Endogenous aryl hydrocarbon receptor ligands-dysregulated transcriptomic profiles and vascular function in rat placentas

Preeclampsia (PE) is a hypertensive disorder and a leading cause of maternal and fetal mortality and morbidity during human pregnancy. Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, regulates vascular development and function during pregnancy. Here, we report the important role of endogenous AhR ligands in vascular growth and function during pregnancy using a rat model. We found that exposure of pregnant rats to an endogenous AhR ligand (ITE, [2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester]) elevated maternal blood pressure and induced proteinuria, while decreased uteroplacental blood flow and fetal/ placental growth, all of which are hallmarks of PE. ITE also dysregulated transcriptomic profiles of rat placentas in a fetal sex-specific manner. The ITE-dysregulated genes were enriched in biological function and pathways highly relevant to diseases of heart, liver, and kidney, vascular function, and inflammation responses. Collectively, we conclude that dysregulation of endogenous AhR ligands may contribute to the PE-impaired vascular function through fetal sex-specific regulation of immune cell infiltration and transcriptomes. These AhR ligand-activated genes and pathways might represent promising therapeutic and sex-specific targets for PE-impaired vascular function.子痫前期（Preeclampsia, PE）是一种高血压性疾病，亦是人类妊娠期间孕产妇与胎儿死亡及发病的主要诱因之一。芳香烃受体（Aryl hydrocarbon receptor, AhR）作为一类配体激活型转录因子，可调控妊娠阶段的血管发育与功能。本研究通过大鼠模型，阐明了内源性AhR配体在妊娠期间血管生长与功能维持中的关键作用。研究发现，妊娠大鼠暴露于内源性AhR配体ITE（[2-(1’H-吲哚-3’-羰基)-噻唑-4-羧酸甲酯]）后，会出现孕产妇血压升高、蛋白尿症状，同时伴随子宫胎盘血流量降低、胎儿及胎盘发育受阻，上述表现均为子痫前期的典型病理特征。此外，ITE还以胎儿性别特异性的方式失调大鼠胎盘的转录组谱；ITE所诱导的失调基因，显著富集于与心、肝、肾疾病、血管功能及炎症反应高度相关的生物学功能与通路中。综上，本研究认为内源性AhR配体失调或可通过免疫细胞浸润的胎儿性别特异性调控及转录组异常，参与子痫前期相关的血管功能受损过程。上述AhR配体激活的基因与通路，有望成为子痫前期血管功能损伤的潜在治疗靶点及性别特异性干预靶点。