Vascular disease still accounts for the majority of deaths in western countries. Vascular intimal thickening is thought to be the initial lesion that occurs even in young individuals. This early lesion subsequently becomes heavily laden with lipid to produce the typical late lesion of atherosclerosis consisting of a fibrous cap that may or may not be ulcerated overlying necrotic, inflammed, potentially calcified and lipid-filled area. Other changes also occur in the ground substance and connective tissue which further weakens the wall of the vessel. The end result is an exuberant lesion which MAY weaken the wall of the vessel and may cause dilation or aneurysm formation, the lesion may partially or completely obstruct the lumen interferring with blood flow, or it may ulcerate and release thrombotic or necrotic debris into the down-stream circulation. The purpose of the present proposal is to try to learn more about the factors which control what is presumed to be the initial lesion, that of intimal hyperplasia or thickening. Morphologically this consists of migration and/or accumulation of smooth muscle cells within the ordinarily very thin intima. Cells which migrate here initially then begin to produce connective tissue proteins and they may also proliferate. Vein grafts are worthwhile studying in this regard because of two reasons. One is that they inevitably develop some degree of intimal thickening and this reaction is quite similar to that which occurs in arterial tissue that has been injured. In addition, vein grafts are frequently used clinically to treat the manifestations of this disease and pathologic changes which occur in vein grafts after they have been transplanted into the arterial circulation account for at least 25% of failures that do occur. Therefore, the long-term objective of this proposal is to study the pathogenesis of the adverse morphologic changes occurring within veins grafted into the arterial circulation with the aim to devise methods of prevention of its occurrence which may also be applicable to prevention of the initial lesion of atherosclerosis in arterial tissues.
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