VON WILLEBRAND'S DISEASE AND ATHEROSCLEROSIS

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Our long-term objective is to investigate the role of von Willebrand factor in the interaction of platelets with the arterial wall and in the development of atherosclerosis. There is experimental evidence that platelets by interacting with the arterial wall and with blood lipids may play a role in the initiation of atherosclerosis. We have shown that pigs with impaired platelet "function" in the form of homozygous von Willebrand's disease (vWd) are resistant to the development of spontaneous atherosclerosis and to atherosclerosis induced diet. Since the basic identifiable defect in these pigs is an absence of a multimeric glycoprotein called von Willebrand factor (vWF), the hypothesis to be tested in this project is whether, specifically, vWF and platelet activation play a role in the process of atherogenesis. This hypothesis will be approached in vWd and normal (N) pigs by means of a long term intermittent infusion study and by a short-term endothelial injury and transfusion study, with vWF and monoclonal antibodies against vWF being infused. Specifically, 1) We will determine in a long-term prospective study with intermittent infusion in pigs: whether vWd pigs infused with vWF gain the capability to develop aortic raised atherosclerotic plaques. 2) We will determine in a short term study with a controlled selective carotid and iliac artery endothelial injury technique: a) whether in vWd pigs infusion with vWF lead to a normal platelet-arterial wall interaction (platelet deposition and/or platelet activation) and to intimal hyperplasia; b) whether in normal pigs infusion with monoclonal antibodies against vWF result in impaired platelet-arterial wall interaction (decreased platelet deposition and/or platelet activation) and reduced intimal hyperplasia. The relative contribution of plasmatic, platelet and arterial wall vWF to platelet-vessel wall interaction will be analyzed by immunofluorescent and electron microscopic localization of vWF in both long-term and short-term infusion studies. As an extension to the "in vivo" studies, "ex vivo" studies in a perfusion flow chamber will be performed to investigate platelet- vessel interaction under controlled laminar flow conditions; in addition, studies in a newly designed perfusion chamber mimicking the vascular geometry of the iliac bifurcation, may provide insight into the role of fluid dynamics (shear rate, oscillatory shear stress) and mass transport in localizing platelet vessel wall interaction and atherogenesis which is most prominent in the lower abdominal aorta and at the iliac artery. If our experiments in pigs give a strong indication that vWF and platelet activation play an important role in the development of atherosclerosis, then a major step will have been accomplished towards a better understanding of this major disease process, which may be helpful for future strategies in its prevention and treatment.