plaque Macrophages Drive Abdominal Aortic Aneurysm Formation

There is no effective pharmacotherapy to prevent the growth and rupture of abdominal aortic aneurysms (AAA), a leading cause of death. We developed a novel preclinical model showing that the interaction of bona fide risk factors (i.e., cigarette smoke (CS) and hypercholesterolemia) induced AAA formation, rupture, and death. Elastin fragmentation resulted from CS-induced exacerbation of the atherosclerotic process, significant given atherosclerosis is a disease of the inner intimal layer of the artery, with the media remaining largely intact. Importantly, arterial injury was driven by CSF-1-dependent macrophages (Mφ) accumulating within developing atherosclerotic plaques that exhibited tissue degrading proteolytic activity in vivo. Single-cell RNA sequencing further demonstrated conservation of Mφ responses in atherosclerotic plaque from murine and human AAA. Our findings advance understanding of the pathological sequelae of atherosclerosis, establishing plaque Mφ as important mediators of tissue damage and a potential target for prevention of AAA growth and rupture. Single-cell RNA sequencing (scRNA-seq) was performed to define macrophage heterogeneity in aortic lesions

腹主动脉瘤（abdominal aortic aneurysms, AAA）是一类主要致死病因，目前尚无有效的药物疗法可阻止其生长与破裂。本研究开发了一款新型临床前模型，证实真正的危险因素——即香烟烟雾（cigarette smoke, CS）与高胆固醇血症——的相互作用可诱发AAA的形成、破裂乃至死亡。香烟烟雾会加剧动脉粥样硬化进程，进而引发弹性蛋白断裂，这一现象具有重要研究价值：动脉粥样硬化本是仅累及动脉内膜层的疾病，动脉中膜大多保持完整。值得注意的是，动脉损伤由集落刺激因子1（CSF-1）依赖的巨噬细胞（macrophages, Mφ）驱动，这类细胞会在正在形成的动脉粥样硬化斑块内聚集，并在体内表现出组织降解蛋白水解活性。单细胞RNA测序（Single-cell RNA sequencing, scRNA-seq）进一步证实，小鼠与人类AAA患者的动脉粥样硬化斑块内，巨噬细胞的应答反应具有保守性。本研究结果加深了我们对动脉粥样硬化病理后遗症的认识，确立了斑块内巨噬细胞作为组织损伤的重要介导因子，同时也为预防AAA的生长与破裂提供了潜在靶点。我们通过单细胞RNA测序（scRNA-seq）明确了主动脉病变中的巨噬细胞异质性。