Regulation of cyclooxygenase, prostanoids and prostanoid receptors in endothelial cells: implications in tumor angiogenesis

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Title Regulation of cyclooxygenase, prostanoids and prostanoid receptors in endothelial cells: implications in tumor angiogenesis
Publication Type dissertation
School or College School of Medicine
Department Pathology
Author Jiang, Huimiao
Date 2004-12
Description Evidence has shown that COX-2 plays important roles in tumor angiogenesis. NSAIDs, cyclooxygenase inhibitors, inhibit tumor growth at least partially through their inhibition in angiogenesis. However, the underlying mechanism by which COX-2 contributes to angiogenesis is not clear. The goal of this dissertation is (a) to determine the expression and role of COX-2 in endothelial cells; (b) to evaluate the direct effect of NSAIDs on endothelial cells, and (c) to study the expression, regulation, and functional analysis of prostanoid receptors in endothelial cells. We find that confluent endothelial cells exhibit little COX-2 protein, while subconfluent or wounded endothelial cells express high levels of COX-2. This high expression of COX-2 in subconfluent or wounded cells leads to increased production of PGE2, a major COX-2 metabolite, into the surrounding media. NS-398, a COX-2 specific inhibitor, attenuates endothelial migration, and adding back PGE2 partially overcomes the reduction in cell migration. This indicates that COX-2/PGE2 contributes to endothelial migration. In addition, exogenous PGE2 up-regulates COX-2 expression in confluent endothelial cells, suggesting an amplification loop between COX-2, prostaglandins and angiogenic stimuli. The anti-tumor effect of NSAIDs can be ascribed to both cyclooxygenase-dependent and -independent components. Here, we discover that NS398 at high concentration (100 ?M) modulates stress fiber formation, focal adhesion assembling and cell-cell contact in endothelial cells. This effect is COX/PGE2-independent since 100 µM exceeds the effective concentration of NS398 that inhibits PGE2, and adding back PGE2 could not recover the effect of NS398 on endothelial cells. Since the cell cytoskeleton plays crucial roles in cell migration and angiogenesis, NS398 also can affect endothelial migration in ways that are COX-2/PGE2-independent. Prostanoids and their receptors mediate the effects of COX-2 activity in endothelial behavior. We find that endothelial cells express EP2, EP3, EN (PGE2 receptor subtypes), FP (PGF2? receptor) and TP (thromboxane A2 receptor) messages. EP2, EP4, FP and TP messages are increased by mechanically wounding the endothelial monolayer. PGE2 activates ERK and p38 signaling pathways through EP2/EP4 receptors in endothelial cells. Moreover, activation of EP2/EP4 induces COX-2 expression in a p38-dependent way, indicating the existence of a potential positive feedback loop in endothelial cells.
Type Text
Publisher University of Utah
Subject Pathophysiology; Etiology; Cancer; Cycloosygenase 2
Subject MESH Neoplasms; Endothelium; Cyclooxygenase Inhibitors
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Regulation of cyclooxygenase, prostanoids and prostanoid receptors in endothelial cells: implications in tumor angiogenesis." Spencer S. Eccles Health Sciences Library. Print version of "Regulation of cyclooxygenase, prostanoids and prostanoid receptors in endothelial cells: implications in tumor angiogenesis." available at J. Willard Marriott Library Special Collection. RC39.5 2004 .J53.
Rights Management © Huimiao Jiang.
Format application/pdf
Format Medium application/pdf
Format Extent 4,005,464 bytes
Identifier undthes,4848
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 4,005,514 bytes
ARK ark:/87278/s6x63pnw
Setname ir_etd
ID 190444
Reference URL https://collections.lib.utah.edu/ark:/87278/s6x63pnw
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