Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice

Baojian Xue; Zhongming Zhang; Terry G Beltz; Fang Guo; Meredith Hay; Alan Kim Johnson

doi:10.1152/ajpregu.00406.2014

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Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice

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Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice

Baojian Xue, Zhongming Zhang, Terry G Beltz, Fang Guo, Meredith Hay and Alan Kim Johnson

American journal of physiology. Regulatory, integrative and comparative physiology, Vol.308(6), pp.R507-R516

03/15/2015

DOI: 10.1152/ajpregu.00406.2014

PMCID: PMC4360069

PMID: 25552661

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Abstract

The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERαflox) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα− mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERαflox mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERα− mice or Ad-Cre-injected ERαflox mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα− mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα− mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension.

Phenotype

Antihypertensive Agents - pharmacology

Male

Ganglionic Blockers - pharmacology

Sympathetic Nervous System - physiopathology

Sympathetic Nervous System - metabolism

Gene Knockdown Techniques

Hypertension - chemically induced

Subfornical Organ - physiopathology

Nestin - genetics

Hypertension - prevention & control

Female

Blood Pressure - drug effects

Hypertension - genetics

Angiotensin II

Disease Models, Animal

Subfornical Organ - metabolism

Heart Rate

Genotype

Hypertension - physiopathology

Estrogen Receptor alpha - deficiency

Hypertension - metabolism

Mice, Knockout

Nestin - metabolism

Animals

Estrogen Receptor alpha - genetics

Details

Title: Subtitle: Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice
Creators: Baojian Xue - Departments of Psychology, University of Iowa, Iowa City, Iowa; and baojian-xue@uiowa.edu
Zhongming Zhang - Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China
Terry G Beltz - Departments of Psychology, University of Iowa, Iowa City, Iowa; and
Fang Guo - Departments of Psychology, University of Iowa, Iowa City, Iowa; and
Meredith Hay - Department of Physiology, University of Arizona, Tucson, Arizona; Evelyn F. McKnight Brain Institute, Tucson, Arizona; and
Alan Kim Johnson - Departments of Psychology, University of Iowa, Iowa City, Iowa; and Department of Pharmacology, University of Iowa, Iowa City, Iowa; François M. Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: American journal of physiology. Regulatory, integrative and comparative physiology, Vol.308(6), pp.R507-R516
DOI: 10.1152/ajpregu.00406.2014
PMID: 25552661
PMCID: PMC4360069
NLM abbreviation: Am J Physiol Regul Integr Comp Physiol
ISSN: 0363-6119
eISSN: 1522-1490
Publisher: American Physiological Society; United States
Grant note: P01 HL014388 / NHLBI NIH HHS MH-80241 / NIMH NIH HHS HL-14388 / NHLBI NIH HHS HL-98207 / NHLBI NIH HHS
Language: English
Date published: 03/15/2015
Academic Unit: Psychological and Brain Sciences; Neuroscience and Pharmacology; Neurology (Pediatrics); Health, Sport, and Human Physiology
Record Identifier: 9984002489702771

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