title: Decreased circulating soluble Tie2 levels in preeclampsia may result from inhibition of vascular endothelial growth factor (VEGF) signaling.
abstract: OBJECTIVE
  Recent studies have found dysregulation in circulating levels of a number of angiogenic factors and their soluble receptors in preeclampsia. In this study, we examined the mechanism of production of soluble Tie2 (sTie2) and its potential connection to the failure of vascular remodeling in preeclamptic pregnancies.
  
  
  METHODS
  Serum samples were collected prospectively from 41 pregnant subjects at five different time points throughout pregnancy. Five of these subjects developed preeclampsia. For a second study, serum and placental samples were collected at delivery from preeclamptic and gestational age-matched controls. We examined serum sTie2 levels, and angiopoietin 1, angiopoietin 2, and Tie2 mRNA expression and localization in placental samples from the central basal plate area. We also examined the effects of vascular endothelial growth factor (VEGF) and a matrix metalloproteinase (MMP) inhibitor on proteolytic shedding of Tie2 in uterine microvascular endothelial cells.
  
  
  RESULTS
  Serum sTie2 levels were significantly lower in preeclamptic subjects starting at 24-28 wk of gestation and continued to be lower through the time of delivery. In culture experiments, VEGF treatment significantly increased sTie2 levels in conditioned media, whereas the MMP inhibitor completely blocked this increase, suggesting that VEGF-induced Tie2 release is MMP dependent.
  
  
  CONCLUSIONS
  Our data suggest, for the first time, an interaction between VEGF and Tie2 in uterine endothelial cells and a potential mechanism for the decrease in circulating sTie2 levels in preeclampsia, likely through inhibition of VEGF signaling. Further studies on VEGF-Tie2 interactions during pregnancy should provide new insights into the mechanisms underlying the failure of vascular remodeling in preeclampsia and other pregnancy complications.
authors.affiliation: Department of Obstetrics and Gynecology, Stanford University, Stanford, California 94305, USA. joycefu@stanford.edu
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Sung
authors.forename: Xiujun
authors.initials: X
authors.lastname: Fan
authors.forename: Sabita
authors.initials: S
authors.lastname: Dhal
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Dwyer
authors.forename: Anahita
authors.initials: A
authors.lastname: Jafari
authors.forename: Yasser Y
authors.initials: YY
authors.lastname: El-Sayed
authors.forename: Maurice L
authors.initials: ML
authors.lastname: Druzin
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Nayak
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D042787:Receptor, TIE-2 / Q000097:blood*; D015398:Signal Transduction / Q000502:physiology*; D014599:Uterus / Q000166:cytology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D020782:Matrix Metalloproteinases