title: Loss of Akt increases soluble endoglin release from endothelial cells but not placenta.
abstract: BACKGROUND
  Preeclampsia is a serious pregnancy complication for which there are no medical treatments. Soluble endoglin is an anti-angiogenic factor implicated in the pathogenesis of the disease, however little is known about its molecular regulation. The PI3K/Akt pathway is down regulated in preeclamptic placentas and decreased PI3K/Akt signaling has been linked to increased soluble endoglin release from endothelial cells. MMP14 is a key protease that functions to release soluble endoglin from the placental surface.
  
  
  OBJECTIVE
  This study aimed to determine whether reduced placental PI3K/Akt causes elevated release of soluble endoglin via MMP14.
  
  
  METHODS
  Akt mRNA and protein expression were assessed in early onset preeclamptic and preterm control placentas (delivered <34weeks gestation). PI3K/Akt inhibition was achieved by administering PI3K inhibitor wortmannin, a specific Akt inhibitor or Akt siRNA to primary human umbilical vein endothelial cells, primary trophoblast and placental explants. The effect of PI3K/Akt inhibition on soluble endoglin release, MMP14, endoglin and TIMP-3 mRNA expression was determined.
  
  
  RESULTS
  We identified significantly reduced pAkt and total Akt in preeclamptic placentas relative to preterm control. Inhibition of PI3K/Akt resulted in significantly elevated soluble endoglin release from HUVECs, had no effect on MMP14 mRNA expression but resulted in significantly reduced TIMP3. In contrast inhibiting PI3K/Akt in placental explants or primary trophoblast did not change soluble endoglin release.
  
  
  CONCLUSIONS
  This study confirms that the PI3K/Akt cell protection pathway is down regulated in preeclampsia, but demonstrates that this dysregulation is unlikely to be responsible for the excessive placental soluble endoglin release characteristic of preeclampsia.
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia. Electronic address: t.klino@unimelb.edu.au.
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Hastie
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Brownfoot
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Manarangi
authors.initials: M
authors.lastname: De Silva
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Cannon
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Tuohey
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D015536:Down-Regulation; D000071063:Endoglin / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D000071063:Endoglin; D053511:Matrix Metalloproteinase 14; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019717:Tissue Inhibitor of Metalloproteinase-3; C064206:ENG protein, human; C088390:TIMP3 protein, human; C507086:MMP14 protein, human
keywords: Akt; MMP14; Placenta; Preeclampsia; Soluble endoglin