The goals of this proposal are to investigate the basic cellular mechanisms that underlie the complex functions of the brain microcirculation, and how this circulation is controlled to meet the fastidious requirements of the brain. The endothelial cells of brain microvessels stand at the interface between the systemic circulation and nervous tissue, and have a vital role in maintaining a stable environment for neuronal function. To accomplish this, the brain capillary endothelium is endowed with unique features, such as tight intercellular junctions, and a variety of transporters for essential lipid-insoluble molecules like glucose and amino acids. Many gaps remain in our knowledge of the basic cellular mechanisms underlying the complex functions of the brain's blood vessels. The proposed experiments will employ complementary biochemical, pharmacological, and ultrastructural techniques to study the brain microcirculation in intact tissue, and in preparations enriched with isolated microvessels. The experiments will address: (1) Cellular mechanisms by which adenosine and its analogues exert their affects on the cerebral circulation. Adenosine receptors and the adenosine transporter will be investigated in isolated cerebral microvessels by ligand binding techniques. (2) The presence of receptors for putative peptide neurotransmitters which may regulate the cerebral circulation: angiotensin II, vasopressin, cholecystokin, and vasoactive intestinal polypeptide. (3) Ultrastructural investigation of heterogeneities in the distribution of the glucose transporter and sodium, potassium-ATPase in different brain regions, and within the microvascular unit, by immunocytochemical methods. (4) Isolation and biochemical characterization of the basal lamina of brain microvessels. (5) Biochemical determination and possible ultrastructural localization of carbonic anhydrase in cerebral microvessels. A better understanding of how the brain microcirculation functions may be a prerequisite for appreciating the pathophysiology of the cerebral circulation. This research may provide scientific bases for rational therapy of cerebral vascular disorders, metabolic encephalopathies and blood-brain barrier dysfunction.
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