Preeclampsia is a serious complication of pregnancy, globally responsible for 60,000 maternal deaths per year. Given there is no cure other than delivery, a therapeutic that quenches disease severity would be a major advance.  Oxysterols have very recently been shown to upregulate soluble endoglin, a key anti-angiogenic factor central to the pathogenesis of preeclampsia (1). Oxysterols activate the Liver X Receptor (LXR), a transcription factor. There is emerging evidence statins (e.g. pravastatin, used clinically to reduce cholesterol levels) have vasculo-protective properties (2).  Interestingly, statins are known to both reduce oxysterol production and inhibit LXR. Therefore, the aim of this study was to characterize LXR expression in placenta from cases of severe preterm preeclampsia and assess whether pravastatin can inhibit oxysterol induced soluble endoglin production in primary gestational tissues.

In placenta, both LXRa and b were strongly localized to the syncytiotrophoblast and blood vessels within villous tips. As expected, LXRa and b staining was increased in placenta from cases of severe preterm preeclampsia (n=6) compared to gestationally matched preterm controls (n=6). Furthermore both LXRa and b mRNA expression were significantly elevated in placenta from severe preeclampsia (n=27) compared to the gestationally-matched preterm controls (n=25; p<0.05).

We next demonstrated a significant (p<0.05) dose dependent increase in soluble endoglin levels following oxysterol treatment in human umbilical vein endothelial cells (HUVEC) and primary trophoblast cells isolated from placenta. Excitingly, soluble endoglin production was significantly decreased in a dose dependent manner following pravastatin treatment of primary HUVECs (p<0.05). Furthermore, pravastatin up-regulated haemo-oxygenase-1 mRNA, a molecule with cytoprotective properties (decreases oxidative stress) and established to be decreased with preeclampsia.

We conclude LXR is upregulated in preeclampsia and pravastatin reduces soluble endoglin, possibly acting through the oxysterol/LXR pathway.  The work supports the therapeutic potential of pravastatin to treat preeclampsia.