title: Decreased Notch pathway signaling in the endometrium of women with endometriosis impairs decidualization.
abstract: BACKGROUND
  Endometriosis is a common gynecological disease affecting one in 10 women of reproductive age and is a major cause of pelvic pain and impaired fertility. Endometrial stromal cells of women with endometriosis exhibit a reduced response to in vitro decidualization. NOTCH1 is critical for decidualization of both mouse and human uterine stromal cells.
  
  
  OBJECTIVE
  This study aimed to determine whether decidualization failure in women with endometriosis is a consequence of impaired Notch signaling.
  
  
  METHODS
  We investigated expression levels of Notch signaling components in the endometrium of women and baboons with or without endometriosis. We identified NOTCH1-regulated genes during decidualization of human uterine fibroblast (HuF) cells by microarray and quantified their expression levels in in vitro-decidualized endometrial stromal cells isolated from women with or without endometriosis.
  
  
  RESULTS
  Notch signaling receptors NOTCH1 and NOTCH4, ligands JAGGED2 and DLL4, as well as direct target genes HES5 and HEY1 were decreased in the eutopic endometrium of women and baboons with endometriosis. Notch signaling was decreased in stromal cells isolated from women with endometriosis, which was associated with impaired in vitro decidualization. Genes that were down-regulated by NOTCH1 silencing in decidualized HuF cells were also decreased in decidualized endometrial stromal cells of women with endometriosis. FOXO1 acts as a downstream target of Notch signaling and endometriosis is associated with decreased expression of NOTCH1-regulated, FOXO1-responsive genes during decidualization.
  
  
  CONCLUSIONS
  Decreased Notch signaling is associated with endometriosis and contributes to impaired decidualization through the down-regulation of FOXO1.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology (R.-W.S., M.R.S., N.R.J., J.-W.J., A.T.F.), Michigan State University, Grand Rapids, Michigan 49503; Cancer Institute (L.M.), Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, New Orleans, Louisiana 70112; Greenville Health Systems (B.A.L.), University of South Carolina, Greenville, South Carolina 29605; and Department of Obstetrics and Gynecology (S.L.Y.), University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Ren-Wei
authors.initials: RW
authors.lastname: Su
authors.forename: Michael R
authors.initials: MR
authors.lastname: Strug
authors.forename: Niraj R
authors.initials: NR
authors.lastname: Joshi
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lessey
authors.forename: Steve L
authors.initials: SL
authors.lastname: Young
authors.forename: Asgerally T
authors.initials: AT
authors.lastname: Fazleabas
mesh_terms: D000818:Animals; D003656:Decidua / Q000502:physiology*; D015536:Down-Regulation; D010064:Embryo Implantation / Q000502:physiology*; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D046228:Microarray Analysis; D008992:Monkey Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010215:Papio; D010532:Peritoneal Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051881:Receptor, Notch1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1