Journal article
Reduced Placental Expression of Regulator of G‐Protein Signaling‐2 (RGS2) and Preeclampsia
The FASEB journal, Vol.32, pp.911.6-911.6
04/2018
DOI: 10.1096/fasebj.2018.32.1_supplement.911.6
Abstract
Although late‐gestational mechanisms of preeclampsia (PreE) have been described, the genetic risk factors and mechanisms driving early‐gestational pathogenesis remain largely unknown. Various activators of Gαq‐mediated signaling pathways have been identified as possible early mediators of PreE, including vasopressin, endothelin, and angiotensin. Regulator of G‐protein Signaling 2 (RGS2) acts as an endogenous terminator of Gαq signaling and previous studies have identified a single nucleotide polymorphism (rs4606) in the RGS2 gene that is associated with increased risk for PreE, and which may reduce RGS2 mRNA. We therefore hypothesize that reduced placental expression of RGS2 increases the risk of PreE due to the subsequent disinhibition of Gαq‐mediated signaling. In silico reanalysis of a publicly‐available dataset (GSE75010) describing the transcriptomes of human placentas uncovered a significant reduction in RGS2 mRNA in placentas from pre‐term PreE pregnancies compared to control pre‐term pregnancies (Con n=35, PreE n=49, p<0.05). This reduction in RGS2 mRNA was confirmed by qPCR using human placental tissue samples from the University of Iowa Maternal‐Fetal Tissue Bank (PreE 19% of Con, n=11 vs 9, p<0.05), though no significant correlation was observed between the rs4606 SNP and PreE in this cohort. In silico reanalysis of a separate dataset (GSE93839) revealed RGS2 mRNA is among the highest‐expressed RGS family members in normal human placenta, and that it may be selectively reduced in both syncytiotrophoblast (73% of Con) and invasive cytotrophoblast (68% of Con) layers of the placenta during PreE. To examine the sufficiency of feto‐placental‐specific reduction in RGS2 on the development of PreE phenotypes, wildtype C57BL/6J female mice were mated with RGS2‐deficient (RGS2‐KO) sires, which results in a wildtype dam carrying all heterozygous feto‐placental units, or wildtype littermates of the RGS2‐KO males. 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 pre‐pregnancy RGS2‐KO, and pregnant control) and increased proteinuria compared to dams mated with littermate males (18.2 ± 2.2, n=7 vs 28.4 ± 2.8, n=10 mg/day, p<0.05), although no intrauterine growth restriction, changes in placental PlGF (Con n=6, 9.8 ± 1.1 vs KO n=12, 11.8 ± 0.8 μg/g) or FLT1 protein (103 ± 30.2 vs 114.6 ± 42.7 ng/g), or markers of hypoxia were observed. Previous studies have indicated that placentas from PreE patients exhibit reduced cAMP content compared to normal placentas, and in vascular smooth muscle, transcription of RGS2 is promoted by CREB occupancy at a cAMP Response Element (CRE) within its promoter. Thus we hypothesized a potential role for cAMP/CREB control of RGS2 in trophoblasts. Forskolin treatment increased CREB binding to the RGS2 promoter (by chromatin immunoprecipitation) and RGS2 mRNA expression (by qPCR) in cultured human HTR8/SVneo trophoblasts. Preliminary data support reduced CREB occupancy at the RGS2 promoter in PreE placenta. These data support a role for reduced placental RGS2 expression in the pathogenesis of PreE, and demonstrate that reduced placental cAMP levels may contribute to the loss of RGS2 expression in placental trophoblasts regardless of rs4606 SNP genotype.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Details
- Title: Subtitle
- Reduced Placental Expression of Regulator of G‐Protein Signaling‐2 (RGS2) and Preeclampsia
- Creators
- Katherine J Perschbacher - University of IowaGuorui Deng - University of IowaJeremy A Sandgren - University of IowaLeslie C Saenz - University of IowaDonna A Santillan - University of IowaEric J Devor - University of IowaGary L Pierce - University of IowaMark K Santillan - University of IowaRory A Fisher - University of IowaKatherine N Gibson‐Corley - University of IowaJustin L Grobe - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.32, pp.911.6-911.6
- Publisher
- The Federation of American Societies for Experimental Biology
- DOI
- 10.1096/fasebj.2018.32.1_supplement.911.6
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Number of pages
- 1
- Language
- English
- Date published
- 04/2018
- Academic Unit
- Health and Human Physiology; Internal Medicine; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Pathology; Ophthalmology and Visual Sciences; Obstetrics and Gynecology
- Record Identifier
- 9984071632802771
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