D R Armant1, R Fritz2, B A Kilburn3, Y M Kim4, J K Nien4, N J Maihle5, R Romero6, R E Leach7. 1. 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. 2. 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. 3. Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI, United States. 4. 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. 5. Georgia Regents University Cancer Center, Augusta, GA, United States. 6. 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. 7. 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.
Abstract
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.
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.
Authors: Richard E Leach; Roberto Romero; Yeon Mee Kim; Tinnakorn Chaiworapongsa; Brian Kilburn; Sanjoy K Das; Sudhansu K Dey; Anthony Johnson; Faisal Qureshi; Suzanne Jacques; D Randall Armant Journal: Lancet Date: 2002-10-19 Impact factor: 79.321
Authors: Andre T Baron; Elsa M Cora; Jacqueline M Lafky; Cecelia H Boardman; Marites C Buenafe; Alfred Rademaker; Dachao Liu; David A Fishman; Karl C Podratz; Nita J Maihle Journal: Cancer Epidemiol Biomarkers Prev Date: 2003-02 Impact factor: 4.254
Authors: Chandni V Jain; Philip Jessmon; Charbel T Barrak; Alan D Bolnick; Brian A Kilburn; Michael Hertz; D Randall Armant Journal: Cell Death Differ Date: 2017-07-21 Impact factor: 15.828
Authors: Rani Fritz; Hamid-Reza Kohan-Ghadr; Jay M Bolnick; Alan D Bolnick; Brian A Kilburn; Michael P Diamond; Sascha Drewlo; D Randall Armant Journal: Fertil Steril Date: 2015-06-11 Impact factor: 7.329
Authors: Karen K Mestan; Nina Gotteiner; Nicolas Porta; William Grobman; Emily J Su; Linda M Ernst Journal: J Pediatr Date: 2017-02-02 Impact factor: 4.406
Authors: Jeffery S Babischkin; Graham W Aberdeen; Jonathan R Lindner; Thomas W Bonagura; Gerald J Pepe; Eugene D Albrecht Journal: Endocrinology Date: 2019-06-01 Impact factor: 4.736
Authors: Don L Armstrong; Michael R McGowen; Amy Weckle; Priyadarshini Pantham; Jason Caravas; Dalen Agnew; Kurt Benirschke; Sue Savage-Rumbaugh; Eviatar Nevo; Chong J Kim; Günter P Wagner; Roberto Romero; Derek E Wildman Journal: Placenta Date: 2017-05-12 Impact factor: 3.481
Authors: Deborah J Stumpo; Carol S Trempus; Charles J Tucker; Weichun Huang; Leping Li; Kimberly Kluckman; Donna M Bortner; Perry J Blackshear Journal: Development Date: 2016-03-07 Impact factor: 6.868
Authors: Amanda K Mauro; Nauman Khurshid; Danielle M Berdahl; Amanda C Ampey; Daniel Adu; Dinesh M Shah; Derek S Boeldt Journal: J Endocrinol Date: 2021-02 Impact factor: 4.286