title: Progestogens stimulate prostacyclin production by human endothelial cells.
abstract: BACKGROUND
  The effects of progestogens on endothelial physiology are poorly studied. Prostacyclin is a potent vasodilator synthesized by two isoforms of cyclooxygenase (COX) in endothelium. We examined the effects of two clinically used progestogens, progesterone and medroxyprogesterone acetate (MPA), on prostacyclin production by cultured human umbilical vein endothelial cells (HUVEC) and the possible role of progesterone receptors and both COX enzymes.
  
  
  METHODS
  Cells were exposed to 1-100 nmol/l of either progesterone or MPA and prostacyclin production was measured in culture medium.
  
  
  RESULTS
  Both progestogens significantly increased prostacyclin release in a time- and dose-dependent manner, being higher than control after 24 h. Progesterone and MPA, both at 10 nmol/l, increased mRNA expression and protein content of both COX. All these effects were mediated through progesterone receptor activation, since they were abolished by treatment of cells with the progesterone receptor antagonist RU-486. Selective inhibitors of COX-1 and -2 (SC-560 and NS-398 respectively) reduced basal prostacyclin release, and eliminated increased production in response to progestogens. In combination with estradiol, progestogens had an additive effect without eliminating estradiol-induced prostacyclin production.
  
  
  CONCLUSIONS
  Our results support the hypothesis that progesterone and MPA increased HUVEC prostacyclin production in a progesterone receptor-dependent manner, by enhancing COX-1 and COX-2 expression and activities.
authors.affiliation: Research Unit, Hospital Clínico Universitario of Valencia and Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Spain. carlos.hermenegildo@uv.es
authors.forename: C
authors.initials: C
authors.lastname: Hermenegildo
authors.forename: P J
authors.initials: PJ
authors.lastname: Oviedo
authors.forename: M C
authors.initials: MC
authors.lastname: García-Martínez
authors.forename: M A
authors.initials: MA
authors.lastname: García-Pérez
authors.forename: J J
authors.initials: JJ
authors.lastname: Tarín
authors.forename: A
authors.initials: A
authors.lastname: Cano
mesh_terms: D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis*; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008565:Membrane Proteins; D015735:Mifepristone / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011372:Progestins; D011720:Pyrazoles; D011980:Receptors, Progesterone; C115461:SC 560; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases