ABSTRACT
Peripheral vascular condition, known as deep vein thrombosis (DVT), is a common ailment that may lead to deadly pulmonary embolism. Inflammation is closely connected to venous thrombosis, which results in blood stasis, leading to ischemia and hypoxia, as indicated by research. The objective of this research was to investigate the mechanism by which exosomes derived from adipose stem cells (ADSCs) prevent deep vein thrombosis. Our data showed that Exo-483 effectively reduced the thrombus weight in DVT rats by intravenous injection. Exo-483 decreased the expression of tissue factor (TF) protein, the influx of inflammatory cells into the thrombosed vein wall, and the levels of cytokines in the serum. Furthermore, Exo-483 suppressed the expression of Mitogen-activated protein kinase 1 (MAPK1) and decreased the expression of NLRP3 inflammasomes. In an oxygen-glucose deprivation (OGD) cell model, the tube-forming and migratory abilities of primary human umbilical vein endothelial cells (HUVEC) and EA.hy926 cells were suppressed by Exo-483 pretreatment.Exo-483 is also linked to regulating Dynamin-related protein 1 (DRP1) production downstream of MAPK1.By decreasing the mitochondrial localization and phosphorylation at the S616 site of DRP1, it diminishes the expression of NLRP3 inflammasomes. Moreover, according to Bioinformatics analysis, miR-483-5p was anticipated to target MAPK1. The research conducted by our team revealed that the miR-483-5p exosome derived from ADSCs exhibited anti-inflammatory properties through the modulation of downstream DRP1-NLRP3 expression by targeting MAPK1.The findings of this research propose that miR-483-5p may be regarded as an innovative treatment target for DVT.
ABSTRACT
BACKGROUND: Deep vein thrombosis (DVT) is a common vascular surgical disease caused by the coagulation of blood in the deep veins, and predominantly occur in the lower limbs. Endothelial progenitor cells (EPCs) are multi-functional stem cells, which are precursors of vascular endothelial cells. EPCs have gradually evolved into a promising treatment strategy for promoting deep vein thrombus dissolution and recanalization through the stimulation of various physical and chemical factors. METHODS: In this study, we utilized a mouse DVT model and performed several experiments including qRT-PCR, Western blot, tube formation, wound healing, Transwell assay, immunofluorescence, flow cytometry analysis, and immunoprecipitation to investigate the role of HOXD9 in the function of EPCs cells. The therapeutic effect of EPCs overexpressing HOXD9 on the DVT model and its mechanism were also explored. RESULTS: Overexpression of HOXD9 significantly enhanced the angiogenesis and migration abilities of EPCs, while inhibiting cell apoptosis. Additionally, results indicated that HOXD9 specifically targeted the HRD1 promoter region and regulated the downstream PINK1-mediated mitophagy. Interestingly, intravenous injection of EPCs overexpressing HOXD9 into mice promoted thrombus dissolution and recanalization, significantly decreasing venous thrombosis. CONCLUSIONS: The findings of this study reveal that HOXD9 plays a pivotal role in stimulating vascular formation in endothelial progenitor cells, indicating its potential as a therapeutic target for DVT management.
