T Cell-Mediated Regulation of Blood pressure In Postmenopausal Hypertension

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Cardiovascular disease is the leading cause of death in the U.S., and hypertension is its number one risk factor. In postmenopausal women, the loss of estrogen after menopause dramatically increases both of these conditions. While estrogen is known to be the major protective factor against hypertension and cardiovascular disease in premenopausal females, the mechanisms through which it is capable of exerting its protection remains ill-defined and impairs our ability to adequately treat or prevent its progression and severity. Postmenopausal women do not respond well to current anti- hypertensives; 64% of women do not have their blood pressure controlled when in menopause. We recently demonstrated that premenopausal females are protected against T cell mediated hypertension. We now show that postmenopausal females are not protected, and T cell mediated hypertension progresses rapidly in the absence of ovarian hormones. Determining the cellular mechanisms through which estrogen regulates T cell function would identify a novel and important anti-hypertensive pathway that would aid in the development of new therapeutic treatments for cardiovascular disease in women. As detailed below, there is evidence to support the notion that this protection is mediated through estrogen-induced signaling in T-regulatory cells, increasing their production of anti-inflammatory and anti-hypertensive genes, and repressing the function of opposing pro-inflammatory and pro-hypertensive types of T cells. The studies outlined in this proposal will investigate central hypothesis that sex hormones attenuate the hypertensive effects of angiotensin II by preventing T cell infiltration/activation, thus protecting against T cell mediated hypertension and renal injury. We propose that by studying the transition from perimenopause to postmenopause, so moving from hypertension resistance to hypertension sensitivity, we are likely to uncover the pathogenic mechanisms leading to postmenopausal hypertension. We will test these hypotheses via the following specific aims 1) Determine the estrogen receptor (ER) dependence of T cell mediated hypertension in postmenopausal females. We will determine if postmenopausal hypertension and renal injury are mediated via ER receptors on T cells versus the host kidney 2) Determine if modulation of T cell subtypes impacts postmenopausal hypertension and renal injury. Estrogen can increase anti-inflammatory T cells (Tregs) and anti-inflammatory cytokine production (IL-10) thus we will use the VCD model of menopause to determine loss of estrogen is associated with an increase in susceptibility to pro-inflammatory cytokine production and renal injury. Translational potential of our studies is high: by studying the onset of T cell-mediated hypertension in postmenopausal females, the pathogenic mechanisms uncovered may lead to novel treatments in decreasing hypertension-related complications in postmenopausal females.