Sex differences in the prevalence and pathogenesis of hypertension are well documented in humans and in animal models of cardiovascular disease. Recent findings from our laboratory indicate that infusions of low doses of angiotensin II or of aldosterone into mice and rats produce markedly greater hypertension in males than in females. In addition, we find that ovariectomy (OVX) abolishes these female-related antihypertensive effects and that administration of estrogen or estrogen receptor agonists selective for estrogen receptor a (ERa) or for estrogen receptor b (ERb) into the brain restores protection in OVX females. Central administration of estrogen prevents experimentally-induced hypertension in males. In other preliminary studies we have found that either decreasing reactive oxygen species (ROS) or increasing nitric oxide (NO) in the brains of rodents attenuates hypertension induced by systemic treatment with angiotensin II or aldosterone. The present proposal will extend these unique findings by addressing the following questions: 1) Where does estrogen act in the brain to evoke its antihypertensive protection? 2) What brain estrogen receptor subtype(s) is/are necessary for this antihypertensive protection? and 3) What are the roles of [Ca2+]i and of altering the balance between ROS and NO in the cellular mediation of estrogen's protective effects? Methods to be used in conducting experiments to answer these questions include: chronic telemetric measurements of blood pressure and heart rate in rats and mice, in vitro imaging of rat paraventricular nucleus neurons to determine the effects of estrogen on angiotensin II- and aldosterone-induced changes in [Ca2+]i and [ROS]i in anatomically identified ("tagged"), putative premotor sympathetic neurons, pharmacological methods, small interference RNA to selectively attenuate expression of estrogen receptor subtypes in the brain, and genetically manipulated mice to selectively remove (knockout) ER1 or ER2. A full understanding of cellular and brain mechanisms underlying the effects of sex estrogen receptor subtypes, and sex steroids in the pathogenesis of hypertension is critical for the continued development of therapies to treat cardiovascular disease in both men and women.

Public Health Relevance

Hypertension is a major risk factor for heart disease, stroke, atherosclerosis, renal disease and blindness. There is a substantial body of evidence indicating that females of child bearing age in comparison to males are protected against high blood pressure and new evidence indicates that part of this protection results from the action of estrogen on the central nervous system Understanding the role of estrogen on the brain to prevent high blood pressure is likely to lead to new methods for prevention and treatment of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098207-04
Application #
8476258
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$357,075
Indirect Cost
$119,025
Name
University of Iowa
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Clayton, Sarah C; Zhang, Zhongming; Beltz, Terry et al. (2014) CNS neuroplasticity and salt-sensitive hypertension induced by prior treatment with subpressor doses of ANG II or aldosterone. Am J Physiol Regul Integr Comp Physiol 306:R908-17
Roncari, C F; David, R B; Johnson, R F et al. (2014) Angiotensinergic and cholinergic receptors of the subfornical organ mediate sodium intake induced by GABAergic activation of the lateral parabrachial nucleus. Neuroscience 262:1-8
Coble, Jeffrey P; Johnson, Ralph F; Cassell, Martin D et al. (2014) Activity of protein kinase C-? within the subfornical organ is necessary for fluid intake in response to brain angiotensin. Hypertension 64:141-8
Xue, Baojian; Zhang, Zhongming; Beltz, Terry G et al. (2014) Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension. Am J Physiol Heart Circ Physiol 307:H191-8
Hay, Meredith; Xue, Baojian; Johnson, Alan Kim (2014) Yes! Sex matters: sex, the brain and blood pressure. Curr Hypertens Rep 16:458
Menani, Jose V; De Luca Jr, Laurival A; Johnson, Alan Kim (2014) Role of the lateral parabrachial nucleus in the control of sodium appetite. Am J Physiol Regul Integr Comp Physiol 306:R201-10
Xue, Baojian; Zhang, Zhongming; Johnson, Ralph F et al. (2013) Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats. Am J Physiol Heart Circ Physiol 305:H699-705
Xue, Baojian; Zhang, Zhongming; Beltz, Terry G et al. (2013) Estrogen receptor-* in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats. Hypertension 61:1255-62
Sladek, Celia D; Johnson, Alan Kim (2013) Integration of thermal and osmotic regulation of water homeostasis: the role of TRPV channels. Am J Physiol Regul Integr Comp Physiol 305:R669-78
Xue, Baojian; Johnson, Alan Kim; Hay, Meredith (2013) Sex differences in angiotensin II- and aldosterone-induced hypertension: the central protective effects of estrogen. Am J Physiol Regul Integr Comp Physiol 305:R459-63

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