The role of von Willebrand Factor in endothelial platelet capture

血管性血友病因子（VWF）是一种血液蛋白，在血管损伤部位形成血凝块中起重要作用，从而有助于阻止失血。VWF是不寻常的，因为它是在被称为内皮细胞（EC）的血管内衬细胞中产生的，而几乎所有其他凝血蛋白都是在肝脏中产生的。一旦产生，VWF被释放到循环中，沉积在血管壁中或储存在EC中。VWF是一种非常大的分子，并以卷起的束循环。一旦血管受损，VWF可以附着在血管壁中通常隐藏但现在已经暴露的结构上。血液流过VWF的作用导致卷起的分子散开，使其从血液中捕获循环细胞碎片，称为血小板。越来越多的血小板在血管损伤的这个部位被捕获并粘在一起，形成血小板栓。这是形成血凝块以阻止失血的第一步。然而，VWF和血小板也可以通过粘附在血管壁上而引起血管损伤。心脏病和中风，统称为心血管疾病（CVD），仍然是英国死亡的主要原因。它们的部分原因是循环中异常血凝块的形成，高水平的VWF与心脏病发作和中风的风险增加有关。然而，目前尚不清楚高水平是否在导致血液凝块中起作用，或者它们是否仅仅是由于受损的血管通过产生更多的VWF而做出反应。尽管如此，动物研究表明，VWF在心脏病发作或中风前血管中脂肪沉积的形成中起着直接作用。形成脂肪存款的第一步之一是血小板附着于血管壁的EC。VWF活性的缺乏导致称为血管性血友病（VWD）的出血性疾病。可以预测，VWD患者的心脏病发作和中风比正常或高水平的人要少。到目前为止，很少有动物和人类的研究试图回答这个问题，他们给出了相互矛盾的结果。最近，对VWF是如何产生和功能的理解有所提高，这表明了为什么这些研究是有缺陷的。这一认识的提高来自于我们对正常对照和VWD患者EC内VWF的研究。简而言之，这些研究表明VWF对这些细胞的生长方式有着深远的影响，并且这种影响与血液中的水平并不密切相关。根据这些不同的证据，我们有充分的理由怀疑VWF在心脏病发作和中风中起重要作用。迄今为止这些研究的缺点是，它们没有显示VWF是如何做到这一点的，以及它是否主要是VWF在我们的血液中循环或VWF储存在EC内负责。这种区别是必不可少的，如果我们想在预防和治疗cvd.Animal模型治疗VWF是不精确和不完整的模型，人类心血管疾病和人口研究过于简化。我们建议通过从正常人和VWD患者分离的人内皮细胞直接研究VWF、EC、受损血管壁和血小板之间的相互作用来克服这些问题。此外，当这些细胞在特殊的培养室中生长时，我们可以重现它们在正常或异常循环中所暴露的压力：这可能是EC如何制造VWF以及它如何捕获血小板的主要决定因素。更好地了解血管疾病开始时的这些关键相互作用，将使我们能够准确地针对新的治疗方法来预防心脏病发作和中风。

Von Willebrand Factor (VWF) is a blood protein with a vital role in forming blood clots at sites of blood vessel injury thus helping to stop blood loss. VWF is unusual in that it is made in the cells lining blood vessels known as endothelial cells (EC), whereas almost all other blood-clotting proteins are made within the liver. Once it is made, VWF is released into the circulation, deposited in the blood vessel wall or stored in EC. VWF is a very large molecule and circulates in a rolled-up bundle. Once a blood vessel has been damaged, VWF can attach to structures in the blood vessel wall that are normally hidden but which have now become exposed. The effect of blood flowing past the VWF causes the rolled-up molecule to unravel allowing it to capture circulating cell fragments, called platelets, from the blood. More and more platelets are captured at this site of blood vessel injury and stick together, forming a platelet plug. This is the first step in forming a blood clot to stop blood loss. However, VWF and platelets can also cause blood vessel damage by sticking to the vessel wall. Heart disease and stroke, collectively known as cardiovascular disease (CVD), remain the leading cause of death in the United Kingdom. They result in part from formation of abnormal blood clots within the circulation and high levels of VWF are associated with an increased risk of heart attacks and strokes. However, at present it is not clear whether the high levels play a role in causing the blood clots or whether they simply result from damaged vessels which have responded by making more VWF. Nonetheless, it has been shown in animal studies that VWF plays a direct role in the formation of the fatty deposits that build up in the blood vessels before a heart attack or stroke. One of the first steps in the formation of a fatty deposit is the attachment of platelets to the EC of the blood vessel wall. A deficiency of VWF activity results in a bleeding disorder known as von Willebrand Disease (VWD). It might be predicted that people with VWD would have fewer heart attacks and strokes than people with normal or high levels. So far, there are few research studies in animals and humans attempting to answer this question and they have given conflicting results. Recently, improved understanding of how VWF is made and functions has indicated why these studies are flawed. This improved understanding has come from our studies of VWF within the EC from normal controls and from patients with VWD. In brief, these studies show that VWF has a profound effect on the way these cells grow and the effect is not closely related to the resulting level in the blood. From these various lines of evidence we have strong reasons to suspect that VWF plays an important role in heart attack and stroke. The drawback of these studies to date is that they do not show how the VWF does this and whether it is primarily VWF circulating in our blood or VWF stored within the EC that is responsible. This distinction is essential if we want to target VWF for therapy in the prevention and treatment of CVD.Animal models are imprecise and incomplete models of human cardiovascular disease and population studies are oversimplified. We propose to overcome these problems by using human endothelial cells isolated from normal and VWD patients to study directly the interaction between VWF, EC, the damaged blood vessel wall and platelets. Moreover, whilst growing these cells in special chambers, we can reproduce the stresses that they are exposed to in the normal or abnormal circulation: this is likely to be a major determinant of how VWF is made by EC and how it captures platelets. Better understanding of these crucial interactions at the beginning of vascular disease, would allow us to target accurately new treatments to prevent heart attacks and strokes.