Endothelial and neuronal isoforms of nitric oxide synthase (NOS) appear to play a major role in regulation of cerebral circulation. The overall objectives of this project is to examine the influence of inducible NOS II and inducible cyclooxygenase (COX-2) on cerebral blood vessels. Both NOS II and COX-2 may be expressed in blood vessels in response to proinflammatory stimuli and under some pathophysiologi-cal conditions. The investigators propose to examine the influence of NOS II and COX-2 on vascular tone and permeability of the blood-brain barrier, and to examine mechanisms which regulate expression of these genes. To define the role of NOS iI in cerebral vessels, studies will now be performed using two state-of-the-art molecular approaches - NOS II knockoutmice and local overexpression using adenoviral- mediated gene transfer of NOS II. The functional importance of nuclear factor-Kappa Beta in mediating these responses will be examined. There may be interactions between the NOS and COX systems. Studies in NOS II knockout mice will allow examination of the functional importance of COX-2 in the presence and absence of NOS II. Interleukin-10 (IL-10) is an anti-inflammatory cytokine which protects against endotoxin shock. The role of IL- 10 in blood vessels is not known. Using IL-10 knockout mice, we plan to examine the hypothesis that interleukin 10 is a major endogenous regulator of expression of NOS II and COX-2 in cerebral vessels. Preliminary data support this hypothesis. Thus, state-of-the-art approaches will be used to study the role of NOS II, COX-2, and IL-10 in cerebral blood vessels. The studies should provide new insight into regulation of the cerebral circulation. Expression of these genes may be important in brain under several pathophysiological conditions including meningitis, ischemia, and in response to inflammatory stimuli.
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