关键词: 溶质载体有机阴离子转运蛋白家族成员2A1(SLCO2A1), 前列腺素E2(PGE₂), 血管内皮细胞, 代谢障碍, SLCO2A1相关慢性肠病(CEAS)

Abstract: 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 between 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. Exogenous 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 signaling, 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 the JAK/STAT pathway(P＜0.000 1). Indomethacin 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.

Key words: solute carrier organic anion transporter family member 2A1(SLCO2A1), prostaglandin E2(PGE₂), vascular endothelial cell, metabolic disorder, chronic enteropathy associated with SLCO2A1 (CEAS)