title: Impaired fetoplacental angiogenesis in growth-restricted fetuses with abnormal umbilical artery doppler velocimetry is mediated by aryl hydrocarbon receptor nuclear translocator (ARNT).
abstract: BACKGROUND
  Fetal growth restriction with abnormal umbilical artery Doppler velocimetry (FGRadv), reflective of elevated fetoplacental vascular resistance, is associated with increased risks of fetal morbidity and mortality even in comparison to those of growth-restricted fetuses with normal placental blood flow. One major cause of this abnormally elevated fetoplacental vascular resistance is the aberrantly formed, thin, elongated villous vessels that are seen in FGRadv placentas.
  
  
  OBJECTIVE
  The purpose of this study was to determine the role of fetoplacental endothelial cells (ECs) in angiogenesis in normal pregnancies and in those complicated by FGRadv.
  
  
  METHODS
  Human placental specimens were obtained from FGRadv and gestational age-matched, appropriately grown control pregnancies for EC isolation/culture and for immunohistochemical studies. Additional mechanistic studies were performed on ECs isolated from subjects with term, uncomplicated pregnancies.
  
  
  METHODS
  We evaluated tube formation and differential angiogenic gene expression in FGRadv and control ECs, and we used ECs from uncomplicated pregnancies to further elucidate the molecular mechanisms by which angiogenesis is impaired in FGRadv pregnancies.
  
  
  RESULTS
  Tube formation assays showed that FGRadv ECs demonstrate fewer branch points and total length compared with those from gestational age-matched controls, and this defect was not rescued by exposure to hypoxia. FGRadv ECs also demonstrated lower aryl hydrocarbon receptor nuclear translocator (ARNT) expression. ARNT knockdown resulted in suppression of key angiogenic genes including vascular endothelial growth factor A expression and led to deficient tube formation.
  
  
  CONCLUSIONS
  ARNT expression in the placental vasculature mediates key angiogenic expression and fetoplacental EC angiogenesis, and low ARNT expression in FGRadv ECs appears to be a key factor in deficient angiogenesis. This, in turn, results in malformed thin villous vessels that structurally contribute to the abnormally elevated fetoplacental vascular resistance that is associated with high morbidity and mortality in fetal growth restriction.
authors.affiliation: Department of Obstetrics and Gynecology (E.J.S., H.X., P.Y., M.D., J.C.), Division of Maternal-Fetal Medicine and/or Division of Reproductive Science in Medicine, and Department of Pathology (L.M.E.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; and Department of Pediatrics (K.N.F., K.K.M.), Division of Neonatology, Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Su
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: Matthew
authors.initials: M
authors.lastname: Dyson
authors.forename: John
authors.initials: J
authors.lastname: Coon
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: Farrow
authors.forename: Karen K
authors.initials: KK
authors.lastname: Mestan
authors.forename: Linda M
authors.initials: LM
authors.lastname: Ernst
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005317:Fetal Growth Retardation / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010920:Placenta / Q000000981:diagnostic imaging / Q000378:metabolism*; D011247:Pregnancy; D014463:Ultrasonography; D014469:Umbilical Arteries / Q000000981:diagnostic imaging*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014655:Vascular Resistance / Q000502:physiology
chemical_list: D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator