Although preeclampsia (PE) is a major cause of maternal and fetal mortality, its pathogenesis is not fully understood. Endogenous digitalis-like cardiotonic steroids (CTS) are implicated in the pathophysiology of PE, as illustrated by clinical observations that Digibind, a digoxin antibody which binds CTS, lowers blood pressure in patients with PE. Recently we reported that plasma levels of marinobufagenin (MBG), a bufadienolide vasoconstrictor CTS, are increased four-fold in patients with severe PE. MBG induces vascular fibrosis in vivo and in vitro. Because levels of MBG in PE are markedly increased, we hypothesized that in PE, elevated placental MBG levels would be associated with development of fibrosis in feto-placental circulation, and with impairment of vascular relaxation. We studied 18 patients with PE and 14 subjects with uncomplicated pregnancy. In umbilical arteries from patients with PE, in the presence of elevated placental levels of MBG, we observed a 2-fold increase in the levels of procollagen-1 and collagen-1, and a reduced level of Fli-1, a transcription factor and a negative regulator of collagen synthesis. As compared to control vessels, isolated rings of umbilical arteries from subjects with PE, in the presence of unaltered responsiveness to endothelin-1, exhibited markedly impaired response to the relaxant effect of sodium nitroprusside (EC50= 141 vs. 0.9 nmol/L P<.001). Thus, in PE, elevated levels of MBG are associated with vascular fibrosis, and impairment of vasorelaxation. Our data showing that in PE, mechanisms of arterial relaxation are less effective in the presence of unaltered contractile responses of umbilical arteries, agree with the idea that prohypertensive effects of CTS are not limited to vasoconstriction and elevation of BP per se, but may also contribute to cardiovascular remodeling in the absence of BP elevations. Our results further demonstrate that MBG is a potential target for immunoneutralization in patients with PE.
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