Hyperhomocysteinemia is an established risk factor for cardiovascular disease and stroke, and anemerging risk factor for Alzheimer's disease and vascular cognitive impairment. The basic mechanismsby which hyperhomocysteinemia predisposes to cerebral vascular disease are still poorly understood. Wehave developed dietary and genetic approaches to examine the mechanisms of vascular dysfunction inhyperhomocysteinemic mice. During the previous funding period of this program, we demonstrated thatcerebral blood vessels are particularly susceptible to vascular dysfunction and hypertrophy duringhyperhomocysteinemia and that the mechanism of these effects is dependent on vascular superoxide andloss of endothelium-derived nitric oxide. We now propose to use new strains of genetically-altered mice todefine the molecular mechanisms which contribute to and protect the cerebral vasculature from oxidativestress, vascular dysfunction, and hypertrophy during hyperhomocysteinemia. Our specific goals are todetermine the mechanistic role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor ofeNOS, in mediating cerebral vascular dysfunction and hypertrophy, and to test the hypotheses thatsuperoxide dismutase (SOD) and peroxisome proliferator-activated receptor gamma (PPARy) protectfrom altered cerebral vascular structure and function during hyperhomocysteinemia.
In Aim 1, we will use mice with altered expression of the ADMA hydrolyzing enzyme, dimethylargininedimethylaminohydrolase (DDAH), to test the hypothesis that hyperhomocysteinemia produces adversecerebral vascular effects through a mechanism involving ADMA.
In Aim 2, we will use mice thatoverexpress, or are deficient in, SOD to test the hypothesis that SOD protects from cerebral vasculardysfunction and hypertrophy during hyperhomocysteinemia.
In Aim 3, we will use mice with alteredexpression of wild-type or dominant-negative PPARy to test the 'hypothesis that PPARy protects fromadverse cerebral vascular endpoints in the setting of hyperhomocysteinemia. A key feature of ourexperimental design is the use of mice with systemic or endothelial-specific expression of wild-type ordominant-negative gene constructs. This project has the potential to define the mechanisms ofhomocysteine's adverse effects on the cerebral circulation and to suggest novel therapeutic approachesto the prevention of cerebral vascular disease associated with hyperhomocysteinemia.
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