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.