Endoglin (CD105) expression is regulated by the liver X receptor alpha (NR1H3) in human trophoblast cell line JAR

Biol Reprod. 2008 Jun;78(6):968-75. doi: 10.1095/biolreprod.107.066498. Epub 2008 Feb 14.

Abstract

Human implantation involves invasion of the uterine wall and remodeling of uterine arteries by extravillous cytotrophoblasts. Defects in these early steps of placental development lead to poor placentation and are often associated with preeclampsia, a frequent complication of human pregnancy. One of the complex mechanisms controlling trophoblast invasion involves the activation of the liver X receptor beta (or NR1H2, more commonly known as LXRbeta) by oxysterols known as potent LXR activators. This activation of LXRbeta leads to a decrease of trophoblast invasion. The identification of new target genes of LXR in the placenta could aid in the understanding of their physiological roles in trophoblast invasion. In the present study, we show that the endoglin (ENG) gene is a direct target of the liver X receptor alpha (NR1H3, also known as LXRalpha). ENG, whose gene is highly expressed in syncytiotrophoblasts, is part of the transforming growth factor (TGF) receptor complex that binds several members of the TGFbeta superfamily. In the human placenta, ENG has been shown to be involved in the inhibition of trophoblast invasion. Treatment of human choriocarcinoma JAR cells with T0901317, a synthetic LXR-selective agonist, leads to a significant increase in ENG mRNA and protein levels. Using transfection and electrophoretic mobility shift assays, we demonstrate that LXR (as a heterodimer with the retinoid X receptor) is able to bind the ENG promoter on an LXR response element and mediates the activation of ENG gene expression by LXRalpha in JAR cells. This study suggests a novel mechanism by which LXR may regulate trophoblast invasion in pathological pregnancy such as preeclampsia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics*
  • Antigens, CD / metabolism*
  • Base Sequence
  • Binding Sites / genetics
  • Cell Line
  • DNA / genetics
  • DNA / metabolism
  • DNA Primers / genetics
  • DNA-Binding Proteins / agonists
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Embryo Implantation / genetics
  • Embryo Implantation / physiology
  • Endoglin
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Hydrocarbons, Fluorinated
  • Ligands
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Pre-Eclampsia / etiology
  • Pregnancy
  • Promoter Regions, Genetic
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism*
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Retinoid X Receptors / metabolism
  • Sulfonamides / pharmacology
  • Trophoblasts / metabolism*

Substances

  • Antigens, CD
  • DNA Primers
  • DNA-Binding Proteins
  • ENG protein, human
  • Endoglin
  • Hydrocarbons, Fluorinated
  • Ligands
  • Liver X Receptors
  • NR1H2 protein, human
  • NR1H3 protein, human
  • Orphan Nuclear Receptors
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Cytoplasmic and Nuclear
  • Retinoid X Receptors
  • Sulfonamides
  • TO-901317
  • DNA