Endogenous aryl hydrocarbon receptor ligands-dysregulated transcriptomic profiles and endothelial function in human fetal endothelial cells

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 endothelial growth and function during pregnancy using human umbilical vein endothelial cells (HUVECs) as a model. We found that ITE, ([2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester], an endogenous AhR ligand) decreased cell proliferation and monolayer integrity in HUVECs in vitro. ITE also dysregulated transcriptomic profiles of HUVECs in a fetal sex-specific manner. The ITE-dysregulated genes were enriched in biological function and pathways highly relevant to cardiovascular diseases, vascular function, and inflammation responses. We conclude that dysregulation of endogenous AhR ligands may contribute to the PE-impaired endothelial function through fetal sex-specific regulation of endothelial transcriptomes. These AhR ligand-activated genes and pathways might represent promising therapeutic and sex-specific targets for PE-impaired endothelial function.