title: Activation of nitric oxide synthesis in human endothelial cells using nomegestrol acetate.
abstract: OBJECTIVE
  Recent clinical trials indicate that synthetic progestins may be unexpectedly relevant for the development of cardiovascular disease. The aim of this study was to establish whether nomegestrol acetate induces signaling events in human endothelial cells that differ from those of other progestins, such as natural progesterone or medroxyprogesterone acetate.
  
  
  METHODS
  We used human endothelial cells to study the action of nomegestrol acetate (either alone or in the presence of estradiol [E2]) on the synthesis of nitric oxide (NO) and on the activity or expression of endothelial nitric oxide synthase (eNOS). We compared the effects of nomegestrol acetate with those of progesterone or medroxyprogesterone acetate. In addition, we characterized the signaling events recruited by these compounds.
  
  
  RESULTS
  Progesterone and nomegestrol acetate increase NO synthesis by transcriptional and nontranscriptional mechanisms, whereas medroxyprogesterone acetate lacks such effects. When used together with physiological E2 concentrations, progesterone and nomegestrol acetate do not interfere with (or even enhance) E2 effects, whereas medroxyprogesterone acetate impairs E2 signaling. A marked difference in the recruitment of mitogen-activated protein kinase and phosphatidylinositol-3 kinase explains the divergent effects of the three gestagens.
  
  
  CONCLUSIONS
  Our findings show significant differences in the signal transduction pathways recruited by progesterone, nomegestrol acetate, and medroxyprogesterone acetate in human endothelial cells that may have relevant clinical implications.
authors.affiliation: Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy. t.simoncini@obgyn.med.unipi.it
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
authors.forename: Antonella
authors.initials: A
authors.lastname: Caruso
authors.forename: Silvia
authors.initials: S
authors.lastname: Garibaldi
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Fu
authors.forename: Maria Silvia
authors.initials: MS
authors.lastname: Giretti
authors.forename: Chiara
authors.initials: C
authors.lastname: Baldacci
authors.forename: Camila
authors.initials: C
authors.lastname: Scorticati
authors.forename: Letizia
authors.initials: L
authors.lastname: Fornari
authors.forename: Paolo
authors.initials: P
authors.lastname: Mannella
authors.forename: Andrea Riccardo
authors.initials: AR
authors.lastname: Genazzani
mesh_terms: D002478:Cells, Cultured; D003271:Contraceptive Agents, Female / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008535:Megestrol / Q000494:pharmacology*; D015735:Mifepristone / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D009649:Norpregnadienes / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D003271:Contraceptive Agents, Female; D009649:Norpregnadienes; D045167:Progesterone Congeners; D009569:Nitric Oxide; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; C038501:nomegestrol acetate; D017258:Medroxyprogesterone Acetate; D008535:Megestrol; D019001:Nitric Oxide Synthase