Diabetes mellitus affects more than 300 million persons worldwide and the number of diabetic patients is estimated to rise by more than 50% within 20 years. Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity in diabetic patients, and a crucial early step, endothelial dysfunction, contributes to the development of atherosclerosis and subsequent cardiovascular complications. The risk for CVD is lower in premenopausal women compared to age-matched men. This difference disappears in the postmenopausal years and is presumably related to the reduced levels of female sex hormones, in general, and estrogen, in particular. However, premenopausal women with diabetes not only lose this sex-based cardiovascular protection, they actually experience a higher relative risk of CVD compared to diabetic men, which suggests that diabetes abrogates some of the beneficial effects of estrogen. Given this epidemiological evidence, the question arises as to what mechanisms underlie the loss of sex- mediated vasoprotection in diabetic women. This proposal will explore the basis for the loss of sex-based cardiovascular protection.
We aim specifically to investigate estrogen-mediated signaling events associated with vascular tone and endothelial function in diabetic and non-diabetic rats, as well as in human endothelial cells exposed to normal or high concentrations of glucose. We recently reported sex differences with regard to endothelial dysfunction in type 1 diabetes (T1D). However, the pathophysiology of Type 2 diabetes (T2D) may differ from that seen in T1D, and it is known that the incidence of T2D is rapidly increasing worldwide. Therefore, we propose to examine vascular function in mesenteric and renal arteries using an established obesity-induced T2D animal model, the Zucker diabetic fatty (ZDF) rat. We will also characterize, for the first time, the vascular function in a novel model of T2D (UC Davis-T2D Mellitus, UCD-T2DM). UCD-T2DM rats appear to more closely resemble the human condition, sharing all of the key features of the disease. We intend to test the central hypothesis that diabetes abolishes the vasoprotective actions of estrogen due to an alteration of estrogen-mediated signaling events associated with the release/bioavailability of endothelium-derived relaxing and/or constricting factors. We further hypothesize that the molecular basis for the diabetes-induced loss of vasoprotection involves an alteration in estrogen-modulated regulation of 1) the activity and expression of specific genes that are associated with arterial function, and/or 2) Ca2+ transport in the endothelial cells. The novelty of this proposal is that we will 1) compare vascular reactivity in a novel model of T2D to that observed in an established model of T2D and 2) test the hypothesis that changes in the spatiotemporal characteristics of Ca2+ signaling may contribute to the loss of estrogen-dependent vasoprotection in diabetic females. The significance of this proposal lies in the uncovering mechanisms that may contribute to the beneficial and detrimental effects of estrogen on vascular cell signaling in healthy and pathological conditions such as T2D.

Public Health Relevance

These studies will establish the nature of the relationship between estrogen and endothelial dysfunction in diabetes. The knowledge gained from this proposal will ultimately 1) enhance our understanding of the cellular and molecular mechanisms underlying the endothelial dysfunction in diabetic premenopausal women (the enhanced insight into these mechanisms is expected to eventually also be beneficial for the male population), 2) identify the roles that estrogen plays in the increased risk of cardiovascular disease in diabetic women, and 3) impact the clinical use of estrogen, and ultimately provide insights for the role of estrogen in the cardiovascular morbidity and mortality in female patients with diabetes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-VH-C (80)A)
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Kirby, Ruth
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University of the Pacific-Stockton
Schools of Pharmacy
United States
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Shaligram, Sonali; Sangüesa, Gemma; Akther, Farjana et al. (2018) Differential effects of high consumption of fructose or glucose on mesenteric arterial function in female rats. J Nutr Biochem 57:136-144
Sangüesa, Gemma; Shaligram, Sonali; Akther, Farjana et al. (2017) Type of supplemented simple sugar, not merely calorie intake, determines adverse effects on metabolism and aortic function in female rats. Am J Physiol Heart Circ Physiol 312:H289-H304