The pathophysiology of cerebral vasospasm after subarachnoid hemorrhage (SAH) is unknown, due in part to the absence of a reproducible small-animal model. A fundamental question in the pathophysiology of vasospasm remains unanswered, namely, whether arterial narrowing results from vasoconstriction or from structural changes in the vessel wall. Structural changes of the arterial wall, perhaps superimposed upon vasoconstriction, may be responsible for the prolonged narrowing of cerebral vessels after SAH. The unifying hypothesis of this proposal is that chronic exposure to oxyhemoglobin initiates both contractile and structural changes in arterial smooth muscle cells, related to either ironcatalyzed lipid peroxidation or to the prolonged accumulation of intracellular calcium. After chronic exposure to hemoglobin, injured smooth muscle cells may lose contractile protein, assume a synthetic phenotype and deposit collagen in the extracellular matrix, thereby producing an inelastic vessel wall which is unresponsive to endogenous or exogenous vasodilators. A new rat femoral artery model has been developed for the selective application of blood components to the vessel wall, and the assessment of resulting arteriopathic change by morphometric, histochemical and physiologic analysis. This new model for vasospasm offers several advantages over existing models, and enables the broadscale testing of potential pathologic processes and therapeutic strategies related to this disorder. The proposed experiments are designed to sequentially determine those agents in blood responsible for vasospasm, and to determine the mechanisms by which such agents effect arterial narrowing.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Neurology A Study Section (NEUA)
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University of Washington
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