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OBJECTIVES To explore the effect of exosomal miR-126 derived from stem cells from the apical papilla (SCAPs) under hypoxia on human umbilical vein endothelial cell (HUVEC) angiogenesis. METHODS miR-126 mimics plasmids were used to upregulate miR-126 in SCAPs. Internalization of PKH26-labeled exosomes was examined by fluorescent microscopy. CCK-8 assay, Transwell assay, scratch assay, tube formation assay and Matrigel plug assay were performed to detect the effects of exosomes on the angiogenic ability of HUVECs. The luciferase reporter assay and rescue assay were performed to examine the relationship between miR-126 and sprouty-related, EVH1 domain-containing protein 1 (SPRED1). The involvement of SPRED1 and the extracellular signal-regulated kinase (ERK) signaling pathway was evaluated by western blotting. RESULTS miR-126 expression was upregulated in SCAPs and in SCAP-derived exosomes under hypoxia. miR-126 expression was increased in HUVECs when cocultured with SCAP-derived exosomes. Induced overexpression of miR-126 in hypoxic SCAPs and secreted exosomes resulted in enhanced angiogenesis both in vitro and in vivo. Western blot analysis revealed that miR-126-mediated SPRED1 downregulation induced activation of ERK signaling. CONCLUSIONS Under hypoxic conditions, exosomes derived from SCAPs can promote HUVEC angiogenesis through expression of miR-126, which subsequently suppresses SPRED1 and activates the ERK signaling pathway.