Abstract 015: Reduced Placental Expression of Regulator of G Protein Signaling-2 (RGS2) in Preeclampsia: Association, Consequence, and Cause

Abstract

To date, the early-gestational mechanisms driving the pathogenesis of preeclampsia (PreE) remain largely unclear. However, altered G protein signaling has been implicated in PreE, including alterations in GPCR agonists such as vasopressin, endothelin, and angiotensin. Regulator of G protein Signaling 2 (RGS2) is an endogenous terminator of Gαq signaling, and mutations in the Rgs2 gene are linked to hypertension and increased risk of developing PreE. Therefore, we hypothesized reduced placental RGS2 may increase the risk of developing PreE by disinhibiting Gαq signaling. In silico reanalysis of a publicly-available microarray dataset (GSE75010) revealed a significant reduction in Rgs2 mRNA in placentas from PreE pregnancies compared to controls (Con n=35, PreE n=49, p<0.05). We confirmed this reduction in Rgs2 mRNA by qPCR using human placental tissue samples (PreE 19% of Con, n=11 vs 9, p<0.05). To examine if reduced feto-placental RGS2 was sufficient to induce PreE phenotypes, wildtype C57BL/6J female mice were mated with Rgs2 -deficient ( Rgs2 -KO) sires or wildtype littermate sires. Dams mated with Rgs2 -KO sires developed diastolic hypertension (Con 92 ± 2 vs Rgs2 -KO 98.2 ± 2 [24 hr avg mmHg]; p<0.05 vs pregnant control and pre-pregnancy Rgs2 -KO) and increased proteinuria compared to dams mated with littermate sires (18.2 ± 2.2, n=7 vs 28.4 ± 2.8, n=10 mg/day, p<0.05). Preliminary histological analysis of placentas from dams mated with an Rgs2 -KO sire suggest decreased spiral artery number and diameter (SA Number: Con 7.7 ± 0.2 vs Rgs2 -KO 5.6 ± 0.4, SA Diameter: Con 128 ± 3 vs Rgs2 -KO 86 ± 12). Previous studies have outlined a CRE element in the Rgs2 promoter that is critical for transcriptional regulation of Rgs2 . Thus, we hypothesized loss of cAMP/CREB regulation may lead to reduced RGS2 in human PreE. Indeed, reduced phosphorylated CREB (p-CREB) binding was observed in PreE placentas (Con 0.146 ± 0.024 vs PreE 0.070 ± 0.021 p<0.05). However, loss of p-CREB was not due to decreases in cAMP levels (Con 1.69 ± 0.35 vs PreE 2.18 ± 0.18 nM). These data support a role for reduced placental RGS2 in the pathogenesis of PreE, and demonstrate that changes in p-CREB regulation may explain the loss of RGS2 expression in placental trophoblasts.