BACKGROUND: Vascular smooth muscle cells (VSMCs) play a central role in atherosclerosis by undergoing phenotypic modulation from a quiescent, contractile state to a range of synthetic phenotypes, including fibroblast-like, macrophage-like, and lipid-laden foam cell-like states. However, a comprehensive multimodal characterization and understanding of the transcriptional programs driving these transitions remain incomplete. METHODS: To comprehensively define the phenotypic diversity of VSMCs during atherosclerosis progression, we performed in-depth profiling using cellular indexing of transcriptomes and epitopes by sequencing and bulk RNA sequencing in a VSMC-lineage-tracing atherosclerotic mouse model. Insights from these data sets guided the design of targeted in vitro experiments to investigate candidate regulatory mechanisms. RESULTS: reprogrammed immune, cell cycle, and lipid homeostasis genes in cultured VSMC and suppressed VSMC phenotypic switching and foam cell characteristics, consistent with a potential regulatory role in VSMC modulation. CONCLUSIONS: These findings advance our understanding of VSMC phenotypic modulation in atherosclerosis and implicate BHLHE40 as a candidate transcriptional regulator of this process. Elucidating mechanisms governing VSMC plasticity may offer new therapeutic opportunities to reduce cardiovascular risk by targeting disease-driving cellular transitions.
Ibikunle et al. (2026) studied this question.