title: Prostaglandin-induced cervical remodelling in humans in the first trimester is associated with increased expression of specific tight junction, but not gap junction proteins.
abstract: BACKGROUND
  Prostaglandins (PG) are widely employed to induce cervical remodelling (CR) in pregnancy. However, the underlying molecular mechanisms are not fully elucidated. Tight junctions (TJ) and gap junctions (GJ) regulate paracellular and intercellular solute transport respectively but their role in the process of CR remains unexplored. We hypothesized that the synthetic prostaglandin E1 analogue Misoprostol (M), widely used in clinical practice to induce CR, may alter TJ and GJ expression as part of the changes in the extracellular matrix (ECM) associated with remodelling. We investigated the effects of Misoprostol exposure on the expression of cervical TJ (claudins 1, 2, 4, 5, 7 and occludin) and GJ (connexins 43, 30 and 26) in the 1st trimester.
  
  
  METHODS
  Cervical biopsies were obtained from pregnant women and comparisons of TJ and GJ protein expression (by western blotting) and immunolocalisation (laser scanning confocal microscopy) made between those who were administered vaginal Misoprostol (n=10) and those who were not (n=5).
  
  
  RESULTS
  We found that Misoprostol-treated tissue (M+) had higher expression of Claudins 1,2,4,7 and occludin (p<0.05) than untreated (M-) tissue. Expression levels of Claudins 1, 2 and 4 were positively correlated to interval from Misoprostol treatment to biopsy, whilst occludin was negatively correlated. Misoprostol-treated cervical tissue demonstrated more endothelial claudin-5 and occludin, whilst expression of GJs were unchanged.
  
  
  CONCLUSIONS
  Our observations suggest, for the first time, that increased expression of tight junction proteins may be one of the mechanisms by which Misoprostol induces CR in humans. Further studies are needed to explore if TJ proteins may be therapeutic targets to alter timing of CR in clinical practice.
authors.affiliation: Academic Unit of Reproductive and Developmental Medicine, University of Sheffield, Sheffield, UK. d.o.c.anumba@sheffield.ac.uk
authors.forename: Vidita V
authors.initials: VV
authors.lastname: Ghulé
authors.forename: Colin
authors.initials: C
authors.lastname: Gray
authors.forename: Andrea
authors.initials: A
authors.lastname: Galimberti
authors.forename: Dilly O C
authors.initials: DO
authors.lastname: Anumba
mesh_terms: D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D020070:Cervical Ripening / Q000187:drug effects* / Q000502:physiology; D002584:Cervix Uteri / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057167:Claudins / Q000032:analysis / Q000378:metabolism; D017630:Connexins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D017629:Gap Junctions / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D008875:Middle Aged; D016595:Misoprostol / Q000494:pharmacology*; D062793:Occludin; D010120:Oxytocics / Q000494:pharmacology; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011453:Prostaglandins / Q000494:pharmacology; D019108:Tight Junctions / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D057167:Claudins; D017630:Connexins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010120:Oxytocics; D011453:Prostaglandins; D016595:Misoprostol