Publication Type |
dissertation |
School or College |
School of Medicine |
Department |
Oncological Sciences |
Author |
Mleynek, Tara Mariella |
Title |
Vascular stability, barrier function, and disease |
Date |
2015-05 |
Description |
Endothelial cells exist in a state of dynamic stability allowing for a balance between quiescence and response. These cells create the barrier system of the vasculature as well as drive the growth of new vessels. The disease Cerebral Cavernous Malformation (CCM) disrupts both processes and is characterized by leaky, cavernous vascular lesions in the CNS, resulting in headache, seizure, and stroke. CCM occurs in both a sporadic and familial form thought to follow the Knudsen two-hit model of retinoblastoma. Studies have been primarily focused on late stage disease, leaving little understanding of the earliest stages and the precise role of the second hit. We sought to study early developmental onset to identify morphological characteristics that could provide mechanistic insight to the key initiating factors. We generated an inducible endothelial knockout mouse model of CCM and found that when the second hit occurs at birth, mice develop cavernous malformations in the brain and the retina. We determined that lesions arise in a spatially and temporally predictable pattern in a limited developmental window. We further showed vessel defects are preceded by endothelial hypersprouting and an impaired cellular response to flow. In the context of CCM, this suggests that an inability of cells to react to their environment could result in lesion development. Our findings that loss of the second hit in adulthood was insufficient to cause disease, combined with the predictable nature of development, iv suggested that environmental factors may be necessary contributors to disease onset. While loss of the genetic hits in adulthood was not enough to cause disease we found that, when combined with localized vascular endothelial growth factor (VEGF), lesions can arise. Changes in the surrounding tissue environment can be caused by disrupted barrier functions, promoting a disease state like that seen in CCM. In our pursuit to further understand barrier function in the face of environmental challenges, we defined the novel process of endothelial extrusion. Extrusion is the removal of an apoptotic cell from a monolayer, prior to its structural collapse, via contraction of an actin ring. Together these studies offer insights into endothelial barrier function, stability, and disease. |
Type |
Text |
Publisher |
University of Utah |
Subject MESH |
Vascular Endothelial Growth Factors; rhoA GTP-Binding Protein; Cadherins; Transforming Growth Factor beta; rap1 GTP-Binding Proteins; Integrases; Gene Silencing; Alleles; Central Nervous System Vascular Malformations; Telangiectasis; Vascular Diseases; Neovascularization, Pathologic; Retinoblastoma; Hemangioma, Cavernous; Apoptosis Inducing Factor; Genetic Predisposition to Disease |
Dissertation Institution |
University of Utah |
Dissertation Name |
Doctor of Philosophy |
Language |
eng |
Relation is Version of |
Digital version of Vascular Stability, Barrier Function, and Disease |
Rights Management |
Copyright © Tara Mariella Mleynek 2015 |
Format Medium |
application/pdf |
Format Extent |
33,655,513 bytes |
Source |
Original in Marriott Library Special Collections |
ARK |
ark:/87278/s6323472 |
Setname |
ir_etd |
ID |
197474 |
Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6323472 |