Cell-Surface Signatures and Targets of Modulated Vascular Smooth Muscle Cells in Atherosclerosis: From State Identification to Precision Intervention

Atherosclerotic plaques contain vascular smooth muscle cell (VSMC)-derived populations that no longer fit a simple contractile-versus-synthetic model. Lineage tracing, single-cell transcriptomics, spatial profiling and multimodal surface-protein measurements now show that VSMC-derived cells occupy heterogeneous lesional states with pathogenic, reversible or plaque-stabilizing properties. This diversity creates a translational bottleneck. Intracellular markers and transcriptomic clusters can define state transitions, but they do not by themselves provide handles for live-cell isolation, molecular imaging, targeted delivery or selective intervention. This narrative review examines how VSMC state discovery can be translated into cell-surface signatures and surface-accessible intervention interfaces. We distinguish state/lineage markers, surface identification and sorting signatures, functional surface interfaces, causally supported candidate targets, and intervention-supported surface targets. Current evidence positions CD29, CD90, CD142, and CD200 primarily as tools for live-cell identification, whereas fibroblast activation protein (FAP) represents the most advanced example of an intervention-supported surface target for the depletion of a disease-associated modulated VSMC state. We propose a state-matched framework in which pathogenic states are selectively depleted, plastic or reversible states are modulated or reprogrammed, and matrix-supportive plaque-stabilizing states are preserved. C-C chemokine receptor type 2 (CCR2), guanylyl cyclase-B/natriuretic peptide receptor 2 (GC-B/NPR2), matrix metalloproteinase 14 (S14), and CD47 span different intermediate levels of therapeutic evidence, from targeted delivery to functional surface modulation and causal intervention, whereas CD36, triggering receptor expressed on myeloid cells 2 (TREM2), and integrins remain constrained by incomplete cell-state or lineage specificity. Major barriers include human protein-level and surface validation, state specificity, spatial accessibility and direct therapeutic testing.