This resubmission consists of a chronological sequence of three overlapping aims which test the overall hypothesis that the vasa vasorum play an important role in the initiation of coronary atherogenesis (i.e., prior to cellular invasion and/or proliferation) by virtue of disturbed solute transport via the vasa vasorum This, in turn, is due to the perfusion pressure in their distal vasa vasorum lumens being less than the compression in the arterial wall. Our approach is to quantitatively describe detailed branching geometry and solute transport of the vasa vasorum of coronary arteries, primarily by use of micro-CT-based imaging methods. This will involve analysis of coronary arteries of normal pigs, a porcine (diet-induced) model of hypercholesterolemia and a porcine (renal artery stent) model of arterial hypertension (both being risk factors for atherogenesis).
AIM I is for the initial development and integration of the various techniques we propose to use throughout the proposal and to establish the normal state.
AIM II applies the developments in Aim I to hypercholesterlemic and to hypertensive pigs' coronary artery walls so as to relate the response of the vasa vasorum to these pathological conditions.
AIM III builds on Aim II in that we will combine the hypercholesterolemia and hypertension to see if they are linearly additive in effect, as would be predicted by our hypothesis. The primary objective is to relate the transport capacity of vasa vasorum to the spatial density of coronary artery vasa vasorum and the fluid dynamic implications of both the 3D branching geometry of the vasa vasorum and the spatial distribution of compressive stresses within the coronary artenal wall. The significance of this proposal is that if the hypothesis of this study is supported, it should give insight into several puzzling observations. One is that atherosclerosis does not generally form in veins (which have vasa vasorum) or in small arteries (which have no vasa vasorum). Equally intriguing is the observation that early atherosclerosis does not form in the outer media or adventitia even though vasa vasorum provide a sizable endothelial surface (which presumably also becomes dysfunctional) in the outer media and adventitia. Another observation is that artenes whose adventitia are manipulated and veins, which are subjected to arterial pressure or surgically manipulated, do develop atherosclerosis.
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