title: Oxidative stress-induced Gadd45α inhibits trophoblast invasion and increases sFlt1/sEng secretions via p38 MAPK involving in the pathology of pre-eclampsia.
abstract: BACKGROUND
  Pre-eclampsia (PE) is one of the most common pregnancy-related complications. We have previously reported that growth arrest and DNA damage-inducible 45 alpha (Gadd45α) is over-expressed in trophoblasts in pre-eclamptic placentas, with an excessive activation of p38 mitogen-activated protein kinase (MAPK) and increased levels of soluble Fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) in maternal sera. Now we further investigate how Gadd45α regulates trophoblast functions and anti-angiogenesis factors secretions during placental development in patients with PE.
  
  
  METHODS
  Human placental villous explants were used to verify the effects of Gadd45α and p38 MAPK in placentation. Then HRT8/SVneo cells exposed to hypoxia/reoxygenation (H/R) were employed as an oxidative stress model to investigate the effects of Gadd45α on invasion and sFlt-1/sEng secretions. Through silencing Gadd45α with lentiviral vector-based short-hairpin RNA and inhibiting p38 MAPK with SB203580, we demonstrated that Gadd45α and its downstream p38 protein played roles in the pathology of pre-eclampsia.
  
  
  RESULTS
  Gadd45α was found to have increased expression in H/R-treated villous explants and HTR8/SVneo cells. Gadd45α knockdown or p38 blockage could promote trophoblast outgrowth and migration in H/R-exposed villous explants, and enhance the potentials of trophoblast migration/invasion and network formation in H/R-exposed HTR8/SVneo cells. These functional changes might be related to the increased activities of MMP2/9. Meanwhile, Gadd45α knockdown or p38 inhibition also decreases sFlt-1/sEng secretions via suppressing oxidative stress.
  
  
  CONCLUSIONS
  Oxidative stress-induced overexpression of Gadd45α might influence the activity of MMPs through activation of p38 MAPK signaling to affect the invasion of trophoblast cells, and increase the secretions of sFlt-1/sEng, which then participate in the pathogenesis of pre-eclampsia.
authors.affiliation: a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China.
authors.forename: Xiru
authors.initials: X
authors.lastname: Liu
authors.affiliation: a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China.
authors.forename: Qinyin
authors.initials: Q
authors.lastname: Deng
authors.affiliation: a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China.
authors.forename: Xin
authors.initials: X
authors.lastname: Luo
authors.affiliation: a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shan
authors.affiliation: a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Qi
mesh_terms: D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D000071063:Endoglin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000209:etiology*; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology; D014327:Trophoblasts / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D000071063:Endoglin; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009687:Nuclear Proteins; D011725:Pyridines; D040281:Vascular Endothelial Growth Factor Receptor-1; D048051:p38 Mitogen-Activated Protein Kinases; C064206:ENG protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C501162:FLT1 protein, human; C093642:SB 203580
keywords: Growth arrest and DNA damage-inducible 45α; pre-eclampsia; soluble Fms-like tyrosine kinase 1; soluble endoglin; trophoblast invasion