Stenosis of medium-sized arteries, such as the coronaries, is the most common and threatening complication of atherosclerosis. When stenosis is established, it tends to progress. The mechanism of this progression is not well understood; presumably it represents the combination of physical factors (related to flow) and biological responses of the arterial lining. We plan a combined biophysical and biological approach to this problem: (1) Stenosis of the rat aorta will be induced with U-shaped clips, restricting the lumen by 10, 25, 50, or 80%. The short and long-term effects will be studied morphologically, searching for evidence not only of endothelial damage, but also of endothelial stimulation (""""""""activation"""""""" - especially as expressed by attachment of white blood cells and increased production of visible large molecules). In parallel, a team of biophysicists will build scaled-up models of the stenotic aortas. Disturbances of flow detected in these models will be correlated with morphologic findings on the rat aortas. (2) Stenosis and arterial fat deposits. Until now it has not been possible to induce an atherosclerotic lesion at a given site at will. Previous work has shown that if rats are fed a high cholesterol diet, fat deposits form just above and just below a stenosis. These deposits represent early atherosclerotic lesions. We therefore plan to use them to study the genesis, regression, and response to therapy of atherosclerotic lesions. (3) Lipoprotein uptake by the arterial wall. It is possible to label the plasma lipoprotein particles with ultramicroscopic particles of gold, visible by electron microscopy. We will therefore study the uptake and fate of these particles in the arterial lining and their role in the genesis of atherosclerotic lesions. To do this we will induce stenosis in the aorta of hypercholesterolemic rats, then (later) isolate the vessel and perfuse it with a fluid containing gold-labeled lipoproteins. (4) Studies on cultured endothelium. Certain events related to stenosis can be studied in tissue cultures of endothelium, because - in a mildly stenotic artery - the increased shear stress induces an activation of the endothelial cells, and a similar activation can be induced in tissue cultures by chemical means. We will therefore analyze, in endothelial cultures, two events (related to cell activation) that occur in stenosis, namely white blood cell attachment and contraction of the endothelial cells.
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