title: In preeclampsia endogenous cardiotonic steroids induce vascular fibrosis and impair relaxation of umbilical arteries.
abstract: BACKGROUND
  Marinobufagenin (MBG), a bufadienolide cardiotonic steroid, induces cardiovascular fibrosis. Because levels of MBG in preeclampsia are increased, and anti-MBG monoclonal antibody reduces blood pressure (BP) in a rat model of preeclampsia, we hypothesized that in preeclampsia, elevated MBG levels would be associated with the development of fibrosis in feto-placental circulation and with impairment of vascular relaxation.
  
  
  METHODS
  We studied 16 patients with preeclampsia (systolic BP=150±4 mmHg; 28±2 years, 37±1 weeks gestational age) and 14 gestational age-matched normal pregnant women (systolic BP=112±2 mmHg).
  
  
  RESULTS
  Preeclampsia was associated with a rise in plasma and placental levels of MBG. In preeclamptic umbilical arteries, the expression of Fli-1, a transcription factor and a negative regulator of fibrosis, was significantly reduced (P<0.001), whereas procollagen-1 expression was increased (P<0.01). As compared to control vessels, isolated rings of umbilical arteries from patients with preeclampsia demonstrated unaltered responsiveness to endothelin-1 (EC50=2.2 and 3.2 nmol/l, respectively), but exhibited an impaired response to the relaxant effect of sodium nitroprusside (EC50=1.5 vs. 32.4 nmol/l, P<.001) following endothelin-1-induced constriction. Ex-vivo treatment of normal umbilical arteries explants with 1 and 10 nmol/l MBG for 24 h mimicked the effects of preeclampsia, specifically suppressed Fli-1 and increased collagen-1 expression while impairing vasorelaxation.
  
  
  CONCLUSIONS
  Our results indicate that in preeclampsia, elevated levels of MBG induce vascular fibrosis via a Fli-1-dependent mechanism which leads to an impairment of vasorelaxation, and suggest that MBG represents a potential target for therapy of this syndrome.
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Nikitina
authors.forename: Anton V
authors.initials: AV
authors.lastname: Mikhailov
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Nikandrova
authors.forename: Elena V
authors.initials: EV
authors.lastname: Frolova
authors.forename: Artem V
authors.initials: AV
authors.lastname: Fadeev
authors.forename: Vera V
authors.initials: VV
authors.lastname: Shman
authors.forename: Victoria Y
authors.initials: VY
authors.lastname: Shilova
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Tapilskaya
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Shapiro
authors.forename: Olga V
authors.initials: OV
authors.lastname: Fedorova
authors.forename: Alexei Y
authors.initials: AY
authors.lastname: Bagrov
mesh_terms: D000328:Adult; D015153:Blotting, Western; D005260:Female; D006801:Humans; D007118:Immunoassay; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D013256:Steroids / Q000378:metabolism*; D014469:Umbilical Arteries / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
chemical_list: D013256:Steroids