Abstract 144: Reduced Placental Regulator of G-Protein Signaling-2 (RGS2) and Preeclampsia

Abstract

The early mechanisms and genetic risk factors driving the pathogenesis of preeclampsia (PE), a cardiovascular disorder of pregnancy, remain largely unclear. Various hormone activators of Gα q second-messenger signaling pathways have been implicated in PE. Regulator of G-protein Signaling 2 (RGS2) acts as an endogenous terminator of Gα q signaling and previous studies identified a SNP (rs4606), which results in reduced RGS2 mRNA, as a risk factor for development of PE and its sequelae. We hypothesized reduced placental expression of RGS2 may precipitate the development of PE due to disinhibited Gα q signaling. In silico reanalysis of publically available dataset GSE75010 revealed RGS2 mRNA is reduced in placentas from pre-term PE pregnancies compared to normal pre-term pregnancies (con: 8.73 ± 0.07 n=35, PE: 8.37 ± 0.055 n=49, p<0.05). Using human placental tissue samples from the University of Iowa Maternal-Fetal Tissue Bank, we confirmed RGS2 mRNA is reduced in PE placentas (19% of control, p<0.05), despite a lack of correlation between the rs4606 SNP and PE. Additionally, in further reanalysis of other datasets, RGS2 mRNA is among the highest-expressed RGS member in normal human placenta, and appears to be selectively reduced in syncytio- and invasive cytotrophoblasts during PE (GSE93839, -26.3%, -23.3% of control). We next examined RGS2 expression in mouse placenta by FISH and found RGS2 mRNA colocalizes with markers of syncytiotrophoblast II (GCMA) and spongiotrophoblast (Tpbpα) layers. To test the effect of RGS2 loss during pregnancy, wildtype C57BL/6J female mice were mated with RGS2-deficient sires and developed diastolic hypertension, placental hypoxia by HIF1α ELISA (con 0.144±0.004, RGS2-KO 0.155±0.004 AU, p<0.05, n=5 each), and reduced placental PlGF mRNA (fold; con=1.0 n=7, RGS2-KO=0.23 n=12, p<0.05), compared to females mated with RGS2 littermate sires. These data support the concept that loss of RGS2 may contribute to the pathogenesis of PE rather than simply correlating with the disorder. Taken together, we have shown placental RGS2 is suppressed in PE, RGS2 is present in cytoplasm of specific layers of trophoblasts, and loss of feto-placental RGS2 is sufficient to cause placental hypoxia and maternal diastolic hypertension.