title: Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice.
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 (ERα(flox)) 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 ERα(flox) 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 ERα(flox) 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.
authors.affiliation: Departments of Psychology, University of Iowa, Iowa City, Iowa; and baojian-xue@uiowa.edu.
authors.forename: Baojian
authors.initials: B
authors.lastname: Xue
authors.affiliation: Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Departments of Psychology, University of Iowa, Iowa City, Iowa; and.
authors.forename: Terry G
authors.initials: TG
authors.lastname: Beltz
authors.affiliation: Departments of Psychology, University of Iowa, Iowa City, Iowa; and.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Physiology, University of Arizona, Tucson, Arizona; Evelyn F. McKnight Brain Institute, Tucson, Arizona; and.
authors.forename: Meredith
authors.initials: M
authors.lastname: Hay
authors.affiliation: 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;
authors.forename: Alan Kim
authors.initials: AK
authors.lastname: Johnson
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005838:Genotype; D006339:Heart Rate; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D018345:Mice, Knockout; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D013356:Subfornical Organ / Q000378:metabolism* / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D047628:Estrogen Receptor alpha; D005730:Ganglionic Blockers; D064231:Nestin; D000804:Angiotensin II
keywords: ANG II; blood pressure; estrogen receptor-α; nervous system; subfornical organ