The Regulation and Perturbation of Vascular Endothelial Permeability

The endothelium forms the inner lining of every blood vessel in the body where it regulates the movement of fluid and solutes between the blood and tissue compartments. It comprises a single layer of endothelial cells that connect to one another through specialized proteins. The passage of solutes across the endothelium can occur between endothelial cells or through them in a process known as transcytosis. A basal level of permeability occurs under normal physiologic conditions. However, aberrant endothelial permeability has been implicated in a number of pathological conditions. These include disorders attributed to increased paracellular permeability, such as the acute respiratory distress syndrome (ARDS) where leakage from the pulmonary microvasculature causes the accumulation of fluid in alveolar airspaces resulting in impaired gas exchange, and pathological transcytosis, such as in atherosclerosis where transport of cholesterol in the form of low-density lipoproteins (LDL) results in plaque accumulation in the subendothelial space.Despite its role in disease pathogenesis, endothelial permeability has been largely neglected as a therapeutic target. This is due to the widely-held view that endothelial dysfunction is a consequence rather than a cause of pathologic changes as well as to our incomplete understanding of the two routes of endothelial permeability and how they are interrelated. In this thesis I present a body of work demonstrating the critical importance of endothelial permeability in lung injury due to influenza infection as well as in atherosclerosis. Using a variety of in vitro approaches as well as animal models, we uncover mechanisms underlying endothelial permeability in these diseases and explore ways of manipulating endothelial permeability as a potential adjuvant therapy. Furthermore, we also examine how paracellular leak and transcytosis are connected at the subcellular level so that manipulation of one pathway leads to changes in the other.The importance of endothelial permeability in human disease has been underappreciated. By highlighting its role in lung injury and atherosclerosis and by elucidating the molecular mechanism of endothelial permeability in these conditions, we offer new insights into the clinical significance of the endothelial barrier and its hitherto untapped potential as a therapeutic target.Ph.D.2017-06-15 00:00:0