The overall objective of this proposal is to examine the influence of endothelial nitric oxide synthase (eNOS) on cerebral blood vessels. Although this has been an active area of investigation, the proposed studies are novel in that we have developed new approaches to examine vascular function using mice which are deficient in expression of the eNOS gene. Because there are no selective inhibitors of eNOS, this approach allows us to directly examine the role of eNOS in the cerebral circulation. This will be particularly valuable for studies performed in vivo. We propose to examine mechanisms of vasodilation in eNOS mutant mice. We will examine responses to endothelium-dependent agonists in heterozygous and homozygous eNOS mutant mice and examine the hypothesis that relaxation of cerebral vessels to NO in the absence of eNOS is mediated by compensatory mechanisms. Preliminary data suggest endothelium-dependent relaxation is altered in heterozygous as well as homozygous eNOS mutants. To examine the hypothesis that eNOS mediates relaxation of cerebral vessels during hypoxia, we will use eNOS mutant mice and study effects of hypoxia on carotid arteries in vitro and cerebral arterioles in vivo. Preliminary data support this hypothesis. Although NO is known to react efficiently with superoxide, relatively little is known regarding the importance of this mechanism in vivo. We propose to examine the hypothesis that eNOS influences vascular effects of superoxide anion in cerebral vessels. We have obtained recent evidence using interleukin-10 (IL-10) mutant mice which suggest the IL-10 has important effects on vascular function including expression of NOS in the vessel wall. We now propose to use IL-10 mutant mice to examine the hypothesis that IL-10 protects eNOS by inhibiting downregulation of eNOS in response to proinflammatory stimuli. Thus, novel approaches will be used to study the role of eNOS and IL-10 in cerebral blood vessels. We have established colonies of eNOS and IL-10 mutant mice and the studies are feasible. These approaches should provide new insight into the role of eNOS and IL-10 in the cerebral circulation.
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