Background
Preeclampsia is a serious multi-system disorder affecting 5% of pregnancies, caused by the placental release of sFlt-1 into the maternal bloodstream. Currently there are no medical treatments. Pravastatin is vasoprotective and recently shown to ameliorate preeclampsia in mice. We investigate the effect of pravastatin on the production of sFlt-1 and endothelial dysfunction using primary human tissues and observe its effect in patients with severe preterm preeclampsia.
Methods
Pravastatin was administered to primary human umbilical vein endothelial cells (HUVECs) and preterm preeclamptic placental explants and sFlt-1 secretion assessed. Farnesyl pyrophosphate, an activator of the cholesterol synthesis pathway, was used to determine its mode of action by reversing its effect.
Endothelial dysfunction was induced with trophoblast conditioned media to HUVECs, and the effect of pravastatin on VCAM and monocyte adhesion determined. xCELLigence was used to measure HUVEC migration and invasion in the presence of sFlt-1 ± pravastatin.
A pilot study was conducted by administering 40mg pravastatin daily to four women with severe preterm preeclampsia and clinical and biochemical changes assessed.
Results
Pravastatin significantly reduced sFlt-1 in primary tissues. It potently induced the cyto-protective enzyme heme-oxygenase1. Addition of farnesyl pyrophosphate reversed the effect of pravastatin on sFlt and suggests the HMG CoA reductase pathway is responsible for its mode of action.
Pravastatin quenched key markers of endothelial dysfunction and reduced leucocyte adhesion to endothelial cells. Migration and invasion was enhanced with pravastatin in the presence of sFlt-1.
Given this robust in vitro data we proceeded to a clinical trial. Pravastatin stabilised or reduced the clinical (blood pressure, proteinuria, urate) and biochemical (sFlt-1) features of preeclampsia in these patients.
Conclusion
Pravastatin reduces sFlt-1 and reverses endothelial dysfunction in primary human tissues, supportive of its potential as a therapeutic for preeclampsia.