In Preeclampsia, Endogenous Cardiotonic Steroids Induce Vascular Fibrosis and Impairment of Vasorelaxation

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. Method 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. Conclusion 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. J Hypertens 29:769-776 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.