Influence of Brain Inflammation on the Occurrence of Embolic Stroke

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Abstract Embolic stroke (or cerebral embolism) accounts for approximately 25% of all strokes. It occurs when an embolus formed elsewhere in the body, lodges in a cerebral blood vessel, suddenly obstructing blood flow. Cerebral emboli most commonly arise from atherosclerotic plaques formed in the aorta, carotid artery, vertebral artery or from the heart. It has been generally accepted that the lodging of an embolus in a brain blood vessel depends on its size, frequency of embolism and the presence of collateral flow. However, increasing evidence now pinpoints brain inflammation as a contributing causative factor for stroke. Platelets are often present in embolic material of both vascular and cardiac origin and they have the ability to interact with activated endothelial cells. This opens the possibility that cerebral emboli may also lodge in brain vessels because of adhesive interactions between platelets in the emboli and inflammation-activated brain endothelial cells. Thus, the proposed study is aimed at determining whether and how endothelial cell activation during brain inflammation affects the lodging of emboli in the cerebrovasculature. Specifically, we will test hypothesis that brain inflammation contributes in part to embolic stroke occurrence by promoting adhesion of platelets from emboli to the brain endothelial cells activated by the brain inflammation through JAM-A dependent mechanisms. JAM-A is a brain endothelial tight junction protein that becomes an adhesion molecule during inflammation. The hypothesis will be addressed in the following aims: a) to examine the role of inflammation- activated brain endothelial cells in the pathogenesis of embolic stroke in mice (Specific Aim 1) and b) to investigate the involvement of JAM-A in the lodging of platelet rich emboli in inflamed brain and assess its potential as a drug target (Specific Aim 2). Collectively, the results from this project will lead to a better understanding of the mechanisms that underpin embolic stroke and will help define new strategies to prevent such stroke and improve outcomes.