PATHOPHYSIOLOGY O THE ENDOTHELIUM

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Interactions among the various components of the vascular wall---endothelium, smooth muscle, connective tissue---and the soluble and cellular constituents of the blood, are prominently involved in the pathophysiology of inflammation, thrombosis, atherosclerosis and immunologic vascular injury. The overall objective of this Program Project is to examine the mechanisms of certain of these interactions in which the endothelium plays a central role. Project 1 will study the mechanisms of leukocyte adhesion to endothelial cells using cell biological, immunological and biochemical approaches in vitro; Project 2 will study macromolecular endocytosis in cultured endothelial and smooth muscle cells, a process relevant to the transfer of substances from blood to interstitium, as well as intracellular metabolism; Project 3 will study the production of mesenchymal cell growth factor(s) by monocyte/macrophages and the role of these cells in intimal (smooth muscle) hyperplasia in vivo; Project 4 will use animal models to examine the role of non-denuding endothelial injury and the interaction of serum lipoproteins and platelets in the pathogenesis of atherosclerosis; Project 5 will examine the biochemical interactions of platelet glycoprotein 1b, von Willebrand's protein and the subendothelial matrix; Project 6 will examine cellular and biochemical mechanisms included in endothelial-mediated responses of smooth muscle cells to vaso-active hormones; Project 7 will study various immunological interactions of endothelium and lymphocytes in vitro. A Cell Culture Core will provide well characterized cultures of vascular and non-vascular cell types, and experience with in vitro model systems for studying cellular interactions. A Morphology Core will provide expertise and facilities for scanning and transmission electron microscopy, ultrastructural immunocytochemistry, autoradiography and other techniques. A Biochemistry Core will provide facilities for gas and high pressure liquid chromatography. These studies thus combine cell biological, biochemical, immunological and experimental pathological approaches to probe vascular disease mechanisms.