The cellular and molecular mechanisms controlling growth in the vascular wall will be studied using a concerted ultrastructural, pharmacological, and biochemical approach. The regulation of cell growth in large blood vessels plays a key role in a number of important physiological and pathological processes, and thus represents a potential control point for diseases such as atherosclerosis and thrombosis. Data has been generated in vivo and in vitro which strongly indicates that endothelial cells function as important regulators of smooth muscle cell growth, and that heparin may play a critical role in the vessel wall as a regulator of smooth muscle cell proliferation. Evidence has also been obtained which implicates macrophages as possible mediators of injury to the vascular wall. The role of heparin binding and internalization in the growth inhibitory action of heparin will be examined. Heparin will be localized intracellularly using a variety of ultrastructural and cytochemical techniques. Based on preliminary experiments, the effect of heparin on several processes thought to be important in the stimulation of cell growth will be determined: uptake of nutrients and growth factors, recycling of ligands and receptors, stimulation of specific protein kinases, and organellar movement. The role of macrophages in vascular injury will be studied by measuring the adherence, superoxide production, and killing effect on endothelial and smooth muscle cells by macrophages from normo- and hypercholesterolemic rats. Membrane changes will be assayed biochemically and biophysically. The hypothesis that the endothelim is moving continuously towards regions of blood vessels which experience high shear forces and thus may have high injury rates, ie towards the heart, will be tested. This will be done by combining in vivo endothelial labeling techniques with microsurgery.
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