Effects of Metformin on pro- and anti-angiogenic factor secretion by placental trophoblast cells

Maternal endothelial dysfunction, a primary characteristic of hypertension during preeclampsia is thought to arise from excess production of anti-angiogenic factors such as soluble fms-like tyrosine-1 (Sflt-1) and soluble endoglin (sEng), by the ischemic placenta. We and others have reported increased levels of sFlt-1 and sEng in rats with reduced uteroplacental perfusion pressure (RUPP) -induced hypertension and in preeclampsia. While our lab has recently found administration of an adenosine monophosphate kinase (AMPK) pathway agonist restores VEGF levels in the RUPP rats and attenuates angiogenic imbalance, the exact mechanism underlying this observation remains unclear. We hypothesize that stimulating the AMPK pathway via metformin (MET) will attenuate hypoxia- induced increases in sEng and sFlt-1 and promote VEGF secretion. Placental cells were incubated at 20% O2, physiological normoxic 8% O2 and hypoxic 1.5% O2, and treated with MET at 0mM, 50mM and 500mM for 12 and 24 hour periods. Our findings show MET increased VEGF and sENG in JEG cells at all O2 concentrations. sEng levels increased in the hypoxic JAR cells compared to 20 % O2 and 8% O2 and MET decreased these levels. Further studies will determine if the placental MET induced AMPK signaling pathways are similar to those in skeletal muscle. Although MET had differential effects on placental cells, the overall ratio of angiogenic factors may be restored, leading to angiogenic balance and relief of endothelial dysfunction via stimulation of the AMPK pathway.