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 (Exo^M2) 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 Exo^M2 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 Exo^M2 treatment. ApoE^-⁣/- mice on a high fat diet were utilized to observe the effects of Exo^M2 on plaque progression and stability. Serial histopathological analysis was performed to elucidate the cellular mechanisms underlying the atheroprotective effects of Exo^M2.

Results: Compared with controls, Exo^M2 significantly inhibited PDGF-BB-induced VSMC proliferation, migration, and phenotypic transformation in vitro. In ApoE^-⁣/- mice, Exo^M2 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: Exo^M2 inhibit AS progression by regulating VSMC proliferation, migration, and phenotypic transformation.

Keywords: M2 macrophages; atherosclerosis; exosomes; smooth muscle cells.