It has been demonstrated that the intimal fibromuscular lesion (IFML), or neointimal fibroplasia, is the lesion responsible for the late failure of at least 50% of all failed human arterial reconstructions and that this lesion is hemodynamically determined. The IFML also is believed by many investigators to be a precursor of atherosclerotic plaque. Based upon the study of failed human arterial reconstructions, an in vivo experimental model for the rapid, hemodynamic induction of IFML in dog arteries has been developed. The early pathogenesis of this lesion has been extensively studied in this model, leading to identification of a limited number of possible initiating factors. The IFML frequently develops in this model at sites displaying a full and apparently normal endothelial lining. The immediate goals of the present proposal are to further exploit this useful, hemodynamic model in order to: 1) further test the theory that endothelial damage is the key initiating factor in the pathogenesis of the IFML through the use of tracer molecules to demonstrate subtle changes in endothelial permeability, 2) correlate the size and severity of the IFML with certain measured and calculated physiological parameters such as shear stress, 3) learn the relative roles of 4 isolated components of flowing blood (formed elements, plasma components, excessive plasma lipoproteins, and physical flow-generated forces) in causing and promoting the IFML by means of controlled perfusion of the model with a variety of pumped specific fluids, 4) ascertain the role, if any, of smooth muscle cell mitosis in the growth of the IFML and identify stem cell and mechanisms of intimal invasion through application of mitostatic drugs to the very rapid model, 5) further develop and refine the method of analyzing audible signals emitted at a vascular site of rapid flow to predict whether IFML will develop at that site, and 6) determine if special high lipid diets given to euthyroid dogs in whom the hemodynamic model has been prepared result in converting the hemodynamically induced IFML into typical atherosclerotic plaque. The ultimate goal of the proposal is to identify the key initiating factor(s) in the pathogenesis of IFML and determine where and how to interdict the lesion, thereby significantly increasing long term patency of arterial reconstructions and possibly blocking formation of atherosclerotic plaque.