EICOSANOID METABOLISM AT THE BLOOD-BRAIN BARRIER

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A growing number of oxygenated derivatives of long chain, polyunsaturated fatty acids are being described in the brain. Included among these compounds are prostaglandins, hydroxyeicosatetraenoic acids (HETEs), and leukotrienes. Although many of these eicosanoids mediate well- characterized physiological or pathophysiological events in other tissues, their role in the biological processes of the brain, and in particular, the cerebral blood vessels, is relatively unknown. A number functions have been proposed, ranging from the control of cerebrovascular tone, to action as transmitter substances or intracellular second messengers, to mediation of pathophysiologic events in stroke, brain trauma, and seizure. We and others have previously identified several metabolites or arachidonic acid and eicosapentaenoic acid produced by isolated brain microvessel preparations and by purified cultures of cerebromicrovascular endothelium and smooth muscle cells. Yet, the production of eicosanoids by cerebromicrovascular cells, the regulation of their production, and the function effects these arachidonic acid derivatives have on the cerebral circulation and adjacent brain parenchyma remain incompletely characterized. Even less is known about the metabolism and function of omega-3 fatty acids in cells of the cerebral circulation. Thus, the following aims are proposed in order to more completely understand the biology of long chain, polyunsaturated fatty acids in cerebral microvessels. First, the metabolism of leukotrienes and HETEs will be explored in cultured cerebral endothelium and isolated brain microvessels. These compounds are produced in many types of brain injury and are potential pathophysiologic mediators. Second, studies will be undertaken to identify the cerebrovascular metabolites of the omega-3 fatty acids, eicosapentaenic acid and docosahexaenoic acid, fatty acids that may prevent or ameliorate the pathology of cerebrovascular disease. Third, the regulation of eicosanoid biosynthesis by interactions among cellular components of the microvascular wall, astrocytes, smooth muscle cells, and endothelium, will be examined. Many aspects of cerebral endothelial differentiation are induced or modulated by astrocytes and similar relationships may exist between endothelium and smooth muscle. In addition, cells that comprise the cerebrovascular wall may share eicosanoid precursors or intermediates. Finally, the functional responses of cerebral microvessels to specific eicosanoids will be studied utilizing a combination of in vivo and in vitro pial vessel preparations and an in vitro model of the blood-brain barrier. Eicosanoids have great potential to act as autocrine or paracrine compounds within the cerebrovascular wall and may thus effect vascular tone and blood-brain barrier properties. This combination of in vitro and in vivo methods is unique and should prove to be a powerful approach to understanding eicosanoid biology in the cerebral microcirculation.