The Role and Mechanism of Endothelial Progenitor Cell-Derived Extracellular Vesicles in Vascular Repair of Ischemic Heart Disease.

Ischemic heart disease (IHD) remains a leading global cause of death, sustained by microvascular dysfunction and defective endogenous repair despite revascularization. Endothelial progenitor cells (EPCs) were initially proposed as regenerative mediators, but direct cell therapy is constrained by poor engraftment, phenotypic heterogeneity, and safety concerns. Accumulating evidence establishes EPC-derived extracellular vesicles (EPC-EVs) as the principal effectors of vascular repair. These vesicles deliver bioactive cargo-including miR-126, miR-210, lncRNAs, and proteins that activate VEGF/PI3K/AKT/eNOS signaling in endothelial cells, promote angiogenesis and endothelial survival, attenuate apoptosis and ferroptosis, and induce reparative M2 macrophage polarization. Compared with cell therapy, EPC-EVs offer superior stability, lower immunogenicity, and manufacturing control as a cell-free platform. Translational challenges persist, including inconsistent EPC definitions, isolation variability, absence of validated potency assays linked to cardiovascular endpoints, and limited long-term safety data. Engineering strategies such as hypoxic preconditioning and targeted delivery may facilitate clinical translation of EPC-EV therapy for IHD.