The endothelial cells (EC) lining the blood vessels are probably involved in the etiology of all vascular disease. The fluid mechanical forces resulting from blood flow and pressure may injure the EC, but this is as yet unproven. Tissue cultured EC provide a tool to prove (or disprove) this hypothesis, by subjecting the cells to physical forces in a controlled environment. Recent studies indicate that shear stress has dramatic effects on EC structure and function. Such in vitro studies bring two problems to the forefront. First, what is the best way to simulate the mechanical forces the ED experience in vivo? Second, if mechanical stress damages EC, what constitutes """"""""damage"""""""", short of outright detachment? We are uniquely qualified to answer these important questions. Our present system for subjecting EC to flow is capable of 1) a wide range of steady or pulsatile shear stresses (1-150 dynes/square cm), fluid dynamically well characterized, 2) continuous light microscopic videorecording, and 3) small """"""""medium-to-cell"""""""" ratio so that cell secretions can be measured, 4) long term (5 da.) experiments. Functional and structural assays for describing EC response in this system will be prostacyclin synthesis, angiotensin converting enzyme activity, macromolecular transport changes, extracellular matrix changes, cytoskeletal changes and morphometric analysis. The effects of steady and pulsatile shear stress, cyclic substrate deformation, and substrate permeability on EC will be assessed independently. Then these factors and forces will be combined into one device which most accurately simulates the blood/vessel wall interface. With this device, interaction between polymorphonuclear leukocytes and EC will be studied as a model of the inflammatory response. Interactions between platelets and EC will be studied as a model of thrombosis. Vascular graft endothelialization will be modelled with EC interactions with fibrin and biomaterials, with particular attention to explaining the lack of endothelialization observed in man. Finally, whether vessel location in the cardiovascular system or species or origin of the vessel affect EC response to physical forces will be determined.
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