PROJECT III - HORMONAL AND INTRARENAL MECHANISMS OF POSTMENOPAUSAL HYPERTENSION PROJECT SUMMARY/ABSTRACT Women who had polycystic ovary syndrome (PCOS) and hyperandrogenemia during their reproductive years have hypertension as they transition through menopause. Hyperandrogenemia in postmenopausal women (PMW), who have had PCOS when young, is also characterized by increased central adiposity and insulin resistance. While hypertension is a major cardiovascular risk factor (1,2), the humoral and intra-renal mechanisms whereby hyperandrogenemia in PMW leads to hypertension has not been elucidated (3,4). We recently characterized a novel model, the postmenopausal hyperandrogenemic female (PMHAF) rat, by treating rats with dihydrotestosterone from weaning to 13-14 mos of age. PMHAF exhibit hypertension, increased adiposity, and metabolic abnormalities, that are similar to hyperandrogenemic PMW. Our overall goal is to use this novel model to investigate potential integrative neuro humoral and renal mechanisms whereby chronic hyperandrogenemia reduces renal excretory function and increases blood pressure (BP) in PMW. We have preliminary data that PMHAF exhibit activation of the sympathetic nervous system, the renin- angiotensin system and increased renal microvascular 20-HETE synthesis (5,6). Based on strong preliminary data, in the proposed studies, we will test the following hypotheses: hypertension in PMHAF occurs via: 1) activation of the renal sympathetic nervous system, mediated via increased adiposity and melanocortin-4-receptor activity in the brain; 2) increased vascular 20-HETE, a vasoconstrictor, due to androgen-induced CYP4A2 omega-hydroxylase activity; and 3) increased renin- angiotensin system activity. Renin-angiotensin activation and increased 20-HETE together would cause increases in renal vascular resistance which in turn shifts renal pressure natriuresis to the right causing hypertension. The combination of renin-angiotensin system activation and renal sympathetic nervous activation would also cause reductions in pressure-natriuresis leading to hypertension. We will test these integrative hypotheses, using a combination of unique animal models (our PMHAF), novel transgenic rats (MC4R null and CYP4A2 null), and state-of-the art physiological, pharmacological, and molecular approaches in the following specific aims: 1) To test the hypothesis that hypertension in PMHAF is due in part to MC3/4R-mediated activation of the renal sympathetic nervous system; 2) To test the hypothesis that hypertension in PMHAF is due to increased 20-HETE via androgen-mediated increases in CYP4A2 omega-hydroxylase; 3) To test the hypothesis that hypertension in PMHAF is due to activation of the renin- angiotensin system, via androgen-mediated increases in angiotensinogen, renin substrate, and/or renal sympathetically-mediated increases in renin activity. Completion of these studies will provide novel information for improved therapeutic options for hyperandrogenemic postmenopausal women, a population that is undertreated and understudied.
PROJECT III - HORMONAL AND INTRARENAL MECHANISMS OF POSTMENOPAUSAL HYPERTENSION NARRATIVE Obesity and its cardiovascular and metabolic consequences, including hypertension, are major health issues affecting a large fraction of the US population. This project provides new information about the underlying mechanisms by which obesity contributes to increased blood pressure and metabolic disorders in experimental models that are highly relevant to common, and difficult to treat, forms of human hypertension caused by obesity and postmenopausal hyperandrogenemia. In the proposed studies, we will study the specific roles played by the melanocortin-4-receptor, the renal sympathetic nervous system, the renin-angiotensin system, and the arachidonic acid metabolites, 20-HETE, in mediating the hypertension in a model of aging hyperandrogenemic female rats, a model of hyperandrogenemic postmenopausal women who had polycystic ovary syndrome during their reproductive years.
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