The human fibrous atherosclerotic plaque causes morbidity by progressively narrowing the arterial lumen and by creating an abnormal thrombotic blood interface. Insights into the development of this pathological lesion have been obtained by studying the response to injury of normal animal artery. The fibrous intimal thickening induced by injury resembles to a certain extent human atherosclerotic plaque, but it is of importance that the animal lesion generally does not progress, nor does it produce stenosis, and it is not chronically thrombogenic. There are many reasons why the human and injury-induced animal lesions are so different. In particular, the human atherosclerotic plaque accumulates prothrombotic factors (plasminogen activator inhibitor and tissue factor) while the injury- induced lesion does not. Furthermore, the human lesion appears to be derived from intimal accumulations of smooth muscle cells (SMCs) established in the embryonic or neonatal period of development while the intimal cells in the injury-induced lesion (at least in the rat) come from the media. The origin of these intimal cells might in part determine their phenotype and growth potential. The overall objective of this proposal is to explore in a rat model: 1. the importance of SMC phenotype, and 2. the role of overexpression of the coagulation factors, plasminogen activator inhibitor type 1 (PAI-1) and tissue factor, in the growth and thrombotic activity of atherosclerotic plaques. These experiments will exploit a novel rat model of atherosclerosis generated by deliberately constructing a synthetic intima in vivo made of SMCs seeded into the carotid artery. The experiments will make use of current molecular biological techniques including retroviral transfer of specific genes (PAI-1 and tissue factor). These experiments should provide new insights into mechanisms of atherosclerotic plaque progression and thrombosis.
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