title: Increased angiogenic factor secretion by decidual natural killer cells from pregnancies with high uterine artery resistance alters trophoblast function.
abstract: OBJECTIVE
  Are the concentrations of factors secreted by decidual natural killer (dNK) cells from pregnancies at high risk of poor spiral artery remodelling different to those secreted from pregnancies at low risk?
  
  
  CONCLUSIONS
  Expression levels of PLGF, sIL-2R, endostatin and angiogenin were significantly increased by dNK cells from high-risk pregnancies, and angiogenin and endostatin were found to alter trophoblast function.
  
  
  BACKGROUND
  During early pregnancy, maternal uterine spiral arteries are remodelled from small diameter, low-flow, high-resistance vessels into larger diameter, higher flow vessels, with low-resistance. This change is essential for the developing fetus to obtain sufficient oxygen and nutrients. dNK cells have been implicated in this process.
  
  
  METHODS
  dNK cells were isolated from first trimester terminations of pregnancies (obtained with local ethical approval) screened for normal- or high-resistance index, indicative of cases least (<1%) and most (>21%) likely to have developed pre-eclampsia had the pregnancy not been terminated (n = 18 each group). Secreted factors and the effects of these on the trophoblast cell line, SGHPL-4, were assessed in vitro.
  
  
  METHODS
  A multiplex assay was used to assess dNK cell-secreted factors. SGHPL-4 cell functions were assessed using time-lapse microscopy, 3D invasion assays, endothelial-like tube formation ability and western blot analysis.
  
  
  RESULTS
  The expression levels of PLGF (P < 0.01), sIL-2R (P < 0.01), endostatin (P < 0.05) and angiogenin (P < 0.05) were significantly increased by dNK cells from high-risk pregnancies. Endostatin significantly decreased SGHPL-4 invasion (P < 0.05), SGHPL-4 tube formation (P < 0.05) and SGHPL-4 Akt(ser473) phosphorylation (P < 0.05). Angiogenin significantly decreased SGHPL-4 invasion (P < 0.05), but increased SGHPL-4 tube formation (P < 0.01) and decreased SGHPL-4 Akt(ser473) phosphorylation (P < 0.05).
  
  
  CONCLUSIONS
  The culture of dNK cells and protein concentrations in vitro may not fully represent the in vivo situation. Although SGHPL-4 cells are extravillous trophoblast derived, further studies would be needed to confirm the roles of angiogenin and endostatin in vivo.
  
  
  CONCLUSIONS
  The altered expression of secreted factors of dNK cells may contribute to pregnancy disorders associated with poor spiral artery remodelling.
  
  
  BACKGROUND
  This study was supported by the Wellcome Trust (project reference 091550). R.F. was a recipient of a PhD studentship from the Division of Biomedical Sciences, St. George's, University of London. The authors have no conflict of interests.
authors: Division of Biomedical Sciences, St. George's, University of London, Cranmer Terrace, London SW17 ORE, UK.
authors: A E
authors: AE
authors: Wallace
authors: R
authors: R
authors: Fraser
authors: S
authors: S
authors: Gurung
authors: S S
authors: SS
authors: Goulwara
authors: G S
authors: GS
authors: Whitley
authors: A P
authors: AP
authors: Johnstone
authors: J E
authors: JE
authors: Cartwright
mesh_terms: D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D062186:Arterial Pressure; D002460:Cell Line; D003656:Decidua / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D043169:Endostatins / Q000378:metabolism; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism; D011261:Pregnancy Trimester, First; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D012039:Regional Blood Flow; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D015398:Signal Transduction; D014327:Trophoblasts / Q000502:physiology*; D014463:Ultrasonography; D055988:Uterine Artery / Q000000981:diagnostic imaging / Q000502:physiology*
chemical_list: D043925:Angiogenesis Inducing Agents; D043169:Endostatins; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D015375:Receptors, Interleukin-2; D000072483:Placenta Growth Factor; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
keywords: angiogenin; decidua; endostatin; natural killer cell; pre-eclampsia