title: Soluble endoglin production is upregulated by oxysterols but not quenched by pravastatin in primary placental and endothelial cells.
abstract: BACKGROUND
  Preeclampsia is a serious pregnancy complication. Soluble endoglin (sEng) is released from the placenta and contributes to the maternal endothelial dysfunction seen in preeclampsia. Recently oxysterols, which activate the Liver X Receptor (LXR), have been implicated in producing sEng, by upregulating matrix metalloproteinase-14 (MMP14; cleaves endoglin to produce sEng) and down-regulating tissue inhibitor of metalloproteinase-3 (TIMP-3; inhibitor of MMP14). The functional experiments in that study were performed on JAR cells (human choriocarcinoma cell line) and placental explants.
  
  
  METHODS
  We characterized LXR in severe preeclamptic placentas, and assessed whether oxysterols increase release of sEng from primary human umbilical vein endothelial cells (HUVECs), primary trophoblasts and placental explants. Given pravastatin is thought to block oxysterol production and inhibit the LXR, we examined whether pravastatin reduces sEng release.
  
  
  RESULTS
  LXRα and β were localized to the syncytiotrophoblast and villous tips and were significantly up-regulated in preeclamptic placenta. Oxysterols upregulated sEng production in HUVECs and placental explants although the increases were far more modest than that recently reported. Oxysterols did not upregulate sEng in primary trophoblasts. Furthermore, mRNA expression of MMP14 and TIMP-3 were not altered by oxysterols in any tissue. Surprisingly, pravastatin did not decrease oxysterol-induced upregulation of sEng.
  
  
  CONCLUSIONS
  LXR is up-regulated in preeclamptic placenta. Oxysterols upregulate sEng production from human tissues, but the increase is modest, suggesting this may not be the main mechanism for the very significant elevations in sEng seen in preeclampsia. Pravastatin does not decrease sEng production.
  
  
  CONCLUSIONS
  Oxysterols modestly up-regulate sEng production which is not quenched by pravastatin.
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg 3084, Victoria, Australia. Electronic address: fiona.brownfoot@gmail.com.
authors.forename: F C
authors.initials: FC
authors.lastname: Brownfoot
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg 3084, Victoria, Australia. Electronic address: nhannan@unimelb.edu.au.
authors.forename: N
authors.initials: N
authors.lastname: Hannan
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg 3084, Victoria, Australia. Electronic address: kenji.onda@unimelb.edu.au.
authors.forename: K
authors.initials: K
authors.lastname: Onda
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg 3084, Victoria, Australia. Electronic address: stong@unimelb.edu.au.
authors.forename: S
authors.initials: S
authors.lastname: Tong
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg 3084, Victoria, Australia. Electronic address: tuuhevaha.kaituulino@gmail.com.
authors.forename: T
authors.initials: T
authors.lastname: Kaitu'u-Lino
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism*; D016022:Case-Control Studies; D004353:Drug Evaluation, Preclinical; D000071063:Endoglin; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D011225:Pre-Eclampsia / Q000188:drug therapy; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D011956:Receptors, Cell Surface; D013261:Sterols; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D017035:Pravastatin
keywords: Oxysterols; Pravastatin; Preeclampsia; Primary human umbilical vein endothelial cells; Soluble endoglin; Trophoblasts