This project addresses the PA-10-015 by proposing to investigate the role and mechanisms of follicle stimulating hormone (FSH) and leutinizing hormone (LH) in the age-induced increase in blood pressure (BP) and body weight (BW) observed in the female Dahl salt-sensitive (DS) rat. We have previously shown that ovariectomy accelerates the age-induced increase in BP and BW in this model and that 172-estradiol (E2) prevents these effects. Aging and ovariectomy, however, also result in a marked rise in FSH and LH. Though some studies implicate these pituitary hormones in BP regulation, their mechanisms of action are poorly understood. These proposed studies will provide key insight into this experimental model of female aging and postmenopausal hypertension.
Aim 1 will determine if preventing the rise in FSH &LH that occurs as a result of ovarian hormone deficiency during normal aging from 4 months old (mo) to 12 mo in the female DS rat will attenuate the age-associated increase in BP, BW, insulin insensitivity, endothelial dysfunction, renal oxidative stress and activation of the vasoconstrictor arm of the renin angiotensin system (RAS) in vascular, renal and adipose tissues. We will also investigate the E2 and progesterone (P4) dependency of these pituitary hormone effects.
Aim 2 will serve as the corollary to Aim 1 and will determine if increasing FSH &LH in young (3-4 mo) female DS rats will result in an increase in BP, BW, insulin insensitivity, endothelial dysfunction, renal oxidative stress and activation of the vasoconstrictor arm of the RAS in vascular, renal and adipose tissues. The clinical significance of this research is the insight it will provide into the mechanisms underlying the marked rise in the prevalence of hypertension in women as they age and after their transition into menopause.

Public Health Relevance

This project is designed to make new discoveries into why age increases blood pressure and the prevalence of hypertension across the female lifespan. We will make these new discoveries by studying the role of the neglected gonadotropins in the age-induced increase in blood pressure that is observed in the Dahl salt-sensitive female rat maintained on a low sodium diet. Animal models of female aging are currently limited in number. Hopefully, furthering our understanding of this experimental model will lead to a greater use of this animal model in aging research on females. Furthermore, by investigating the gonadotropin hormone mechanisms responsible for the age-induced increase in blood pressure and hypertension, we may open the door to developing new therapeutic treatments for post-menopausal women and women with ovarian hormone deficiency - both of which experience marked changes in their gonadotropin profile from the ovarian hormone replete state.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG039779-02
Application #
8322633
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Murthy, Mahadev
Project Start
2011-09-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$157,338
Indirect Cost
$54,838
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Wang, Dan; Wang, Cheng; Wu, Xie et al. (2014) Endothelial dysfunction and enhanced contractility in microvessels from ovariectomized rats: roles of oxidative stress and perivascular adipose tissue. Hypertension 63:1063-9
Liu, Jun; Yosten, Gina L C; Ji, Hong et al. (2014) Selective inhibition of angiotensin receptor signaling through Erk1/2 pathway by a novel peptide. Am J Physiol Regul Integr Comp Physiol 306:R619-26
Ji, Hong; Zheng, Wei; Li, Xiangjun et al. (2014) Sex-specific T-cell regulation of angiotensin II-dependent hypertension. Hypertension 64:573-82
Sandberg, Kathryn; Ji, Hong (2013) Is ? the ? dog in estrogen receptor-mediated protection from hypertension? Hypertension 61:1153-4
Sandberg, Kathryn; Samson, Willis K; Ji, Hong (2013) Decoding noncoding RNA: da Vinci redux? Circ Res 113:240-1