The atherosclerotic plaque microenvironment: cellular plasticity, extracellular matrix remodeling, and plaque stability

The plaque microenvironment (PME) integrates systemic lipid exposure with local vascular, immune and stromal responses. Vascular smooth muscle cells, endothelial cells, monocytes, macrophages, fibroblast-like cells and lymphocytes interact within a continuously remodeled extracellular matrix. Their context-dependent states influence inflammation, lipid handling, matrix organization and the balance between plaque stability and vulnerability. This narrative review examines these cellular and extracellular components, with particular attention to phenotypic modulation, endothelial-to-mesenchymal transition and the limitations of inferring cellular origin from shared markers. Human single-cell findings expand the conventional M1/M2 view of macrophages. Therapeutic evidence is considered across experimental models, human pathology, intravascular imaging and randomized clinical outcome trials. Systemic lipid lowering and selected anti-inflammatory interventions can modify atherosclerotic disease, but changes in plaque composition do not by themselves establish reductions in myocardial infarction or stroke. Carotid and coronary findings also require site-specific interpretation. Integrating mechanistic observations with the level and anatomical setting of the evidence provides a framework for evaluating established therapies and developing selective PME-directed strategies.