Pathogenesis of pre-eclampsia: marinobufagenin and angiogenic imbalance as biomarkers of the syndrome

Pre-eclampsia (preE), a pregnancy disorder with the de novo onset of hypertension and proteinuria after 20 weeks of gestation, has multiple triggers that initiate pathophysiologic mechanisms. This review addresses translational aspects of preE by synthesizing information on preE pathogenesis, describing diagnostic biomarkers that predict disease, and suggesting strategies to lessen adverse outcomes. Key to this understanding is the role of cardiotonic bufodienolides, with marinobufagenin (MBG) as the prototype, and angiogenic factors in preE pathogenesis. Data from a rat model believed to mimic human preE show that urinary excretion of MBG increases before the onset of hypertension and proteinuria and that affected animals have an increased vascular leakage and blood brain barrier permeability. Angiogenic imbalance occurs with the onset of the syndrome in this model. Also, we report that MBG levels in preE patients exceed those in normal pregnancy and that angiogenic factors are altered in patients showing signs and symptoms of overt disease. In vitro administration of MBG inhibits cytotrophoblast function and triggers hyperpermeability in endothelial cell monolayers. We advance the hypotheses that MBG precedes preE; MBG causes disruption of tight junction proteins leading to vascular leak via activation of MAPK which triggers apoptotic mechanisms resulting in further endothelial dysfunction leading to edema with the release of angiogenic factors. This review provides new evidence about the role of MBG and vasoactive intermediates in preE pathogenesis including the neurologic sequela and may reveal new therapeutic targets for the prevention of preE complications.