Hypoxia Exacerbates the Impairment of PIGF/JAK-STAT3 Signaling and Drug Metabolizing Enzymes in Preeclampsia

The placenta growth factor (PlGF) plays a significant role in the pathophysiology of preeclampsia (PE). However, the mechanisms by which PlGF production and PlGF-mediated signaling pathway are regulated in PE still remain unclear. Here we showed that in PE patients the plasma level of sFlt-1 was increased and the PlGF level was decreased. Flt-1 expression on the cell surface of the trophoblast was down-regulated in PE. And also the PE trophoblast showed the lower levels of STAT3 phosphorylation and SOCS3 expression. Furthermore, hypoxia treatment was able to down-regulate the PlGF production by placental explants from both healthy controls and PE patients. In contrast to the little effect on Flt-1 expression and promotional effects on STAT3 phosphorylation and SOCS3 expression by healthy placental explants, hypoxia treatment exacerbated the down-regulations of STAT3 phosphorylation and the expression of Flt-1 and SOCS3 by PE placental explants. Our results indicate that the STAT3/SOCS3 signaling is somehow maintained by hypoxia in healthy placenta for normal pregnancy processing while in PE placental microenvironment the STAT3/SOCS3 signaling is further impaired by hypoxia for the pathogenesis of PE disease. Our results also indicated altered expression of drug-metabolizing enzymes was in part the pathogenesis of PE.