Preeclampsia is one of the most serious complications of pregnancy, claiming the lives of 75,000 mothers annually and countless more infants. Poor implantation and placental ischemia result in elevated secretion of anti-angiogenic factors sFlt-1 and soluble endoglin, which cause widespread maternal endothelial dysfunction, culminating in multi-system organ failure for the mother. There is no cure for preeclampsia, and disease progression can only be halted via delivery of the baby and placenta.
Although discovered more than a decade ago, surprisingly, very little is known about the molecular regulation of sFlt1, hindering development of molecularly targeted therapeutics. In the last 12 months, our team has unraveled a number of pathways involved in the molecular regulation of sFlt1 release in preeclampsia.
The mitochondria are organelles that produce energy, and are known to be dysregulated in preeclampsia. Our team has shown that there are fewer overactive mitochondria within preeclamptic placentas. Moreover our preliminary evidence suggests inhibiting the mitochondrial electron transport chain or stimulating the energy-sensing axis can inhibit sFlt1 release.
We have also identified ATF3 as a key transcription factor, highly expressed in the placenta, but decreased in preeclamptic placentas. Our data suggests it is responsible for negatively regulating sFlt1 release.
Similarly, the Epidermal Growth Factor Receptor (EGFR) is another protein, highly expressed in placenta. Intriguingly, we’ve shown that EGFR activity is increased in preeclamptic placentas and that inhibiting EGFR signaling can quench sFlt1 release.
Esomeprazole, metformin and sulfasalazine are three drugs, safe in pregnancy, which our team has shown reduce the secretion of sFlt1 from placenta, and offer potential therapeutics to treat preeclampsia. Our novel mechanistic data suggests that these drugs each target different aspects of the pathways described above, opening up the possibility of combining therapeutics based upon their abilities to regulate distinct pathways involved in sFlt1 secretion.