Platelets, Cytokines, and Proangiogenic Factors in the Maintenance of Vessel Integrity

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Shi, Dallas Shujing
Title Platelets, Cytokines, and Proangiogenic Factors in the Maintenance of Vessel Integrity
Date 2015-08
Description Almost all vascular diseases are linked to an inflammatory milieu that produces a toxic brew of angiogenic and inflammatory cytokines, which distort tissue architecture and function. These cytokines are produced by a cohort of cells, including endothelial cells, which line blood vessels, and immune cells such as platelets, which are derived from megakaryocytes. Under nonpathological conditions, these cells help to maintain vessel integrity, but when activated by disease states they release cytokines to cause immediate, direct, and disruptive effects on the vascular barrier. In this dissertation I present the results of studies that examine the molecular signaling required to produce one of these immune cells, the platelet, during vessel maintenance as well as examination of the pathological contribution of cytokines on another immune cell, the endothelial cell. I show that under nonpathological conditions, platelets are required for vessel homeostasis, and it is through inhibition of RhoA signaling by proteasomal degradation that platelets are formed. Under pathological conditions, I demonstrate that pro-inflammatory and proangiogenic cytokines signal through a small GTPase, ARF6, in endothelial cells, and that ARF6 is the proximal convergence point regulating downstream signaling leading to endothelial barrier disruption and vessel permeability. This reveals ARF6 as a therapeutic target in vascular diseases such as arthritis and diabetic retinopathy. These studies fundamentally inform a iv mechanism for the genesis of platelets in maintenance of normal barrier function and establish a therapeutic target when vessel homeostasis is disrupted in endothelial cells.
Type Text
Publisher University of Utah
Subject MESH Multiple Myeloma; Blood Vessels; Angiogenesis Inducing Agents; Blood Platelets; Cytokines; Vascular Diseases; Capillary Permeability; Endothelial Cells; Endocytosis; Homeostasis; rhoA GTP-Binding Protein; Permeability; Vascular Endothelial Growth Factors; Thrombopoiesis; Signal Transduction; Vascular Endothelial Growth Factor A; Transcription Factors; Proteasome Inhibitors; Intercellular Signaling Peptides and Proteins; Receptor Protein-Tyrosine Kinases; ADP-Ribosylation Factors; Neuropilins
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Platelets, Cytokines, and Proangiogenic Factors in the Maintenance of Vessel Integrity
Rights Management Copyright © Dallas Shujing Shi 2015
Format Medium application/pdf
Format Extent 13,073,010 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6dz3hnr
Setname ir_etd
Date Created 2016-05-04
Date Modified 2021-05-06
ID 197363
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