title: Disruption of gap junctions reduces biomarkers of decidualization and angiogenesis and increases inflammatory mediators in human endometrial stromal cell cultures.
abstract: BACKGROUND
  Uterine decidualization is critical to embryonic implantation and sustained pregnancy.
  
  
  OBJECTIVE
  To evaluate the role of gap junction intercellular communications and connexin (Cx) proteins in the morphological and biochemical differentiation of decidualized human endometrial stromal cell (ESC) cultures.
  
  
  METHODS
  Translational cell biological study.
  
  
  METHODS
  Academic medical center.
  
  
  METHODS
  Endometrial tissue was provided by five healthy reproductive age women on no hormonal medication, undergoing laparoscopy in the early proliferative phase of the menstrual cycle.
  
  
  METHODS
  Endometrial biopsy under general anesthesia, establishment and decidualization of ESC with 10 nM 17β-estradiol, 100 nM progesterone and 0.5 mM dibutyryl-cAMP (E/P/c), and manipulation of gap junctions in vitro via a combination of pharmacological or transgenic approaches.
  
  
  METHODS
  Decidualized ESC evaluated morphologically for epithelioid transformation, gap junctions by dye diffusion and Cx43, prolactin, VEGF and IL-6 expression by RT-PCR, Western and ELISA methods.
  
  
  RESULTS
  Cx43 accumulation and functional gap junctions between decidualized ESC increase concomitantly with morphological differentiation following E/P/c treatment. Disruption of gap junctions using pharmacological inhibitors or Cx43 shRNA prevents morphological differentiation and inhibits prolactin and VEGF secretion. By contrast, IL-6 secretion from decidualized ESC is augmented by both approaches.
  
  
  CONCLUSIONS
  The findings suggest that decidualized ESC function as a coordinated secretory organ to regulate embryonic implantation via intercellular cooperation mediated by gap junctions. When adjacent cells can communicate through these junctions, decidual prolactin and VEGF secretion appears to be optimized for vascular development of the placental bed. Conversely, when intercellular communications are disrupted, angiogenesis is impaired and an inflammatory state is induced.
authors.affiliation: Department of Gynecology and Obstetrics, Emory University, Atlanta, GA 30322, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Wu
authors.forename: Indrani C
authors.initials: IC
authors.lastname: Bagchi
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.forename: Neil
authors.initials: N
authors.lastname: Sidell
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taylor
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000235:genetics; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D000442:Octanols / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D034622:RNA Interference; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018031:Connexin 43; D018836:Inflammation Mediators; D015850:Interleukin-6; D000442:Octanols; D042461:Vascular Endothelial Growth Factor A; C119129:18alpha-glycyrrhetinic acid; D011374:Progesterone; D004958:Estradiol; D003994:Bucladesine; D006034:Glycyrrhetinic Acid