44-OR

Abstract

Objectives Preclinical studies suggest pravastatin is a candidate therapeutic for preeclampsia, leading to clinical trials. Surprisingly, the amount of functional interrogation of pravastatin (indeed all statins) on primary gestational tissues published thus far is very limited. The objective of this study was to determine the effect of statin administration to primary gestational tissues in vitro. Methods Pravastatin, simvastatin and rosuvastatin (HMG Co-A reductase inhibitors) were administered to primary endothelial cells (HUVECs), primary trophoblasts and preterm preeclamptic placental explants and the effect on sFlt1 and sEng secretion assessed. To identify the mechanism involved, farnesyl pyrophosphate, a HMG Co-A reductase pathway activator was added and sFlt1 and sENG was measured. Endothelial dysfunction was induced by addition of TNF α or trophoblast conditioned media to HUVECs, and the effect of statins on VCAM and monocyte adhesion determined. Finally HUVEC migration in the presence of sFlt1 ± statins was measured using the xCELLigence system (measures in real time). Results Statins significantly reduced sFlt1 release, reducing mRNA expression of the human placental specific variant, sFlt1-e15a and up-regulating heme-oxygenase-1. Pravastatin also significantly reduced sFlt1 release from preeclamptic placental explants. Concerning however, all three statins significantly increased secretion of sEng in a dose dependent manner. Addition of farnesyl pyrophosphate blocked statin-induced sFlt-1 reduction and sEng increase from HUVEC cells, indicating these changes are mediated via inhibition of HMG Co-A reductase. Primary trophoblast conditioned media and TNF α significantly upregulated markers of endothelial dysfunction, VCAM and Endothelin-1, which were quenched by adding statins. Statins also decreased monocyte adhesion to primary HUVECs, enhanced HUVEC tube forming and restored sFlt1 impaired HUVEC migration towards VEGF. Conclusions We characterized the effect of three statins on primary human endothelial cells and trophoblast cells. Our data confirms statins reduce sFlt1 and improve endothelial dysfunction. However, of potential concern is that statins increase sEng release. Disclosures F.C. Brownfoot: None. T.J. Kaitu’u-Lino: None. N. Hannan: None. R. Hastie: None. P. Cannon: None. K. Onda: None. S. Tong: None.