? DESCRIPTION (provided by applicant): 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.
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