title: Reduced expression of the epidermal growth factor signaling system in preeclampsia.
abstract: BACKGROUND
  The epidermal growth factor (EGF) signaling system regulates trophoblast differentiation, and its disruption could contribute to perinatal disease. We hypothesized that this pathway is altered in preeclampsia, a disorder associated with trophoblast apoptosis and failure to invade and remodel the uterine spiral arteries.
  
  
  METHODS
  Six EGF family peptides and a truncated EGF receptor splice variant (p110/EGFR) were examined using immunohistochemistry in the trophoblast of placentas (N = 76) from women with preeclampsia, and compared to placentas from women of similar gestational age (GA) with preterm labor (PTL) or small for gestational age (SGA) fetuses, as well as normal term placentas. EGF, transforming growth factor-α (TGFA), and heparin-binding EGF-like growth factor (HBEGF) were evaluated using ELISA in maternal plasma from another 20 pregnancies with or without preeclampsia. Cell death was evaluated in the HTR-8/SVneo human cytotrophoblast cell line using TUNEL to evaluate the protective effects of EGF peptides.
  
  
  RESULTS
  Trophoblast HBEGF, TGFA, and EGF were significantly reduced in preeclampsia compared to PTL and SGA, while p110/EGFR accumulated significantly on the surface of the chorionic villi (p < 0.05). Plasma EGF levels were significantly decreased in preeclamptic patients, compared to non-preeclamptic patients (p < 0.05). HBEGF, EGF, TGFA, epiregulin, and betacellulin each blocked cytotrophoblast cell death in vitro (p < 0.05).
  
  
  CONCLUSIONS
  Three members of the EGF family are dysregulated in placentas with preeclampsia, whereas p110/EGFR, a potential EGF receptor antagonist, is overexpressed. These findings are consistent with the concept that disruption of the EGF signaling system contributes to aberrant trophoblast development associated with preeclampsia.
authors.affiliation: Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI, United States; Department of Anatomy & Cell Biology, Wayne State University School of Medicine, Detroit, MI, United States; Program in Reproductive and Adult Endocrinology, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD United States. Electronic address: D.Armant@Wayne.edu.
authors.forename: D R
authors.initials: DR
authors.lastname: Armant
authors.affiliation: Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI, United States; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States.
authors.forename: R
authors.initials: R
authors.lastname: Fritz
authors.affiliation: Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI, United States.
authors.forename: B A
authors.initials: BA
authors.lastname: Kilburn
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
authors.forename: Y M
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
authors.forename: J K
authors.initials: JK
authors.lastname: Nien
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA, United States.
authors.forename: N J
authors.initials: NJ
authors.lastname: Maihle
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States.
authors.forename: R
authors.initials: R
authors.lastname: Romero
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States; Department of Obstetrics, Gynecology and Women's Health, Spectrum Health Medical Group, Grand Rapids, MI, United States.
authors.forename: R E
authors.initials: RE
authors.lastname: Leach
mesh_terms: D000328:Adult; D017209:Apoptosis; D002461:Cell Line, Transformed; D002824:Chorionic Villi / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor / Q000097:blood / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D010929:Placentation; D011225:Pre-Eclampsia / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000097:blood / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D010446:Peptide Fragments; D020033:Protein Isoforms; C587886:TGFA protein, human; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Epidermal growth factors; Placenta; Preeclampsia