Abstract P316: Effects of Paternal Contribution of a Null Allele of Regulator of G Protein Signaling-2 ( Rgs2 ) upon the Placental Transcriptome of C57BL/6J Mice

Abstract

Preeclampsia (PreE), a cardiovascular disorder of pregnancy, remains a major cause of maternal and fetal mortality worldwide. The early etiology of the disorder is unclear, though increased G protein-coupled receptor signaling has been implicated. Regulator of G protein Signaling-2 (RGS2) is a negative regulator of G protein signaling, and mutations of RGS2 have been associated with increased risk for PreE in humans. Our ongoing work has demonstrated that breeding wildtype C57BL/6J dams with Rgs2 -deficient ( Rgs2 -KO; B6.129P2- Rgs2 tm1Dgen /Mmnc) sires is sufficient to cause ~50% reduced placental expression of Rgs2 mRNA, and to induce hypertension, renal and placental morphological phenotypes typical of PreE in the wildtype dams. To test the hypothesis that reduced RGS2 (via paternal contribution of an Rgs2 -null allele) is sufficient to cause molecular changes within the placenta that are typical of PreE, we performed RNA sequencing on placentas collected on gestational day 12.5 from C57BL/6J dams mated with either Rgs2 -KO sires or wildtype littermates of these sires. RNA was isolated and sequenced using an Illumina HiSeq 4000. Transcript counts were quantified and aligned to the mouse genome (UCSC genome browser) using Kallisto, followed by differential gene expression analysis using DEseq2 (FDR = 0.1). 726 genes were differentially expressed (479 up, 247 down), including some ( Hsd11b2 (up), Adm (down)), that are similarly changed in human PreE placenta (PMID: 28618048 & 26268791). Ingenuity Pathway Analysis indicated that reduced placental Rgs2 expression was associated with mitochondrial dysfunction, unfolded protein response, and oxidative stress (all p < 1e-3), which also parallels findings in human PreE placenta. Collectively these data support the conclusion that reduced Rgs2 expression in the feto-placental unit is sufficient to induce transcriptomic changes within the placenta that are typical of PreE.