BACKGROUND: Extracellular vesicles derived from pericytes (PCEVs) have been shown to improve vascular permeability, with their therapeutic effects attributed to the presence of pro-regenerative molecules. We hypothesized that angiopoietin 1 (Angpt1) carried by PCEVs contributes to their therapeutic effects after sepsis. METHODS: A cecal ligation and puncture (CLP)-induced sepsis rat model was used in vivo, and the effects of PCEVs on vascular endothelial cells were studied in vitro. First, proteomic and Gene Ontology enrichment analyses were performed to analyze the therapeutic mechanism of PCEVs, revealing that the angiogenesis-related protein Angpt1 was highly expressed in PCEVs. We then down-regulated Angpt1 in PCEVs. The role of PCEV-carried Angpt1 on intestinal barrier function, PCs recruitment, and inflammatory cytokines was measured by using septic Sprague-Dawley rats and platelet-derived growth factor receptor beta (PDGFR-β)-Cre + mT/mG transgenic mice. RESULTS: PCEVs significantly improved vascular permeability, proliferation, and angiogenesis in CLP-induced gut barrier injury both in vivo and in vitro. Further studies have shown that PCEVs exert a protective effect on intestinal barrier function and PC recruitment. Additionally, PCEVs reduced serum inflammatory factor levels. Our data also demonstrated that the protein levels of phospho-PI3K and phospho-Akt both increased after PCEVs administration, whereas knocking out Angpt1 suppressed the protective effects of PCEVs through decreased activation of PI3K/Akt signaling. CONCLUSION: PCEVs protect against sepsis by regulating the vascular endothelial barrier, promoting PC recruitment, protecting intestinal function, and restoring properties via activation of the Angpt1/PI3K/AKT pathway.