SLCO2A1突变介导血管内皮细胞功能障碍参与慢性肠病(CEAS)发生发展OA

Objective To investigate the pathogenic mechanism of chronic enteropathy associated with SLCO2A1 with SLCO2A1 gene(CEAS),a hereditary disease caused by SLCO2A1 mutations,and to provide theoretical insight into potential therapeutic strategies.Methods Molecular docking was performed to model the binding structure be-tween prostaglandin E2(PGE2)and SLCO2A1.PGE2 levels in urine and peripheral blood were measured by ELISA.CD31 and IGFBP7 expression in intestinal tissues was assessed by immunohistochemistry.Public databases were used to confirm the high expression of SLCO2A1 in endothelial cells.Human umbilical vein endothelial cells(HUVECs)were used as an in vitro model,and SLCO2A1 was knocked down by siRNA.Fluorescent PGE2 uptake assays,tube formation assays,and transcriptomic sequencing were performed to evaluate functional changes.Exoge-nous PGE2 and indomethacin were further used to mimic pathological intra-and extracellular PGE2 accumulation,followed by assessment of angiogenesis and transcriptomic alterations.Results CEAS patients showed an increased urinary PGE2 levels(P＜0.01)but a decreased peripheral blood PGE2 level(P＜0.001).Intestinal tissues exhibited reduced CD31 expression(P＜0.001)and increased IGFBP7 expression(P＜0.05).SLCO2A1 knockdown in HUVECs significantly impaired PGE2 uptake and reduced angiogenic capacity(P＜0.05).Transcriptomic analysis revealed enrichment of differentially expressed genes in pathways related to cell communication,JAK-STAT signa-ling,and calcium signaling.After exogenous PGE2 treatment,angiogenesis remained lower in SLCO2A1-knockdown cells than in controls(P＜0.000 1),accompanied by sustained activation of theJAK/STATpathway(P＜0.000 1).In-domethacin inhibited angiogenesis only in wild-type cells(P＜0.000 1)and had no significant effect on SLCO2A1-knockdown cells.Conclusions SLCO2A1 deficiency disrupts PGE2 transport and leads to an abnormal extracellular PGE2 accumulation.This process may inhibit endothelial angiogenesis through sustained activation of JAK/STAT-mediated inflammatory signaling,thereby contributing to CEAS progression.