Stimulation of serotonergic 5-HT2A receptor signaling increases placental aromatase (CYP19) activity and expression in BeWo and JEG-3 human choriocarcinoma cells

It is known that serotonin can influence the production and function of sex hormones, such as estrogens. Estrogens are critical for maintenance of pregnancy and regulate placental and fetal development. The key enzyme controlling estrogens synthesis during pregnancy is placental aromatase (CYP19). To better understand the regulation of placental aromatase, this study determined whether serotonin is involved in the regulation of this enzyme. BeWo and JEG-3 choriocarcinoma cells were used as models of the human placental trophoblast to evaluate the effects of serotonin and selective 5-HT2A receptor agonists on CYP19 activity and expression. Serotonin and selective 5-HT2A receptor agonists as well as PKC activation increased aromatase activity and expression in BeWo and JEG-3 cells. Dexamethasone, which regulates aromatase expression via JAK/STAT activation in certain tissues, had no effect. Increased CYP19 gene transcription by 5-HT2A receptor and PKC stimulation was mediated by activation of the placental I.1 aromatase promoter. This study shows that the serotonergic system modulates placental aromatase expression, which would result in altered estrogens biosynthesis in trophoblast cells. Future detailed studies of serotonin–estrogen interactions in placenta are crucial for an improved understanding of the endo-, para- and autocrine role of serotonin during pregnancy and fetal development.