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 γ (ERRγ) serves a critical and O2-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 ERRγ expression was significantly increased in placentas from preeclamptic women compared with that in gestation-matched normotensive women. To further investigate a functional role for ERRγ during pregnancy, we analyzed ERRγ-deficient mice. Maternal systolic blood pressure was significantly reduced in pregnant ERRγ(+/-) females bred to ERRγ(+/-) males compared with that in wild-type (WT) mice and was markedly up-regulated by treatment of WT pregnant mice with the ERRγ agonist DY131. Placentas of ERRγ(+/-) 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 ERRγ(+/-) pregnant mice as was serum aldosterone. These effects were associated with a decrease in maternal adrenal Cyp11b1 (steroid 11β-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 ERRγ. Collectively, these findings reveal a potential role of ERRγ in maternal blood pressure homeostasis during pregnancy and suggest that aberrant ERRγ expression may contribute to the pathogenesis of preeclampsia.
Department of Biochemistry (Y.L., P.K., C.-C.C., J.L., L.W., C.R.M.), North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038; Department of Obstetrics and Gynecology (Y.L.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; and Department of Obstetrics and Gynecology (C.T., J.M.A., C.R.M.) and Department of Internal Medicine (J.M.S., L.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038.
Yanmin
Y
Luo
Premlata
P
Kumar
Chien-Cheng
CC
Chen
Jordan
J
Latham
Lei
L
Wang
Carmen
C
Tudela
James M
JM
Alexander
John M
JM
Shelton
Leslie
L
McKown
Carole R
CR
Mendelson
D000818:Animals; D001794:Blood Pressure; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D010920:Placenta / Q000098:blood supply / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
C490917:ESRRG protein, human; D011960:Receptors, Estrogen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase