Single-Cell Dynamics of Atherosclerosis

Atherosclerosis is a temporally organized disease characterized by dynamic changes in vascular cell identities. However, the molecular programs governing vascular cell state transitions during atherosclerosis progression remain poorly defined. Here, we construct a high-resolution single-cell transcriptomic atlas of atherosclerosis in mice, extensively validated using human lesions, encompassing ~3 million cells across multiple disease stages and vascular regions. Using computational modeling, we map smooth muscle cell (SMC) lineage transitions and phenotypic switching. We show that loss of PI16 promotes SMC-to-fibroblast conversion, connecting aberrant extracellular matrix remodeling to plaque vulnerability. Additionally, we identify key transcriptional regulators in endothelial cells and SMCs driving early atherogenic remodeling. Collectively, our study provides a comprehensive single-cell roadmap of vascular cell plasticity in atherosclerosis with direct translational implications.