In preeclampsia, endogenous cardiotonic steroids induce vascular fibrosis and impair relaxation of umbilical arteries
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 BP150 +/- 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.
Nikitina ER, Mikhailov AV, Nikandrova ES, Frolova EV, Fadeev AV, Shman VV, Shilova VY, Tapilskaya NI, Shapiro JI, Fedorova OV, Bagrov AY. In preeclampsia endogenous cardiotonic steroids induce vascular fibrosis and impair relaxation of umbilical arteries. J Hypertens 2011; 29:769–776