Nicotinamide opposes ET-1's adverse effect on uterine decidualization via EDNRB

Endothelin-1 is involved in pathogenesis of preeclampsia. Mice ( Edn1 ^H/+ ) having excess endothelin-1 developed preeclampsia-like phenotypes during pregnancy in a maternal genotype-dependent manner. Here, we investigate whether decidualization is impaired in Edn1 ^H/+ dams, and whether nicotinamide (a potent inhibitor of endothelin-1) exerts beneficial effect. We compared implantation sites between wild type (WT) and Edn1 ^H/+ dams with or without nicotinamide treatment. Implantation sites of Edn1 ^H/+ dams exhibited abnormal ectoplacental cone and sinusoids with reduced vascular density in mesometrial regions of deciduae. There was more VEGF in decidua of Edn1 ^H/+ dams than WT dams. Markers of decidualization were decreased in Edn1 ^H/+ dams. Nicotinamide supplementation corrected this abnormality. During differentiation (decidualization) of cultured human endometrial stomal cells, endothelin-1 impaired the upregulated expression of decidualization markers. The endothelin-1's effect was reversed by nicotinamide. These results show nicotinamide counteracts ET-1's detrimental effects on endometrial decidualization and has potential to improve embryo implantation and subsequent pregnancy outcomes.