Macrophage-like smooth muscle cells in atherosclerosis.

The structural and functional homeostasis of the vascular wall critically depends on vascular smooth muscle cells (VSMCs) and their secreted extracellular matrix. As the primary cellular component of the vascular tunica media, VSMCs work in concert with elastic fiber networks to maintain vascular tension through their contractile properties. However, the most remarkable characteristic of VSMCs lies in their exceptional phenotypic plasticity. When subjected to mechanical injury or biochemical stimulation, differentiated contractile VSMCs undergo dedifferentiation, transforming into an intermediate state with highly synthetic activity. This phenotypic switching enables VSMCs to dedifferentiate into various functional subtypes, including fibroblast-like, macrophage-like, osteoblast-like, and adipocyte-like VSMCs. While this process confers proliferative and synthetic capabilities to repair vascular damage, it may conversely accelerate vascular pathology under disease conditions. Recent breakthroughs in single-cell RNA sequencing and lineage tracing technologies have revealed that most of lesional macrophages in atherosclerotic plaques are derived from macrophage-like cells (MLCs) dedifferentiated from the VSMCs lineage. These MLCs significantly compromise plaque stability by promoting pathological changes such as necrotic core expansion and fibrous cap thinning. This review systematically elucidates the dynamic roles of VSMC-to-MLC conversion throughout the progression of atherosclerosis. Building on these findings, future research should focus on deciphering the molecular switches that maintain VSMC phenotypic homeostasis. The identification of these key regulatory nodes will provide a theoretical foundation for developing novel therapeutic strategies aimed at stabilizing atherosclerotic plaques.