Nicotinamide Counteracts the Detrimental Effect of Endothelin-1 on Uterine Decidualization During Early Pregnancy by Influencing EDNRB.

Endothelin-1 (ET-1) is involved in the pathogenesis of preeclampsia. Mice (Edn1H/+) having excess endothelin-1 developed preeclampsia-like phenotypes during pregnancy in a maternal genotype-dependent manner. Here, we investigated whether decidualization is impaired in Edn1H/+ dams, and whether nicotinamide (a potent inhibitor of ET-1) exerts beneficial effect. We compared implantation sites between wild type (WT) and Edn1H/+ dams with or without nicotinamide treatment. Implantation sites of Edn1H/+ dams exhibited abnormal ectoplacental cones and sinusoids, along with reduced vascular density in the mesometrial regions of the decidua. VEGF levels were higher in the decidua of Edn1H/+ dams compared with WT dams. Markers of decidualization were decreased in Edn1H/+ dams. Nicotinamide supplementation corrected this abnormality. During differentiation (decidualization) of cultured human endometrial stomal cells, ET-1 impaired the upregulated expression of decidualization markers. The effect of ET-1 was reversed by nicotinamide. These results show nicotinamide counteracts the detrimental effects of ET-1 on endometrial decidualization and has potential to improve embryo implantation and subsequent pregnancy outcomes.