Extracellular vesicle-mediated liver-cardiovascular crosstalk: mechanistic evidence and translational perspectives

Liver disease and cardiovascular disease are linked by metabolic, immune, hemodynamic, and vascular pathways. Extracellular vesicles (EVs) add a cargo-specific mode of inter-organ communication, but the strength of evidence differs markedly among proposed routes. This review critically examines EV-mediated signaling at the liver-cardiovascular interface, with emphasis on endothelial remodeling and angiogenic phenotypes. Evidence is strongest for liver-to-vascular signaling: EVs released by steatotic or injured hepatocytes can promote endothelial activation and hyperpermeability, impair macrophage cholesterol efflux, induce osteogenic switching of vascular smooth muscle cells, and modify pulmonary or sinusoidal endothelial programs. Context-specific liver-heart signaling has also been reported after cardiac transplantation. Evidence for cardiac-to-liver EV signaling is emerging: cardiac ischemia-derived EVs have been linked to hepatic inflammatory responses in preclinical models, although cardiac-cell-specific origin, hepatic recipient-cell identity, and cargo-level causality remain incompletely resolved. We therefore distinguish established inter-organ transfer from local EV signaling, systemic association, and mechanistic hypotheses. We also assess EV phenotyping, single-vesicle and spatial technologies, endogenous EV-targeted interventions, engineered delivery, and organ-on-chip systems. Progress will require standardized EV nomenclature and separation, source-resolved tracing, physiologically relevant dosing, and studies that phenotype both hepatic and cardiovascular compartments. A rigorous evidence hierarchy should enable EV biology to inform vascular mechanism, patient stratification, and therapeutic design without overstating organ-to-organ causality.