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We previously showed that cholesterol loading in vitro converts mouse aortic vascular smooth muscle cells (VSMC) from a contractile state to one resembling macrophages. In human and mouse atherosclerotic plaques, it has become appreciated that ≈40% of cells classified as macrophages by histological markers may be of VSMC origin. Therefore, we sought to gain insight into the molecular regulation of this clinically relevant process.VSMC of mouse (or human) origin were incubated with cyclodextrin-cholesterol complexes for 72 hours, at which time the expression at the protein and mRNA levels of contractile-related proteins was reduced and of macrophage markers increased. Concurrent was downregulation of miR-143/145, which positively regulate the master VSMC differentiation transcription factor myocardin. Mechanisms were further probed in mouse VSMC. Maintaining the expression of myocardin or miR-143/145 prevented and reversed phenotypic changes caused by cholesterol loading. Reversal was also seen when cholesterol efflux was stimulated after loading. Notably, despite expression of macrophage markers, bioinformatic analyses showed that cholesterol-loaded cells remained closer to the VSMC state, consistent with impairment in classical macrophage functions of phagocytosis and efferocytosis. In apoE-deficient atherosclerotic plaques, cells positive for VSMC and macrophage markers were found lining the cholesterol-rich necrotic core.Cholesterol loading of VSMC converts them to a macrophage-appearing state by downregulating the miR-143/145-myocardin axis. Although these cells would be classified by immunohistochemistry as macrophages in human and mouse plaques, their transcriptome and functional properties imply that their contributions to atherogenesis would not be those of classical macrophages.

Original publication




Journal article


Arteriosclerosis, thrombosis, and vascular biology

Publication Date





535 - 546


From the Marc and Ruti Bell Program in Vascular Biology, Division of Cardiology, Department of Medicine, NYU School of Medicine, New York (Y.V., H.N., M.O., N.S., C.P.C., K.J.M., E.A.F.); Center for Cardiovascular Sciences, Albany Medical College, NY (X.L.); Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom (F.O.M.); Department of Biomedical Sciences, Oregon State University, Corvallis (S.A.R.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (J.M.M.).


Muscle, Smooth, Vascular, Aorta, Thoracic, Jurkat Cells, Foam Cells, Myocytes, Smooth Muscle, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Disease Models, Animal, Necrosis, Cholesterol, Apolipoproteins E, Trans-Activators, Nuclear Proteins, MicroRNAs, Oligonucleotide Array Sequence Analysis, Coculture Techniques, Gene Expression Profiling, Transfection, Signal Transduction, Phagocytosis, Gene Expression Regulation, Binding Sites, Cell Lineage, Phenotype, Time Factors, Atherosclerosis, Sterol Regulatory Element Binding Protein 2, Cholesterol, HDL, Cell Transdifferentiation, Plaque, Atherosclerotic