title: Estrogen receptor-β and fetoplacental endothelial prostanoid biosynthesis: a link to clinically demonstrated fetal growth restriction.
abstract: BACKGROUND
  Fetal growth restriction (FGR) due to placental dysfunction impacts short- and long-term neonatal outcomes. Abnormal umbilical artery Doppler velocimetry indicating elevated fetoplacental vascular resistance has been associated with fetal morbidity and mortality. Estrogen receptors are regulators of vasomotor tone, and fetoplacental endothelium expresses estrogen receptor-β (ESR2) as its sole estrogen receptor.
  
  
  OBJECTIVE
  Our objective was to elucidate the mechanism whereby ESR2 regulates placental villous endothelial cell prostanoid biosynthesis.
  
  
  METHODS
  We conducted immunohistochemical analysis of human placental specimens and studies of primary fetoplacental endothelial cells isolated from subjects with uncomplicated pregnancies.
  
  
  METHODS
  We evaluated in vivo levels of ESR2 and cyclooxygenase-2 (PTGS2) in villous endothelial cells from fetuses with or without FGR and/or abnormal umbilical artery Doppler indices and in vitro effects of ESR2 on prostanoid biosynthetic gene expression.
  
  
  RESULTS
  ESR2 and PTGS2 expression were significantly higher within subjects with FGR with abnormal umbilical artery Doppler indices in comparison with controls (P < 0.01). ESR2 knockdown led to decreased cyclooxygenase-1 (PTGS1), PTGS2, prostaglandin F synthase (AKR1C3), and increased prostacyclin synthase (PTGIS), with opposing results found after ESR2 overexpression (P < 0.05). ESR2 mediates prostaglandin H2 substrate availability and, in the setting of differential regulation of AKR1C3 and PTGIS, altered the balance between vasodilatory and vasoconstricting prostanoid production.
  
  
  CONCLUSIONS
  Higher ESR2 expression in the placental vasculature of FGR subjects with abnormal blood flow is associated with an endothelial cell phenotype that preferentially produces vasoconstrictive prostanoids. Endothelial ESR2 appears to be a master regulator of prostanoid biosynthesis and contributes to high-resistance fetoplacental blood flow, thereby increasing morbidity and mortality associated with FGR.
authors.affiliation: Northwestern University Feinberg School of Medicine, 250 East Superior Street, Suite 05-2175, Chicago, Illinois 60611, USA. e-su@northwestern.edu
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Su
authors.forename: Linda
authors.initials: L
authors.lastname: Ernst
authors.forename: Nadine
authors.initials: N
authors.lastname: Abdallah
authors.forename: Robert
authors.initials: R
authors.lastname: Chatterton
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Diana
authors.initials: D
authors.lastname: Monsivais
authors.forename: John
authors.initials: J
authors.lastname: Coon
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000328:Adult; D015153:Blotting, Western; D016208:Databases, Factual; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism*; D005333:Fetus / Q000098:blood supply / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009129:Muscle Tonus / Q000502:physiology; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D034622:RNA Interference; D012039:Regional Blood Flow / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
chemical_list: D047629:Estrogen Receptor beta; D011453:Prostaglandins; D004958:Estradiol; D011451:Prostaglandin-Endoperoxide Synthases