Preeclampsia is a serious disease of pregnancy, accounting for 60,000 maternal deaths worldwide. It is a multi-system disease affecting the maternal vasculature, kidneys, liver, haematological system and fetoplacental unit. There are no efficacious medical treatments for preeclampsia except delivery. If this occurs at preterm gestations, the need to deliver to save the mother can inflict a significant risk of death and disability on the fetus. Thus, a therapeutic that quenches the disease process could be used for women diagnosed with severe preterm preeclampsia, allowing them to safely gain gestation. This could drastically improve neonatal outcomes.

Soluble endoglin (sEng) is an anti-angiogenic factor identified as a critical player in severe preeclampsia.  It is significantly up regulated in preeclamptic serum and correlates with disease severity. My group has studied sEng; 1) investigating the key molecular steps regulating the release of sEng from preeclamptic placenta and 2) investigating therapeutic approaches for preeclampsia that decreases sEng production.

In 2012, we performed in vitro and in vivo studies showing MMP14 to be the key protease that mediates final cleavage and release of soluble endoglin from placenta into the maternal circulation. MMP14 is present on the surface of the placenta, upregulated in preeclampsia, and cleaves membrane bound endoglin to produce sEng. We subsequently screened five other membrane-bound (MT) MMPs in preeclampsia, and showed that none of these other MT-MMPs contributed to sEng release.

We are currently assessing the mechanisms regulating sEng release upstream of MMP14. We are examining the possibility that oxysterols (produced with cellular hypoxia) activates Liver X Receptor (LXR), which down regulates TIMP-3. The down-regulation of TIMP-3, a natural inhibitor of MMPs, allows MMP-14 to freely cleave endoglin. We have shown both LXRa and LXRb mRNA and protein are upregulated in preeclamptic placenta. Moreover we have demonstrated a dose dependent increase in sEng levels following oxysterol treatment in both primary HUVECs and primary trophoblasts.   

Interestingly, there is emerging evidence that statins (used clinically to reduce cholesterol levels) may have vasculo-protective properties.  As such, they could be a surprising candidate therapeutic for preeclampsia. Our group has performed preclinical studies where we have found adding pravastatin to primary HUVECs cells potently decreases production of sEng in a dose-dependent manner. We are currently interrogating mechanisms, mapping this pathway to MMP14 regulation. To translate this potential treatment into the clinic, we are about to start an early phase clinical trial where we will administer oral pravastatin to 12 women diagnosed with severe preterm preeclampsia. One of the key outputs we will examine is sEng levels in the maternal blood after treatment with pravastatin as a key biomarker of disease activity.