Thrombotic occulsion limits the usefulness of small and medium caliber synthetic vascular grafts. Initially, thrombus formation may be triggered by factors related to graft surface chemistry, graft texture, altered blood flow, tissue injury leading to generation of procoagulant thrombin, and incomplete healing of the graft flow surface. At later times, thrombotic graft occlusion occurs secondary to anastomotic intimal hyperplasia, process involving the ingrowth and proliferation of vascular cells from the adjacent vessel, and the production by these cells of collagen and other connective tissue proteins. We hypothesize that early vascular cell proliferation, and the stimulation of vascular wall cells to produce connective tissue matrix components, are initially promoted by thrombotic blood reactions. Accordingly, early intimal hyperplasia may be inhibited by reducing graft thrombogenicity or by blocking thrombin's procoagulant and mitogenic activities. Secondly, we propose that once triggered, late vascular lesion development is less strongly dependent upon ongoing hemostatic reactions a graft anastomoses; rather, these lesions may develop in response to the enhanced expression of growth factors, such as platelet-derived growth factor (PDGF), and to the diminished production by endothelium of growth inhibitory substances, such as nitric oxide. These hypotheses will be tested in primates using a recently developed and innovative method for efficiently targeting pharmacologic mediators of these pathways to graft neointimal lesions. Early cellular responses as well as later lesion formation will then be thoroughly characterized using appropriate histologic, immunocytochemical, and morphometric techniques. Specifically, we will: 1) Define the role of PDGF in graft healing responses using local infusions of PDGF and monoclonal antibodies against the PDGF-receptor. 2) Evaluate the effects of locally delivered heparin for inhibiting both blood coagulation and smooth muscle cell proliferation at graft anastomoses. 3) Define the role of thrombus formation in graft healing outcomes by local delivery of inhibitors which specifically block blood coagulation and thrombosis. 4) Assess the role of the nitric oxide (NO) pathway in regulating endothelial cell and smooth muscle responses by local infusion into vascular grafts of a fast-acting NO-donor. Overall, these studies will define the roles of key hemostatic and growth factor-mediated pathways which contribute to intimal lesion formation. They will also establish the feasibility of local drug delivery approaches, when combined with specific pharmacologic interventions against these pathways, for maintaining graft patency.
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