Indole-3-lactic acid derived from tryptophan metabolism alleviates the sFlt-1-induced preeclampsia-like phenotype via the activation of aryl hydrocarbon receptor

Aims: Preeclampsia (PE) is an unusual multisystem condition that occurs during pregnancy and is characterized by maternal endothelial dysfunction and damage to various organs. The catabolism of L-tryptophan (Trp) is involved in various biological activities, including healthy pregnancy. Our previous work revealed that PE significantly elevated the concentration of indole-3-lactic acid (ILA), a Trp derivative, during the third trimester of pregnancy. However, the effects of ILA on the occurrence of PE and its influence on fetoplacental vascular functionality remain unknown. Materials and methods: Twenty-five Trp metabolites were detected in maternal serum. The effects of ILA on the functions of human umbilical vein endothelial cells (HUVECs) were examined. Furthermore, a soluble fms-like tyrosine kinase-1 (sFlt-1) induced PE-like mouse model was established and treated with ILA. Key findings: We found that the ratio of ILA to Trp gradually increased as pregnancy progressed. PE did not significantly change the concentration of ILA during either the first or second trimester. Moreover, as an aryl hydrocarbon receptor (AhR) ligand, ILA promoted HUVEC proliferation, migration and tube formation through the PI3K/AKT signaling pathway after AhR activation. Importantly, ILA administration alleviated sFlt-1-induced PE-like symptoms in mice. Similarly, our in vitro study demonstrated that ILA significantly relieved sFlt-1induced HUVEC dysfunction by increasing the VEGFA and PIGF levels. Significance: These data strongly suggest that PE-elevated ILA in the third trimester is a protective mechanism against vascular dysfunction. Therefore, we propose that ILA is a novel and promising therapeutic approach for the treatment of PE that promotes endothelial cell functions.