This is a revised proposal for competitive renewal to test the hypothesis that in individuals with risk factors for stroke, chronic activation of monocytes and/or endothelium promote a perivascular accumulation of monocyte/macrophages and an intensified, cytokine-mediated interaction between monocyte/macrophages and endothelial cells which prepares local segments of extracranial and intracranial vessels for subsequent thrombosis or hemorrhage. According to this hypothesis endothelium will express adhesion molecules which enable adhesion of monocytes in both large and small vessels leading to an accumulation of monocytes into local segments of the blood vessels. These monocyte clusters could then periodically signal the endothelium via release of prothrombotic, proinflammatory and chemotactic cytokines to convert the endothelium to a procoagulant state and, in effect, prepare those vessel segments in a manner similar to the localized Shwartzman paradigm. During the first three years of this project we have collected data which support this hypothesis in that we have found the endothelial expression of the intercellular adhesion molecule-1, monocyte activation and endothelial adhesiveness to be greater in animals with the stroke-risk factor hypertension than in their normotensive controls. Rats with the major stroke-risk factors, hypertension and advanced age, had increased numbers of perivascular macrophages around cerebral blood vessels and these animals responded to a provocative agent with elaboration of cytokines and procoagulant factors to a greater degree than rats devoid of such risk factors. In the studies over the next three years, we will examine whether the chronic stage of activation of monocyte/macrophages increases the probability of strokes in rats with stroke-risk factors and whether inhibition of cytokine activity or monocyte adhesion will reduce brain and blood vessel pathology and the incidence of strokes in the above models. Monitoring of neurological deficits, histological damage, adhesion molecule and cytokine expression and release, monocyte activation and endothelial adherence in carotid arteries and brain microvessels before and after treatment with inhibitors of cytokine activity or monocyte adhesion, should permit direct testing of the above hypothesis. Due to the IRG concern of the reliance on the rat model of high stroke risk, we will also determine adhesion molecule expression, monocyte adhesion and cytokine expression in blood vessels obtained from human subjects with and without stroke-risk factors. These studies are likely to provide significant contributions to THE PREVENTION OF STROKES as they will increase our understanding of how risk factors for stroke operate.
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