Reduced expression of the epidermal growth factor signaling system in preeclampsia

Placenta. 2015 Mar;36(3):270-8. doi: 10.1016/j.placenta.2014.12.006. Epub 2014 Dec 27.


Introduction: 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).

Discussion: 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.

Keywords: Epidermal growth factors; Placenta; Preeclampsia.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Apoptosis
  • Cell Line, Transformed
  • Chorionic Villi / metabolism
  • Chorionic Villi / pathology
  • Cohort Studies
  • Down-Regulation*
  • Epidermal Growth Factor / blood
  • Epidermal Growth Factor / chemistry
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Heparin-binding EGF-like Growth Factor / blood
  • Heparin-binding EGF-like Growth Factor / metabolism*
  • Humans
  • Peptide Fragments / blood
  • Peptide Fragments / metabolism
  • Placenta / metabolism*
  • Placenta / pathology
  • Placentation
  • Pre-Eclampsia / blood
  • Pre-Eclampsia / metabolism*
  • Pre-Eclampsia / pathology
  • Pregnancy
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Transforming Growth Factor alpha / blood
  • Transforming Growth Factor alpha / metabolism*
  • Trophoblasts / metabolism
  • Trophoblasts / pathology
  • Young Adult


  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Peptide Fragments
  • Protein Isoforms
  • TGFA protein, human
  • Transforming Growth Factor alpha
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors