Aging has an enormous negative impact on the cerebral circulation. One of the primary mechanismsthought to underlie many of the major changes that occur with aging involves oxidative stress. The overallgoal of this project is to define molecular mechanisms which protect the cerebral vasculature fromoxidative stress and dysfunction during aging. Although cerebral vascular disease, stroke, and vasculardementia all increase markedly with age, almost nothing is known regarding the importance of oxidativestress in the cerebral circulation with aging. In preliminary data, we observed superoxide-mediatedvascular dysfunction during aging that was of greater magnitude and occurred earlier in cerebral arteriesthan in the carotid artery or aorta.
Our first Aim i s to test the hypothesis that oxidative stress plays a majorrole in mediating this dysfunction. Peroxisome proliferator activated receptors (PPARs) are transcriptionfactors that may produce antioxidant effects. The role of PPARy in the cerebral circulation is not known.
Our second Aim i s to examine the hypothesis that PPARy protects the cerebral vasculature under normalconditions and during aging. Using a mouse expressing a human dominant negative mutation in PPARy,a 'humanized' mouse, we have obtained preliminary evidence that PPARy exerts major protective effectsin cerebral blood vessels. We will determine if oxidative stress contributes to impairment of vascularfunction in adult mice expressing this dominant negative form of PPARy. We will also determine if asynthetic activator of PPARy or genetic overexpression of wild-type PPARy in endothelium decreasesoxidative stress and improves vascular function in aging. One mechanism by which oxidative stress mayproduce vascular dysfunction involves asymmetric dimethylarginine (ADMA), an endogenous inhibitor ofendothelial NO synthase.
In Aim 3, we will use mice overexpressing the ADMA hydrolyzing enzyme,dimethylarginine dimethylaminohydrolase, to test the hypothesis that aging produces adverse vasculareffects through an ADMA-dependent mechanism. Our preliminary data support these hypotheses.Because synthetic activators of PPARy are already approved for clinical use, this area of basic researchhas implications for translational medicine. Our focus on mechanisms of oxidative stress and endothelialdysfunction seems appropriate since endothelial dysfunction has a major impact on the vessel wall andhas emerged as an independent predictor of clinical events. These studies should provide new insightinto mechanisms of vascular protection during aging and fit well within several major themes of thisprogram - cardiovascular risk factors, oxidative stress, and mechanisms of vascular protection.
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