VON WILLEBRAND'S DISEASE AND ATHEROSCLEROSIS

我们的长期目标是调查von的作用 血小板与动脉相互作用中的Willebrand因子 并在动脉粥样硬化的发展中起重要作用。的确有 实验证据表明，通过与血小板相互作用， 动脉壁和血脂可能在发病中起作用。 动脉粥样硬化。我们已经证明，受损的猪 纯合子von Willebrand‘s的血小板“功能” 疾病(VWD)是抵抗自发发展的 动脉粥样硬化和致动脉粥样硬化饮食。自.以来 这些猪的基本可识别缺陷是缺乏 被称为von Willebrand因子(VWF)的多聚体糖蛋白 这个项目中要检验的假设是，具体地说， VWF和血小板活化在血管紧张素转换酶激活过程中发挥作用 动脉粥样硬化的形成。这一假设将在vwd和 正常(N)猪长期间歇输液 通过一项短期内皮损伤和输血研究， 用vWF和抗vWF的单抗输注。 具体地说，1)我们将从长远的角度确定 猪的间歇输液研究：vWD猪是否输液 利用vWF获得发展主动脉抬高的能力 动脉粥样硬化斑块。2)我们将在短期内确定 选择性颈动脉和髂动脉对照研究 血管内皮损伤技术：a)在vWD猪输注 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)在正常猪中是否输注了单抗 抗vWF导致血小板-动脉壁相互作用受损 (减少血小板沉积和/或血小板激活)和 减少血管内膜增生。的相对贡献率 血浆、血小板和动脉壁vWF对血小板血管壁的影响 相互作用将通过免疫荧光和电子技术进行分析 VWF在长期和短期内的微观定位 输液研究。 作为“体内”研究的延伸，“体外”研究在一个 将进行灌流流室来研究血小板- 受控层流条件下的容器相互作用 此外，在新设计的灌注室中模拟 髂骨分叉的血管几何形状可提供 洞察流体动力学(剪切速率、振荡)的作用 剪切应力)和局部血小板血管壁的质量传输 相互作用与动脉粥样硬化形成 下腹主动脉和髂动脉。 如果我们在猪身上的实验提供了一个强烈的迹象，即vWF和 血小板活化在高血压的发生发展中起重要作用 动脉粥样硬化，那么就完成了重要的一步 为了更好地了解这一重大疾病过程， 这可能有助于今后的预防和预防策略 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.