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) ER? 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 ER? mediates these protective actions. In this study, a "floxed" ER? transgenic mouse line (ER?(flox)) was used to create models in which ER? was knocked down in the brain or just in the SFO. Female mice with ER? ablated in the nervous system (Nestin-ER?(-) mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ER? knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ER?(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 ER? in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ER?(-) mice or Ad-Cre-injected ER?(flox) mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ER?(-) mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ER?(-) mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ER? 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 ER? is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension.

SUBMITTER: Xue B 

PROVIDER: S-EPMC4360069 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature