CTS-0077520 Rumchitzki, Davis S. CUNY City College
Atherosclerosis is by far the leading cause of death, bot above and below age 65, in the United States and all western countries. Atherosclerosis is a disorder mainly of the large, relatively thick-walled arteries; smaller arteries and veins under normal conditions are spared. Atherosclerosis appears to begin with the accumulation of extracellular lipoproteins in the artery wall and develops into lesions. This accumulation is often associated with high plasma low-density lipoprotein (LDL) concentrations and thus lipoprotein transport into and accumulations within the artery wall is the focus of intense study. We hypothesize that qualitative and quantitative vessel-vessel differences in these processes underlie their different susceptibilities to atherosclerosis. Our group has develop a set of detailed theories, portions of which seem to be vessel-independent, that explains much of the data on these processes in large arteries. What is lacking is a detailed understanding of how they differ in other tissues. To begin to fill this gap we propose an experimental/theoretical study of LDL transport into and accumulation in the valve leaflet, a tissue whose structure is radically different from the aorta's, but which also accumulates LIPID AT HIGH PLASMA LDL. We present preliminary data suggesting an exciting new hypothesis that, even in the absence of an internal elastic laminar, valve endothelial cells lay down a very thin matrix layer that is much sparser than the bulk of its extracellular matrix; if present, this layer would play a central role in filtration and subendothelial tracer transport (goal 2 below). In addition, data on the transmural pressure dependence of these processes are inconclusive, and we propose to address this in the aortic context.
Our specific goals are:
1. To understand the effect of transmural pressure on the transport and accumulation of LDL cholesterol in the artery wall in light of the observation that atherosclerosis-prone vessels live at high transmural pressures and of the apparently inconsistent historic data on pressure dependence. 2. To experimentally/theoretically study filtration and tracer convective-diffusion in valve leaflets; to explain in large variation in Tompkins et al's (Circ. Res., 64 1213, 1989) experimental tracer concentration vs depth profiles in valves; 3. To couple goal 2's results to our extracellular lipid liposome formation and growth kinetic models to explain the liposome size distributions in valves of cholesterol-fed rabbits. We advance a new hypothesis that liposome accumulation kinetics are tissue-independent and that the valve-aorta difference in lipid accumulation thus lies in their different transendothelial LDL transport.
Successful completion of the project would lead to a better understanding of how vessel structure and conditions, such as transmural pressures, to which the vessel is exposed influence the transport into and accumulation of large molecules (with lipoprotein cholesterol the major molecule of interest) in vessel walls. We hypothesize that this will underlie the vessel's relative susceptibility to atherosclerosis. This knowledge could be useful in the long term in potentially selecting a vessel, in a patient-specific way, to be sued as a bypass for clogged coronary artery.
