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 (Mf) accumulating within developing atherosclerotic plaques that exhibited tissue degrading proteolytic activity in vivo. Single-cell RNA sequencing further demonstrated conservation of Mf responses in atherosclerotic plaque from murine and human AAA. Our findings advance understanding of the pathological sequelae of atherosclerosis, establishing plaque Mf as important mediators of tissue damage and a potential target for prevention of AAA growth and rupture. Overall design: Single-cell RNA sequencing (scRNA-seq) was performed to define macrophage heterogeneity in aortic lesions