Reduced mRNA expression of Regulator of G Protein Signaling-2 (RGS2) in the placenta is associated with human preeclampsia and sufficient to cause features of the disorder in mice

Katherine J Perschbacher; Guorui Deng; Jeremy A Sandgren; John W Walsh; Phillip C Witcher; Sarah A Sapouckey; Caitlyn E Owens; Shao Yang Zhang; Sabrina M Scroggins; Nicole A Pearson; Eric J Devor; Julien A Sebag; Gary L Pierce; Rory A Fisher; Anne E Kwitek; Donna A Santillan; Katherine N Gibson-Corley; Curt D Sigmund; Mark K Santillan; Justin L Grobe

doi:10.1161/HYPERTENSIONAHA.119.14056

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Reduced mRNA expression of Regulator of G Protein Signaling-2 (RGS2) in the placenta is associated with human preeclampsia and sufficient to cause features of the disorder in mice

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Reduced mRNA expression of Regulator of G Protein Signaling-2 (RGS2) in the placenta is associated with human preeclampsia and sufficient to cause features of the disorder in mice

Katherine J Perschbacher, Guorui Deng, Jeremy A Sandgren, John W Walsh, Phillip C Witcher, Sarah A Sapouckey, Caitlyn E Owens, Shao Yang Zhang, Sabrina M Scroggins, Nicole A Pearson, …

Hypertension (Dallas, Tex. 1979), Vol.75(2), pp.569-579

02/2020

DOI: 10.1161/HYPERTENSIONAHA.119.14056

PMID: 31865781

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Abstract

Cascade-specific termination of G protein signaling is catalyzed by the Regulator of G protein Signaling (RGS) family members, including RGS2 . Angiotensin, vasopressin, and endothelin are implicated in preeclampsia, and RGS2 is known to inhibit G protein cascades activated by these hormones. Mutations in RGS2 are associated with human hypertension and increased risk of developing preeclampsia and its sequelae. RGS family members are known to influence maternal vascular function, but the role of RGS2 within the placenta has not been explored. Here, we hypothesized that reduced expression of RGS2 within the placenta represents a risk factor for the development of preeclampsia. Although cAMP/CREB signaling was enriched in placentas from human pregnancies affected by preeclampsia compared to clinically-matched controls and RGS2 is known to be a CREB-responsive gene, RGS2 mRNA was reduced in placentas from pregnancies affected by preeclampsia. Experimentally reducing Rgs2 expression within the feto-placental unit was sufficient to induce preeclampsia-like phenotypes in pregnant wildtype C57BL/6J mice. Stimulation of RGS2 transcription within immortalized human HTR8/SVneo trophoblasts by cAMP/CREB signaling was discovered to be dependent upon the activity of histone deacetylase activity, and more specifically, histone deacetylase-9 ( HDAC9 ), and HDAC9 expression was reduced in placentas from human pregnancies affected by preeclampsia. We conclude that reduced expression of RGS2 within the placenta may mechanistically contribute to preeclampsia. More generally, this work identifies RGS2 as an HDAC9 -dependent CREB-responsive gene, which may contribute to reduced RGS2 expression in placenta during preeclampsia. Reduced expression of RGS2 within the placenta is a risk factor for the development of PreE. Understanding the causes and consequences of reduced placental expression of RGS2 may identify novel diagnostic and therapeutic approaches to PreE.

Pregnancy

Hypertension

Placenta

G protein signaling

Pre-Eclampsia

Details

Title: Subtitle: Reduced mRNA expression of Regulator of G Protein Signaling-2 (RGS2) in the placenta is associated with human preeclampsia and sufficient to cause features of the disorder in mice
Creators: Katherine J Perschbacher - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Guorui Deng - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Jeremy A Sandgren - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
John W Walsh - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Phillip C Witcher - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Sarah A Sapouckey - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Caitlyn E Owens - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Shao Yang Zhang - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Sabrina M Scroggins - Department of Obstetrics & Gynecology, University of Iowa, Iowa City, IA 52242 USA
Nicole A Pearson - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Eric J Devor - Department of Obstetrics & Gynecology, University of Iowa, Iowa City, IA 52242 USA
Julien A Sebag - Department of Physiology, University of Iowa, Iowa City, IA 52242 USA
Gary L Pierce - Department of Health & Human Physiology, University of Iowa, Iowa City, IA 52242 USA
Rory A Fisher - Department of Pharmacology, University of Iowa, Iowa City, IA 52242 USA
Anne E Kwitek - Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226 USA
Donna A Santillan - Department of Obstetrics & Gynecology, University of Iowa, Iowa City, IA 52242 USA
Katherine N Gibson-Corley - Department of Pathology, University of Iowa, Iowa City, IA 52242 USA
Curt D Sigmund - Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226 USA
Mark K Santillan - Department of Obstetrics & Gynecology, University of Iowa, Iowa City, IA 52242 USA
Justin L Grobe - Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226 USA
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.75(2), pp.569-579
DOI: 10.1161/HYPERTENSIONAHA.119.14056
PMID: 31865781
NLM abbreviation: Hypertension
ISSN: 0194-911X
eISSN: 1524-4563
Language: English
Date published: 02/2020
Academic Unit: Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Pathology; Iowa Neuroscience Institute; Obstetrics and Gynecology; Fraternal Order of Eagles Diabetes Research Center; UI Research Foundation; Neuroscience and Pharmacology; Health, Sport, and Human Physiology ; Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9984070681502771

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