title: Diminished survival of human cytotrophoblast cells exposed to hypoxia/reoxygenation injury and associated reduction of heparin-binding epidermal growth factor-like growth factor.
abstract: OBJECTIVE
  The antiapoptotic action of heparin-binding epidermal growth factor (HBEGF)-like growth factor and its regulation by O(2) constitutes a key factor for trophoblast survival. The hypothesis that cytotrophoblast survival is compromised by exposure to hypoxia-reoxygenation (H/R) injury, which may contribute to preeclampsia and some missed abortions, prompted us to investigate HBEGF regulation and its role as a survival factor during H/R in cytotrophoblast cells.
  
  
  METHODS
  A transformed human first-trimester cytotrophoblast cell line HTR-8/SVneo was exposed to H/R (2% O(2) followed by 20% O(2)) and assessed for HBEGF expression and cell death.
  
  
  RESULTS
  Cellular HBEGF declined significantly within 30 minutes of reoxygenation after culture at 2% O(2). H/R significantly reduced proliferation and increased cell death when compared with trophoblast cells cultured continuously at 2% or 20% O(2). Restoration of cell survival also was achieved by adding recombinant HBEGF during reoxygenation. HBEGF inhibited apoptosis through its binding to either human epidermal receptor (HER)-1 or HER4, its cognate receptors.
  
  
  CONCLUSIONS
  These results provide evidence that cytotrophoblast exposure to H/R induces apoptosis and decreased cell proliferation. HBEGF accumulation is diminished under these conditions, whereas restoration of HBEGF signaling improves trophoblast survival.
authors.affiliation: Department of Obstetrics and Gynecology, University of Illinois School of Medicine, Chicago, IL, USA. richard.leach@hc.msu.edu
authors.forename: Richard E
authors.initials: RE
authors.lastname: Leach
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kilburn
authors.forename: Anelia
authors.initials: A
authors.lastname: Petkova
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: D Randall
authors.initials: DR
authors.lastname: Armant
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002245:Carbon Dioxide / Q000378:metabolism; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D066247:Receptor, ErbB-4; D015427:Reperfusion Injury / Q000150:complications*; D014327:Trophoblasts / Q000502:physiology*
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D002245:Carbon Dioxide; C512478:EGFR protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D010100:Oxygen