To develop effective preventative and therapeutic regimens for cardiovascular disease, it is important to understand control of he functional state of the vascular endothelial cells (EC). EC are naturally subjected to physical forces in situ. Thus definition of the precise roles of physical forces in maintaining normal and in producing pathological EC behavior is important. Shear stress, the force tangential to the EC resulting from blood flow is considered to be the mechanical force that is most injurious to the endothelium. Whether pulsatile variations in shear stress differ as a stimulus from steady shear stress is unknown. This research will analyze the mechanisms of adaptive EC responses to steady shear stress, and compare these with responses to pulsatile shear stress.
The specific aims are to 1. Determine the morphologic changes in EC adhesions as they remodel under shear stress, 2. Determine the composition and distribution of ablumenal adhesion plaque components in shear stressed EC, 3. Determine the distribution of lumenal surface membrane proteins under shear stress, 4. Determine the effects of shear stress on directional migration using a """"""""wound"""""""" model, 5. Determine whether inositol lipid turnover and arachidonic acid metabolism are linked to the shear stress induced structural response of EC, and 6. Compare the effects of shear stress on EC cultured on a permeable substrate to those of EC cultured on conventional substrates. The following techniques will be used to accomplish the specific aims; digital analysis of video enhanced interference reflection and immunofluorescent live cells under shear stress, microinjection of fluorescently labelled cytoskeletal proteins and fluorescence photobleach recovery of incorporated protein, transmission electron microscopy, radioimmunoassays, and spectrofluorometry. The long term results of our basic cell biological and engineering studies will elucidate the mechanisms whereby endothelium carries out its functions of modulating hemostasis and thrombosis and controlling vascular tone and permeability. EC abnormalities may contribute to atherosclerosis, thrombosis, hemostatic disorders, as well as to inflammation, immune reactivity and tumorigenesis. How shear stress alters EC function will elucidate these disease processes.
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