Estrogen-Related Receptor γ Serves a Role in Blood Pressure Homeostasis During Pregnancy

Persistent hypoxia caused by shallow trophoblast invasion and poor placental perfusion may underlie the pathophysiology of preeclampsia, a leading cause of maternal and neonatal morbidity and mortality. Previously, we found that estrogen-related receptor gamma (ERR gamma) serves a critical and O-2-dependent role in differentiation of human trophoblasts in culture and expression of tissue kallikrein and voltage-gated K+ channels. In this study, we surprisingly observed that ERR gamma expression was significantly increased in placentas from preeclamptic women compared with that in gestation-matched normotensive women. To further investigate a functional role for ERR gamma during pregnancy, we analyzed ERR gamma-deficient mice. Maternal systolic blood pressure was significantly reduced in pregnant ERR gamma(+/-) females bred to ERR gamma(+/-) males compared with that in wild-type (WT) mice and was markedly up-regulated by treatment of WT pregnant mice with the ERR gamma agonist DY131. Placentas of ERR gamma(+/-) mice manifested increased vascular endothelial growth factor A expression compared with that in WT mice. Notably, circulating levels of the antiangiogenic factor, soluble fms-like tyrosine kinase-1, were significantly reduced in ERR gamma(+/-) pregnant mice as was serum aldosterone. These effects were associated with a decrease in maternal adrenal Cyp11b1 (steroid 11 beta-hydroxylase) and Cyp11b2 (aldosterone synthase) expression. In contrast, adrenal Cyp11b1 and Cyp11b2 mRNA were increased in pregnant WT mice treated with DY131. Moreover, chromatin immunoprecipitation and luciferase reporter assays identified Cyp11b2 as a transcriptional target of ERR gamma. Collectively, these findings reveal a potential role of ERR gamma in maternal blood pressure homeostasis during pregnancy and suggest that aberrant ERR gamma expression may contribute to the pathogenesis of preeclampsia.