Dysregulated cholesterol uptake and efflux of bone marrow-derived α-SMA+ macrophages contribute to atherosclerotic plaque formation

Macrophages play differential roles in the pathogenesis of atherosclerosis due to their different phenotypes. Although α-SMA⁺ macrophages have been found to present in bone marrow and atherosclerotic plaques, their role in atherosclerosis remains unclear. By performing partial carotid ligation (PCL) on monocyte/macrophage lineage-tracked mice, we observed bone marrow-derived α-SMA⁺ macrophages in the subendothelium and atherosclerotic plaques under disturbed flow conditions. The functional role of α-SMA⁺ macrophages in atherosclerotic plaque formation was examined using macrophage-specific Acta2 knockout (Acta2^MKO) mice generated by crossing Acta2^f/f transgenic mice with LysM-Cre mice. The size of the aortic plaques was 77.43% smaller in Acta2^MKO mice than in Acta2^f/f mice following adeno-associated virus-mutant PCSK9 injection and high-fat diet (HFD) feeding for 12 weeks. A significant reduction in lipid deposition, macrophage infiltration and the α-SMA⁺ area was observed in the aortic roots of Acta2^MKO mice compared with Acta2^f/f mice. Mechanistically, using Acta2-overexpressing Raw264.7 cells (Acta2^hi cells) and bone marrow-derived macrophages (BMDMs) from Acta2^MKO mice (Acta2^MKO BMDMs), we showed that macrophage α-SMA increased the expression of the scavenger receptor SR-A, induced Ox-LDL binding and uptake, and reduced the level of the cholesterol transporter ABCA1, potentially via the AKT pathway. Together, our results indicate that bone marrow-derived α-SMA⁺ macrophages contribute to atherosclerotic plaque formation due to dysregulated cholesterol uptake and efflux, providing potential targets for the prevention and treatment of atherosclerosis.