AIMS: Inflammatory responses promote pathological neovascularization and vascular remodeling in carotid plaques, contributing to plaque destabilization. This study aims to clarify specific cellular subpopulations that mediate pathological neovascularization and vascular remodeling in different plaque regions. METHODS: This study systematically analyzed the cellular composition and functional distribution in the atherosclerotic core (AC) and proximal adjacent (PA) regions of carotid plaques using single-cell RNA sequencing. RESULTS: We observed that a subset of endothelial cells contributing to pathological neovascularization was prominent in the AC region, while the PA region exhibited a reduction in contractile vascular smooth muscle cells (VSMCs) and an increase in osteogenic VSMCs, collectively contributing to vascular remodeling. Additionally, fibroblast-mediated inflammatory regulation was predominantly enriched in the PA region, whereas the AC region harbored more macrophage subsets involved in lipid metabolism and immune responses. CONCLUSION: The pathological neovascularization mediated by endothelial cell subpopulations in the AC region, along with the reduced contractile VSMCs and increased osteogenic VSMCs in the PA region, is a factor that promotes plaque instability.