Endothelial von Willebrand factor and the tissue-specific regulation of angiogenesis and vascular integrity

内皮血管性血友病因子和血管生成和血管完整性的组织特异性调节

• 批准号: MR/X021106/1
• 负责人: Anna Randi
• 金额: $ 134.89万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021106%2F1
• 关键词: Endothelial; von; Willebrand; factor; tissue

Blood vessels are essential for life: they reach every cell in the body to bring nutrients and oxygen and collect waste. They are divided into large arteries (taking blood from the heart to tissues) and veins (bringing blood back to the heart) and branch into progressively smaller vessels. The very small vessels are uniquely different in different organs of the body because of the distinct functions of these organs. New blood vessels are formed through a process called angiogenesis. This is essential in healthy individuals, for examples during the menstrual cycle or during the healing of cuts and wounds; but angiogenesis is abnormal in many diseases. Blood vessels are lined by cells called endothelial cells, which control blood vessels' function and integrity. This is critical to prevent bleeding. In blood, cells and factors circulate to check breaks in the vessel wall and, when necessary, step in to form clots and prevent bleeding. To maintain the integrity of the vessels, is also essential that blood vessels are properly formed, otherwise blood coagulation may not be sufficient to stop the bleeding. In some diseases, malformations of blood vessels due to defects in angiogenesis can be the cause of bleeding. The most common bleeding disorder in humans is called von Willebrand Disease, caused by genetic mutations in a gene called von Willebrand Factor (VWF). VWF is produced by the cells that line blood vessels, endothelial cells and released in blood to control bleeding. In most patients with VWD, bleeding from the nose or after small surgery is not severe and can be resolved with treatments that increase VWF levels in blood. But some patients have recurrent bleeding from the intestine, with blood in the stools; this can be frequent and severe, may cause anemia and repeated visits to the doctor. Unfortunately, this type of bleeding does not respond well to conventional treatments. This is because these patients also have malformations in the small blood vessels in the intestine, which can break and bleed. We thought that these vascular malformations may be caused by the abnormal or reduced VWF levels in these patients, and a few years ago, we set up a study to address this question. We found that VWF does indeed control angiogenesis and vascular integrity. Therefore, in patients with VWD there may be a double hit in favour of bleeding, with lack of proper clot formation and leaky abnormal blood vessels. In this study, we plan to take this discovery forward, and ask the following questions: 1) how does VWF control the formation and integrity of blood vessels in the gut; 2) can we identify drugs that can improve vascular abnormalities in VWD and therefore reduce GI bleeding. To do so, we plan to study endothelial cells lacking in VWF and identify their "molecular signature" by studying all the changes in the expression of endothelial genes that are caused by lack of VWF. We plan to compare this signature with similar cell signatures caused by drugs, to find possible overlapping fingerprints that can point to useful drugs. Toi move towards personalised medicine, we will validate some of these findings in endothelial cells isolated from VWD patients. Finally, we will use models that comprise different types of cells found in the intestine and organise them around blood vessels, to recreate a mini "gut-on-a-chip" to study the role of VWF and the effect of drugs on angiogenesis. With these studies we hope to make significant progress for patients with VWD and other patients suffering from intestinal vascular malformations, which are the most common cause of bleeding in the general population over 60 years of age. In the process, we will develop new models which can be useful to many other researchers who study the role of vascular abnormalities in human bleeding diseases.

血管对生命至关重要：它们到达体内的每个细胞，以带来营养和氧气并收集废物。它们分为大动脉（将血液从心脏流到组织）和静脉（将血液恢复到心脏），并分支成逐渐较小的血管。由于这些器官的独特功能，在身体的不同器官中，非常小的容器在体内的不同器官中唯一不同。通过称为血管生成的过程形成新的血管。这在健康个体中至关重要，在月经周期或切割和伤口愈合期间的例子；但是血管生成在许多疾病中都是异常的。血管被称为内皮细胞的细胞衬里，该细胞控制血管的功能和完整性。这对于防止出血至关重要。在血液中，细胞和因素循环以检查血管壁中的断裂，并在必要时介入以形成凝块并防止出血。为了维持血管的完整性，还必须正确形成血管，否则血管可能不足以阻止出血。在某些疾病中，由于血管生成缺陷引起的血管畸形可能是导致出血的原因。人类中最常见的出血障碍称为von Willebrand疾病，是由一个称为von Willebrand因子（VWF）的基因突变引起的。 VWF是由排列血管，内皮细胞并在血液中释放以控制出血的细胞产生的。在大多数VWD患者中，鼻子或小手术后出血并不严重，可以通过增加血液中VWF水平的治疗方法来解决。但是一些患者会从肠道中复发出血，粪便中有血液。这可能是频繁而严重的，可能会引起贫血并反复去医生。不幸的是，这种出血对传统治疗的反应不佳。这是因为这些患者在肠中的小血管中也有畸形，可能会破裂和流血。我们认为这些血管畸形可能是由于这些患者的异常或降低的VWF水平引起的，几年前，我们进行了一项研究来解决这个问题。我们发现VWF确实控制了血管生成和血管完整性。因此，在患有VWD的患者中，可能会有双重打击，有利于出血，缺乏适当的凝块形成和漏水异常的血管。在这项研究中，我们计划将这一发现前进，并提出以下问题：1）VWF如何控制肠道中血管的形成和完整性； 2）我们可以识别可以改善VWD血管异常的药物，从而减少胃肠道出血。为此，我们计划研究缺乏VWF的内皮细胞，并通过研究缺乏VWF引起的内皮基因表达的所有变化来识别其“分子特征”。我们计划将这种特征与药物引起的类似细胞特征进行比较，以找到可能指向有用药物的重叠指纹。 TOI转向个性化医学，我们将在从VWD患者中分离出的内皮细胞中验证其中一些发现。最后，我们将使用包含肠中发现的不同类型的细胞并在血管周围组织它们的模型，重新创建迷你“肠道胆汁芯片”，以研究VWF的作用以及药物对血管生成的作用。通过这些研究，我们希望为VWD患者和其他患有肠道血管畸形的患者取得重大进展，这是60岁以上普通人群出血的最常见原因。在此过程中，我们将开发新的模型，这些模型对许多研究血管异常在人体出血疾病中的作用的研究人员可能很有用。