Advanced glycation end products as an upstream molecule triggers ROS-induced sFlt-1 production in extravillous trophoblasts: a novel bridge between oxidative stress and preeclampsia

Placenta. 2013 Dec;34(12):1177-82. doi: 10.1016/j.placenta.2013.09.017. Epub 2013 Oct 2.


Although abnormal soluble fms-like tyrosine kinase-1 (sFlt-1) production is thought to be an important factor in the pathogenesis of pre-eclampsia, the mechanisms that regulate the production of sFlt-1 during pre-eclampsia are unclear. Accumulation of advanced glycation end products (AGEs) is prevalent in obesity, advanced maternal age, diabetes mellitus, and polycystic ovary syndrome. Alterations in the regulation and signaling of angiogenic pathways have been considered as a link between these conditions and pre-eclampsia. The purpose of this study was to explore the possible effects of AGEs on sFlt-1 secretion in extravillous trophoblasts (EVT). A EVT cell line (HRT-8/SVneo) was treated with various concentrations of AGEs-BSA. The mRNA expression of sFlt-1, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) in EVT were detected with real-time polymerase chain reaction. The secretion of sFlt-1, VEGF, and PlGF protein from EVT was measured with ELISA. The levels of intracellular reactive oxygen species (ROS) production were determined by DCFH-DA. Exposure of EVT to AGEs-BSA induced increased intracellular ROS generation and overexpression of sFlt-1 at mRNA and protein levels in a dose dependent manner. Anti-RAGE immunoglobulin G or apocynin (an inhibitors of NADPH oxidase) could decrease the intracellular ROS generation and subsequently suppressed the production of sFlt-1 at mRNA and protein levels. Our data suggested that AGEs may be a new class of important mediator in the regulation of angiogenic pathways of EVT. Accumulation of AGEs might contribute to the pathogenesis of preeclampsia by promoting sFlt-1 production through activation of RAGE/NADPH oxidase dependent pathway in EVT.

Keywords: Advanced glycation end products; Soluble fms-like tyrosine kinase 1; Trophoblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Regulation, Developmental
  • Glycation End Products, Advanced / antagonists & inhibitors
  • Glycation End Products, Advanced / metabolism*
  • Glycation End Products, Advanced / pharmacology
  • Humans
  • Immunoglobulin G / pharmacology
  • Molecular Targeted Therapy
  • NADPH Oxidases / antagonists & inhibitors
  • Oxidative Stress* / drug effects
  • Placenta Growth Factor
  • Pre-Eclampsia / drug therapy
  • Pre-Eclampsia / metabolism*
  • Pregnancy
  • Pregnancy Proteins / genetics
  • Pregnancy Proteins / metabolism
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / agonists
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism*
  • Serum Albumin, Bovine / antagonists & inhibitors
  • Serum Albumin, Bovine / pharmacology
  • Trophoblasts / drug effects
  • Trophoblasts / metabolism*
  • Up-Regulation* / drug effects
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism*


  • Acetophenones
  • Enzyme Inhibitors
  • Glycation End Products, Advanced
  • Immunoglobulin G
  • PGF protein, human
  • Pregnancy Proteins
  • RNA, Messenger
  • Reactive Oxygen Species
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • advanced glycation end products-bovine serum albumin
  • Placenta Growth Factor
  • Serum Albumin, Bovine
  • acetovanillone
  • NADPH Oxidases
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1