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. Overall design: To investigate the role of ITE on placental function. Pregnant rats were treated with ITE.