Hypertension affects ~33% of adults in the U.S. and is a risk factor for cardiovascular disease. Fewer than 40% of hypertensive patients control their blood pressure (BP) with current medication, leaving 60% at heightened risk for cardiovascular morbidity and mortality. Although both sexes develop hypertension, young women are protected from hypertension relative to age-matched men. The identification of mechanisms by which females delay increases in BP is an underutilized approach that can be exploited to develop improved treatment options for both sexes. A critical barrier to improving BP control rates is the lack of knowledge regarding the molecular mechanisms driving elevated BP in either sex. Our goal is to address these gaps by advancing our understanding of the role of T cells in BP control in males and females. There is growing support for a causal role for effector T cells in hypertension in male animal models. Data in females are largely lacking, however, we reported that female spontaneously hypertensive rats (SHR) have more regulatory T cells (Tregs) than males. Tregs limit increases in BP in males and our preliminary data shows that Treg expansion decreases BP in female SHR. Our central hypothesis is that although effector T cells cause hypertension in both sexes, greater Tregs in females mitigate T cell-mediated hypertension via increased interleukin (IL)-10 induced nitric oxide (NO) production. Treg-mediated attenuation hypertension in male animals is associated with increased NO-dependent vasodilation, and preliminary data indicates NOS activity increases concomitant with increases in Tregs only in female SHR.
Two Specific Aims will test our hypothesis.
Aim 1 will test the hypothesis that greater Tregs in females limit increases in BP relative to males. We will determine the impact of sex on renal and vascular T cell activation and function and measure BP responses, proteinuria, and vascular function following total T cell depletion and Treg depletion/expansion. Adoptive transfer studies will determine if T cells from males vs. females have innate differences impacting differentiation, or if the local environment is more critical in defining the immune profile. Renal transplant studies will determine of the role of the kidney vs. circulating factors n defining T cell profiles.
Aim 2 will test the hypothesis that females have greater Treg-mediated increase in NO bioavailability via IL-10 resulting in improved vascular endothelial and renal function. We will measure NO bioavailability following Treg depletion/expansion in the absence and presence of IL-10 blockers. We will measure the contribution of Treg and IL-10-mediated NO release on the pressure natriuresis curve and vascular function. We will assess the contribution of Treg-mediated NO production on BP control during chronic NOS inhibition. Results will provide necessary pre-clinical foundation to support the development of novel, more refined approaches to target specific immune components in a sex- specific manner to improve BP control rates. Therapies targeting the pathophysiological cause of hypertension will undoubtedly improve BP control rates and prevent premature death from cardiovascular disease.

Public Health Relevance

Uncontrolled hypertension increases the risk of chronic kidney disease, stroke, heart attack, heart failure and peripheral artery disease and in ~85% of cases, the cause of hypertension remains unknown. Although both sexes develop hypertension, young women are protected from hypertension relative to age-matched men. The identification of mechanisms by which females exhibit a delayed increase in BP is an underutilized approach that can be exploited to develop improved treatment options for both sexes. The proposed project will improve scientific knowledge by advancing our understanding of the molecular mechanisms regulating blood pressure in both sexes which is in line with the missions of the NIH and in compliance with proposed mandates to balance sex in animal studies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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OH, Youngsuk
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Augusta University
Schools of Medicine
United States
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Gillis, Ellen E; Brinson, Krystal N; Rafikova, Olga et al. (2018) Oxidative stress induces BH4 deficiency in male, but not female, SHR. Biosci Rep 38:
Taylor, Lia E; Sullivan, Jennifer C (2018) Cutting the Fat. Hypertension 72:1081-1083
Ramirez, Lindsey A; Sullivan, Jennifer C (2018) Sex Differences in Hypertension: Where We Have Been and Where We Are Going. Am J Hypertens 31:1247-1254
Taylor, Lia E; Gillis, Ellen E; Musall, Jacqueline B et al. (2018) High Fat Diet Induced Hypertension is Associated with a Pro-Inflammatory T Cell Profile in Male and Female Dahl Salt Sensitive Rats. Am J Physiol Heart Circ Physiol :
Chen, Ying; Sullivan, Jennifer C; Edwards, Aurélie et al. (2017) Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability. Am J Physiol Renal Physiol 313:F174-F183
Sullivan, Jennifer C; Gillis, Ellen E (2017) Sex and gender differences in hypertensive kidney injury. Am J Physiol Renal Physiol 313:F1009-F1017
Tipton, Ashlee J; Musall, Jacqueline B; Crislip, G Ryan et al. (2017) Greater transforming growth factor-? in adult female SHR is dependent on blood pressure, but does not account for sex differences in renal T-regulatory cells. Am J Physiol Renal Physiol 313:F847-F853
Crislip, G Ryan; O'Connor, Paul M; Wei, Qingqing et al. (2017) Vasa recta pericyte density is negatively associated with vascular congestion in the renal medulla following ischemia reperfusion in rats. Am J Physiol Renal Physiol 313:F1097-F1105
Gillis, Ellen E; Sullivan, Jennifer C (2016) Sex Differences in Hypertension: Recent Advances. Hypertension 68:1322-1327
Gillis, Ellen E; Sasser, Jennifer M; Sullivan, Jennifer C (2016) Endothelin, sex, and pregnancy: unique considerations for blood pressure control in females. Am J Physiol Regul Integr Comp Physiol 310:R691-6

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