VON WILLEBRAND'S DISEASE AND ATHEROSCLEROSIS

我们的长期目标是研究冯 血小板与动脉相互作用中的Willebrand因子 血管壁和动脉粥样硬化的发展。 有 实验证据表明，血小板通过与 动脉壁与血脂可能起起始作用 动脉粥样硬化 我们已经证明， 血小板“功能”的形式纯合子冯维勒布兰德的 疾病（vWd）是耐自发的发展， 动脉粥样硬化和动脉粥样硬化诱导的饮食。 以来 这些猪的一个基本缺陷是缺乏 称为血管性血友病因子（vWF）的多聚体糖蛋白， 在这个项目中要检验的假设是，具体来说， vWF和血小板活化在这一过程中发挥作用， 动脉粥样硬化 这一假设将在vWd和 正常（N）猪通过长期间歇输注 研究和短期内皮损伤和输血研究， 输注vWF和抗vWF的单克隆抗体。 具体而言，1）我们将从长远角度确定 猪间歇输注研究：vWd猪是否输注 随着vWF的获得， 动脉粥样硬化斑块 2)我们将在短期内确定 对照选择性颈动脉和髂动脉研究 内皮损伤技术：a）在vWd猪中是否输注 vWF导致正常的血小板-动脉壁相互作用（血小板 沉积和/或血小板活化）和内膜增生; B）是否在正常猪体内输注单克隆抗体 抗vWF导致血小板-动脉壁相互作用受损 （血小板沉积和/或血小板活化减少）和 减少内膜增生。 的相对贡献 血浆、血小板和动脉壁vWF与血小板-血管壁 将通过免疫荧光和电子显微镜分析相互作用 长期和短期vWF的显微定位 输注研究。 作为“体内”研究的延伸，在一个实施例中的“离体”研究是一种新的研究。 将进行灌注流动室以研究血小板- 受控层流条件下的血管相互作用; 此外，在一个新设计的灌注室模拟研究， 髂动脉分叉的血管几何形状，可以提供 深入了解流体动力学的作用（剪切速率，振荡 剪切应力）与血小板血管壁定位中物质运输 相互作用和动脉粥样硬化，这是最突出的， 下腹主动脉和髂动脉。 如果我们在猪身上的实验强烈表明vWF和 血小板活化在糖尿病的发展中起着重要作用。 动脉粥样硬化，那么一个重大的步骤将已经完成 为了更好地理解这一重大疾病过程， 这可能有助于未来的预防策略， 治疗

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.