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Characterizing Angiodysplasia in Type 2 Von Willebrand Disease (VWD) Using Blood Outgrowth Endothelial Cells (BOECs).

出版	Queen's University, 2015
URL	http://books.google.com.hk/books?id=DWBKjwEACAAJ&hl=&source=gbs_api

註釋Gastrointestinal bleeding associated with angiodysplasia is a common, often intractable complication in patients with von Willebrand disease (VWD). von Willebrand factor (VWF), the protein deficient in VWD, was recently identified as a negative regulator of angiogenesis, which may explain the pathologic blood vessel growth in VWD. Blood outgrowth endothelial cells (BOECs) can be isolated from the peripheral blood and used to investigate the underlying pathologic mechanisms of VWD and angiodysplasia in the natural genetic environment of the endothelial cell. This thesis explores the normal range of angiogenesis in BOECs derived from healthy donors. In addition, we used this normal range to identify abnormal angiogenesis in BOECs derived from type 2 VWD patients. We found that the range of angiogenesis and VWF expression in BOECs from the normal population was highly variable. BOECs from a type 2A VWD patient with a HMWM VWF deficiency exhibited aberrant VWF multimerization, storage and secretion ex vivo. These deficits corresponded with increases in several functional parameters reflecting angiogenesis, namely proliferation, adhesion and migration. Along with the type 2A VWD BOECs, the type 2B VWD BOECs demonstrated an increased release of the angiogenic mediator angiopoietin-2 (Ang-2) and increased proliferation. VWF processing was normal in the in vitro environment of the type 2B BOECs. The type 2M VWD BOECs displayed abnormal storage of VWF and also exhibited increases in some metrics of angiogenesis. Though a VWF deficiency was not identified in the type 2N VWD patient, these BOECs exhibited increased angiogenesis as well. Finally, angiogenesis was explored in endothelial cells derived from a liver hemangioma of a type 1 VWD patient. Though they were proliferative, migratory and had decreased adhesion and tubule formation, it is unclear if VWF influenced this pro-angiogenic phenotype. In conclusion, these experiments have further elucidated the mechanisms of pathogenesis in angiodysplasia associated with VWD and provided insights into the use of BOECs for recapitulating the patient phenotype.