# Mechanisms of shear stress-mediated ERK1/2 modulating signal transduction pathways in endothelial cells

 Title: Mechanisms of shear stress-mediated ERK1/2 modulating signal transduction pathways in endothelial cells Author: Traub, Oren Abstract: Mechanical forces are important modulators of cellular function in various tissues and are particularly important in the cardiovascular system. The endothelial cell layer, by virtue of its unique location in the vessel wall, is exposed to fluid forces of much greater magnitude than those experienced by other mammalian tissues and thus has developed mechanically-related responses to fluid shear stress. While the effects of shear on endothelial cell function have been well studied, the mechanisms by which endothelial cells sense mechanical stimuli and convert them to biochemical signals are not well characterized. The primary goal of this project is to study the intracellular signal transduction mechanisms activated by fluid shear stress. In this dissertation, we (1) detail the construction and characterize the efficacy of different apparatus to simulate shear stress in vitro on cultured cells; (2) demonstrate that PKC is involved in the shear stress-mediated ERK1/2 activation as well as characterize PKC-$\varepsilon$ as the necessary isoform for this signaling pathway; (3) characterize the ion dependency of shear stress-mediated ERK1/2 activation and show that sodium entry is inhibitory; and (4) identify and characterize mechanosensitive voltage-gated sodium channels in endothelial cells that are involved in the ERK1/2 response to shear stress. The results will allow us to define temporal and functional interactions of endothelial cell signaling mechanisms with shear stress and allow us to characterize their contribution to the modulation of endothelial cell function by hemodynamic forces. This knowledge is important not only to our understanding of the pathogenesis of atherosclerosis but also to a wide variety of biological processes that are modulated by physical forces, such as bone growth, muscle hypertrophy, hair cell sound transduction. Description: Thesis (Ph. D.)--University of Washington, 1998 URI: http://hdl.handle.net/1773/6309

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