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Atherosclerotic Plaque Macrophages Drive Abdominal Aortic Aneurysm Formation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE284253 | GEO | 2025/03/06

REPOSITORIES: GEO

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Project description:Background：Atherosclerosis is the major cause of cardiovascular disease. Endothelial injury is one of the initiating factors of atherosclerosis. Injured endothelial cells overexpress adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), facilitating the binding and accumulation of monocytes-macrophages into the vascular wall via the ligands. Adipose-derived stem cells (ADSCs) have been extensively researched for their anti-inflammatory properties and therapeutic potential in various diseases. Targeting atherosclerotic regions with ADSCs may offer a promising therapeutic strategy to alleviate local inflammation associated with atherosclerosis.Methods：The ligands of very late antigen-4 (VLA-4) and lymphocyte function-associated antigen-1 (LFA-1) were expressed in the ADSC to construct the Macrophage (Mφ)-mimicking ADSCs. Cell proliferation, adhesion, and migration assays were used to characterize the Mφ-mimicking ADSCs. An atherosclerosis model was established in ApoE-/- mice via partial carotid artery ligation. Mφ-mimicking ADSCs were administered through tail vein injection. Distribution of these cells was tracked by far-red fluorescent probe. Histological analyses, including H&E staining, Oil Red O staining, and immunofluorescence were conducted to assess the impact on plaque size, composition, and macrophage polarization.Results：Mφ-mimicking ADSCs were successfully constructed and characterized. These cells exhibited enhanced adhesion and migration capabilities. The culture medium from Mφ-mimicking ADSCs increased the proportion of M2 macrophages and decreased the lipid uptake capacity. In the atherosclerosis mouse model, fluorescently labeled Mφ-mimicking ADSCs specifically adhered to and accumulated in atherosclerotic regions, demonstrating targeted localization. Mφ-mimicking ADSC treatment resulted in a reduction in plaque size and a decrease in the number of M1 macrophages within the arterial wall.Conclusions：Mφ-mimicking ADSCs confirmed their preserved anti-inflammatory properties and enhanced adhesion and migration abilities. In vivo, Mφ-mimicking ADSCs exhibited targeted localization ability to regions of endothelial dysfunction in atherosclerosis and attenuate plaque progression. These findings suggest that Mφ-mimicking ADSCs may serve as a potential therapeutic strategy for alleviating atherosclerosis and reducing inflammation.

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Atherosclerotic Plaque Macrophages Drive Abdominal Aortic Aneurysm Formation

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