Preeclampsia is a serious complication of pregnancy where sFlt1 is released into the maternal circulation, inflicting endothelial dysfunction leading to organ injury. There is emerging evidence statins (HMG Co-A reductase inhibitors, taken for hypercholesterolaemia) have vascular protective properties. Given preeclampsia affects the maternal vasculature, statins may be a novel candidate therapeutic. We examined whether statins decrease sFlt-1 release, and reduce endothelial dysfunction in primary human tissues (experiments independently replicated 3-4 times).
We administered increasing doses of pravastatin, simvastatin and rosuvastatin to primary human umbilical vein endothelial cells (HUVECs) and purified primary trophoblast cells. Statins significantly upregulated heme-oxygenase1 (antioxidant molecule) and reduced sFlt1 release in a dose dependent manner. Importantly, statins reduced mRNA expression of a newly described human and placental specific variant, sFlt1-e15a. We next examined whether the reduction of sFlt1 induced by statins was mediated via blockade of the HMG Co-A reductase pathway. We added statins ± farnesyl pyrophosphate (HMG Co-A reductase pathway activator) to HUVEC cells. Farnesyl pyrophosphate blocked the ability of statins to reduce sFlt1 production, suggesting statins reduce sFlt-1 via the HMG Co-A reductase pathway.
We next induced endothelial dysfunction by adding 1) primary trophoblast conditioned media and 2) TNFα, to primary HUVECs. Both induced significant increases in the expression of the VCAM and Endothelin-1, markers of endothelial dysfunction. These increases were blocked by statins in a dose dependent manner. Statins also decreased monocyte adhesion to primary HUVECs and enhanced HUVEC tube forming. Using the xCELLigence system (measures experiments in real time), we found sFlt1 inhibited HUVEC cell migration, but migration was restored by adding statins.
In conclusion, statins reduce sFlt1 via the HMG CoA reductase pathway. Furthermore, we used various functional assays to show statins quench endothelial dysfunction. This data strongly supports the possibility that statins could be an effective treatment for preeclampsia.