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：它们到达身体的每一个细胞，带来营养和氧气，并收集废物。它们分为大动脉（将血液从心脏输送到组织）和静脉（将血液带回心脏），并分支成逐渐变小的血管。非常小的血管在身体的不同器官中是独特的，因为这些器官的功能不同。新的血管是通过一个叫做血管生成的过程形成的。这在健康个体中是必不可少的，例如在月经周期期间或在伤口愈合期间;但血管生成在许多疾病中是异常的。血管由内皮细胞排列，内皮细胞控制血管的功能和完整性。这对防止出血至关重要。在血液中，细胞和因子循环以检查血管壁的破裂，并在必要时介入以形成凝块并防止出血。为了保持血管的完整性，血管正确形成也是至关重要的，否则血液凝固可能不足以止血。在某些疾病中，由于血管生成缺陷导致的血管畸形可能是出血的原因。人类最常见的出血性疾病称为血管性血友病，由血管性血友病因子（VWF）基因突变引起。VWF由血管内皮细胞产生，并在血液中释放以控制出血。在大多数VWD患者中，鼻子出血或小手术后出血并不严重，可以通过增加血液中VWF水平的治疗来解决。但有些患者有反复出血的肠道，血液在粪便中;这可能是频繁和严重的，可能会导致贫血和反复去看医生。不幸的是，这种类型的出血对常规治疗反应不佳。这是因为这些患者在肠道的小血管中也有畸形，可能会破裂和出血。我们认为这些血管畸形可能是由这些患者的VWF水平异常或降低引起的，几年前，我们建立了一项研究来解决这个问题。我们发现VWF确实控制血管生成和血管完整性。因此，在VWD患者中，可能存在有利于出血的双重打击，缺乏适当的凝块形成和渗漏的异常血管。在这项研究中，我们计划将这一发现向前推进，并提出以下问题：1）VWF如何控制肠道血管的形成和完整性; 2）我们能否确定可以改善VWD血管异常的药物，从而减少GI出血。为此，我们计划研究缺乏VWF的内皮细胞，并通过研究由缺乏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，以找到可能的重叠指纹，从而指向有用的药物。为了实现个性化医疗，我们将在从VWD患者中分离的内皮细胞中验证其中的一些发现。最后，我们将使用包含在肠道中发现的不同类型细胞的模型，并将它们组织在血管周围，以重新创建一个迷你的“肠道芯片”来研究VWF的作用和药物对血管生成的影响。通过这些研究，我们希望在VWD患者和其他患有肠血管畸形的患者中取得重大进展，肠血管畸形是60岁以上普通人群中最常见的出血原因。在这个过程中，我们将开发新的模型，这对许多其他研究血管异常在人类出血性疾病中的作用的研究人员来说是有用的。