Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY Obesity, which affects more than 42% of adults in the US, is the leading risk factor for hypertension. While premenopausal women are commonly viewed as protected from hypertension and cardiovascular disease, compelling evidence establishes that obesity abrogates the protective effects of female sex and predisposes women to vascular dysfunction and hypertension. Obesity-associated hypertension (OAH) involves the adipokine leptin in both males and females but through sex-specific mechanisms. We have shown that leptin elevates sympathetic activity in males whereas it stimulates aldosterone production and leads to the activation of the mineralocorticoid receptor (MR) signaling in endothelial cells in obese female mice. Clinical data indicate that obese women have disproportionately high aldosterone levels and are more responsive to MR blockers. However, a critical gap in knowledge is the source of these sex differences. Preliminary studies revealed that the absence of female sex hormone production with gonadectomy (GDX) had no additional effect on obese female mice. This novel data suggest that OAH remains leptin-dependent and aldosterone-mediated in the absence of female sex hormones and that female sex steroids play a limited role in the control of the development of OAH. Based on these findings, the central hypothesis of this proposal is that female sex chromosomes potentiate the adrenal leptin-CYP11B2-aldosterone axis in obesity. This hypothesis will be tested in 2 aims. Aim 1 will test the hypothesis that female sex chromosomes predispose to leptin-mediated aldosterone production and hypertension. We will investigate the mechanisms controlling leptin and aldosterone production, as well as BP regulation and vascular function, in leptin-infused GDX four-core genotype mice, a model dissociating gonadal phenotype from sex chromosomes. Aim 2, will test the hypothesis that human female adrenals are predisposed to exacerbated aldosterone production in response to leptin and obesity. We will take advantage of our access to freshly obtained human adrenals and human adrenocortical cells to determine whether female sex and obesity predispose adrenals to leptin-mediated aldosterone production and investigate the effects of obesity, sex and menopause on the signaling pathways regulating aldosterone production. From these studies, we expect to identify a role for sex chromosome complement in the sex specificity of the mechanisms of OAH as well as demonstrate that human female adrenals are more sensitive to leptin-mediated aldosterone production than that of males. The project will be conducted under the co-mentorship of Dr. Eric Belin de Chantemèle and Dr. Jennifer Sullivan, Vascular Biology Center and Department of Physiology at Augusta University, which has a rich history of successful pre- and post-doctoral training. The proposed project is for 3 years of funding with the proposed aims divided amongst the 3 years of funding, culminating with a dissertation defense at the end of the third year. We anticipate that findings from this novel proposal will unmask the origin and provide new information about the mechanism for sex differences in hypertension in obese women and lead to improved therapies.
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