ObjectiveTo investigate the regulatory effect of miR-21-5p in bone marrow mesenchymal stem cell-derived exosome （BMSC-Exo） on angiogenesis through the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsBone marrow mesenchymal stem cells （BMSCs） were isolated from rats， cultured， and divided into negative control group （NC group） and inhibitor group， which were transfected with miR-21-5p negative control and miR-21-5p inhibitor， respectively， and then exosomes were extracted and identified. Exosomes were co-cultured with human umbilical vein endothelial cells （HUVECs）. MTT assay was used to measure cell proliferation （24， 48， and 72 hours）， tube formation assay was used to assess angiogenesis ability， and Western blot was used to measure the protein expression levels of phosphorylated Akt （p-Akt）， total Akt， and vascular endothelial growth factor （VEGF）. The change in the angiogenesis ability of HUVECs was observed after treatment with the PI3K inhibitor LY294002. The independent samples t-test was used for comparison of continuous data between two groups， and a one-way analysis of variance was used for comparison between multiple groups， while the least significant difference t-test was used for further comparison between two groups. ResultsFlow cytometry showed that the third-generation BMSCs showed high expression levels of CD29 （98.18%） and CD90 （97.85%） and a low expression level of CD45 （0.22%）. Quantitative real-time reverse transcription-polymerase chain reaction showed that compared with the NC group， there was a significant reduction in the relative expression level of miR-21-5p in BMSCs after transfection with miR-21-5p inhibitor （0.38±0.05 vs 1.00±0.08， t=11.38， P<0.01）. MTT assay showed that compared with the control group， the 25， 50， 100， and 200 μg/mL exosome treatment groups had a significant increase in the proliferative activity of HUVECs （all P<0.05）， among which 100 μg/mL exosome treatment for 72 hours showed the most significant pro-proliferative effect， while the 400 μg/mL exosome treatment group showed a significant reduction in the proliferative activity of HUVECs （P<0.01）. Tube formation assay showed that compared with the control group and the NC-Exo group， the inhibitor-Exo group showed a significant reduction in angiogenesis ability （both P<0.05）， and compared with the inhibitor-Exo group， there was a further significant reduction in angiogenesis ability after addition of the PI3K inhibitor LY294002 （P<0.01）. Western blot showed that compared with the control group and the NC-Exo group， the inhibitor-Exo group had significant reduction in the protein expression levels of p-Akt and VEGF （all P<0.05）， and compared with the inhibitor-Exo group， the protein expression levels of p-Akt and VEGF further decreased significantly after the addition of LY294002 （both P<0.01）. ConclusionBMSC-Exo targets and activates the PI3K/Akt signaling pathway through miR-21-5p， upregulates the expression of VEGF， and promotes vascular endothelial cell proliferation and angiogenesis.