BACKGROUND: Carotid atherosclerosis is orchestrated by cell-cell communication that drives progression along a clinical continuum (asymptomatic to symptomatic). Extracellular vesicles (EVs) are cell-derived nanoparticles representing a new paradigm in cellular communication. Little is known about their biological cargo, cellular origin/destination, and functional roles in human atherosclerotic plaque. METHODS: EVs were enriched via size exclusion chromatography from human carotid endarterectomy samples dissected into paired plaque and marginal zones (symptomatic n=16, asymptomatic n=13). EV-cargos were assessed via whole transcriptome microRNA-sequencing and mass spectrometry-based proteomics. EV multiomics was integrated with bulk and single-cell RNA-sequencing datasets to predict EV cellular origin and ligand-receptor interactions, and multimodal biological network integration of EV-cargo was completed. EV functional impact was assessed with endothelial angiogenesis assays. RESULTS: Carotid plaques contained more EVs than adjacent marginal zones, with differential enrichment for EV-microRNAs and EV-proteins in key atherogenic pathways. EV cellular origin analysis suggested that tissue EV signatures originated from endothelial cells, smooth muscle cells, and immune cells. Integrated tissue vesiculomics and single-cell RNA-sequencing indicated complex EV-vascular cell communication that changed with disease progression and plaque vulnerability (ie, symptomatic disease). Plaques from symptomatic patients, but not asymptomatic patients, were characterized by increased involvement of endothelial pathways and more complex ligand-receptor interactions, relative to their marginal zones. Plaque EVs were predicted to mediate communication with endothelial cells. Pathway enrichment analysis delineated an endothelial signature with roles in angiogenesis and neovascularization, well-known indices of plaque instability. This was validated functionally, wherein human carotid symptomatic plaque EVs induced sprouting angiogenesis in comparison to their matched marginal zones. CONCLUSIONS: Our findings indicate that EVs may drive dynamic changes in plaques through EV-vascular cell communication and effector functions that typify vulnerability to rupture, precipitating symptomatic disease. The discovery of endothelial-directed angiogenic processes mediated by EVs creates new therapeutic avenues for atherosclerosis.