Clinical outcomes after bypass grafting are adversely affected by the development of degenerative graft disease. The differences between vein grafts and arterial grafts regarding the susceptibility to atherosclerosis underscore the importance of local factors in the development of the disease. Thus the overall goal of this project is to clarify the cellular mechanisms which confer the susceptibility to atherosclerosis in these types of vascular grafts. Two hypotheses are put forward. Hypothesis 1. Different mechanisms of repair in remodeling are proposed for the two types of grafts. The arterialization of veins activates highly reactive fibroblasts where as arterial grafts undergo the repair process by smooth muscle cells. The formation of atherosclerotic lesions will be compared in venous and arterial grafts in a pig model. Experiments in vivo will determine cell activation, intravascular lipids, and foam cells throughout graft remodeling. The expression of proteoglycans and enzymes regulating their side chain assembly as well as lipoprotein lipase will be characterized. Differences between isolated fibroblasts and medial smooth muscle cells regarding cell function will be assessed. Hypothesis 2. The differences in cellular mechanism of vascular remodeling determine the retention and catabolism of atherogenic lipoproteins in these two types of vascular grafts. The retention of radiolabelled LDL will be compared between venous and arterial grafts. The role of isolated proteoglycans and the composition of glycosaminoglycan chains will be studied with regard to their binding affinities to LDL. Vascular fibroblasts and smooth muscle cells will be characterized in vitro regarding mechanisms of LDL retention as well as catabolism. Thus this proposal examines putative mechanisms responsible for graft attrition in relation to cellular heterogeneity of the vessel.
