title: Activation of adenosine A2B receptor impairs properties of trophoblast cells and involves mitogen-activated protein (MAP) kinase signaling.
abstract: BACKGROUND
  Shallow trophoblast invasion of the maternal spiral arteries contributes to impaired placental perfusion and is hypothesized to be involved in the pathophysiology of preeclampsia. Hypoxia is a potent stimulus for the release of adenosine.
  
  
  METHODS
  We investigated the effects of hypoxia and A2B adenosine receptor signaling on migration, invasion, proteolytic activity of matrix metalloproteinase (MMP)-2, expression of MMP-2 and vascular endothelial growth factor (VEGF) mRNA, and production of human chorionic gonadotropin (hCG) in trophoblast cells (HTR-8/SVneo, BeWo).
  
  
  RESULTS
  The adenosine A2B receptor agonist 5-N-ethylcarboxamidoadenosine (NECA) reduced trophoblast (HTR-8/SVneo and BeWo) migration at 2%, 8% and 21% O2 compared to untreated control cells. A2B adenosine receptor stimulation decreased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and stress-activated protein kinase/Jun-amino-terminal kinase (SAPK/JNK) at all three O2 concentrations. ProMMP-2 activity, MMP-2 mRNA levels and hCG levels were markedly decreased after A2B adenosine receptor activation in trophoblast cells. Adenosine receptor A2B stimulation decreased VEGF expression at 2% and 8% O2 but led to increased levels at 21% O2.
  
  
  CONCLUSIONS
  These data indicate A2B receptor activation blunts trophoblast migration possibly as a result of reduced activation of the MAPK signaling pathway and lower proMMP-2 levels. These data suggest a role for adenosine receptor A2B in placental development and possibly in the pathophysiology of preeclampsia.
authors.affiliation: Gynecology Research Unit, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Darashchonak
authors.affiliation: Gynecology Research Unit, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sarisin
authors.affiliation: Gynecology Research Unit, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Kleppa
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Powers
authors.affiliation: Gynecology Research Unit, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany. Electronic address: vonVersen-Hoeynck.Frauke@mh-hannover.de.
authors.forename: F
authors.initials: F
authors.lastname: von Versen-Höynck
mesh_terms: D002460:Cell Line; D002465:Cell Movement; D006063:Chorionic Gonadotropin / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011225:Pre-Eclampsia / Q000209:etiology; D011247:Pregnancy; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D006063:Chorionic Gonadotropin; D043704:Receptor, Adenosine A2B; D042461:Vascular Endothelial Growth Factor A; D020928:Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D010100:Oxygen
keywords: Adenosine receptor; Hypoxia; MAPK; Preeclampsia; Trophoblast cells