M2 Macrophage-Derived Exosomes Inhibit Atherosclerosis Progression by Regulating the Proliferation, Migration, and Phenotypic Transformation of Smooth Muscle Cells.

ABSTRACT

BACKGROUND: Vascular smooth muscle cell (VSMC) intimal migration, proliferation, and phenotypic transformation from a contractile to a synthetic state are hallmarks of the progression of atherosclerotic plaques. This study aims to explore the effects of exosomes derived from M2 macrophages (ExoM2) on the pathological changes of VSMCs in atherosclerosis (AS). METHODS: Cell Counting Kit-8 (CCK8) and wound healing assays were used to examine the impact of ExoM2 on platelet-derived growth factor-BB (PDGF-BB)-induced VSMC proliferation and migration, respectively. Western blotting was employed to analyze changes in the expression levels of contractile markers (e.g., alpha-smooth muscle actin [α-SMA]) and synthetic ones (e.g., osteopontin [OPN]) in VSMCs with or without ExoM2 treatment. ApoE-⁣/- mice on a high fat diet were utilized to observe the effects of ExoM2 on plaque progression and stability. Serial histopathological analysis was performed to elucidate the cellular mechanisms underlying the atheroprotective effects of ExoM2. RESULTS: Compared with controls, ExoM2 significantly inhibited PDGF-BB-induced VSMC proliferation, migration, and phenotypic transformation in vitro. In ApoE-⁣/- mice, ExoM2 treatment led to a marked reduction in plaque size, necrotic core area, the CD68/α-SMA ratio, and matrix metalloproteinase 9 (MMP9) and OPN levels, while enhancing plaque stability. CONCLUSIONS: ExoM2 inhibit AS progression by regulating VSMC proliferation, migration, and phenotypic transformation.