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

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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.