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The role of neutrophil-derived microvesicles in the focal nature of atherosclerosis: mechanisms of interaction and uptake.

Ward, Ben (2017) The role of neutrophil-derived microvesicles in the focal nature of atherosclerosis: mechanisms of interaction and uptake. PhD thesis, University of Sheffield.

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Abstract

Atherosclerosis is an inflammatory disease of arteries that develops at focal regions of the vasculature. At these sites, disturbed flow results in elevated adhesion molecule expression that facilitates inflammatory cell transmigration into the vessel wall. Although neutrophil depletion is associated with reduced lesion progression, neutrophils are seldom found within developing plaques and the mechanism by which they contribute to the atherogenic process remains unclarified. Upon activation, neutrophils release microvesicles (MVs) that are able to interact with and activate the endothelium. Here we tested the hypothesis that a pro-atherogenic diet can alter the number and function of neutrophil microvesicles, which preferentially interact with and are internalised by endothelial cells at sites of disturbed flow, contributing to the focal nature of atherogenesis. In the current study, a number of in vitro techniques were used to investigate microvesicle interactions with endothelial cells. Neutrophils were isolated from human peripheral blood, stimulated to produce microvesicles with fMLP. Commercially available human coronary artery endothelial cells (HCAECs) were used in order to model interactions with adult arterial endothelium. These cells were subject to physiologically relevant patterns and magnitudes of shear stress using a parallel plate flow chamber system throughout. The current study highlights the significant roles of known risk factors, high fat overfeeding and shear stress in exacerbating atherogenic processes via neutrophil-derived microvesicles. Our improved understanding of how microvesicles harness endothelial cell adhesion molecule expression at disturbed flow sites, as well endocytic pathways, to deliver their content is important for our understanding of the aetiology of atherosclerosis. Furthermore, these findings have the potential to improve future attempts to deliver therapies utilising these pathways. In conclusion, neutrophil microvesicles are produced in vivo in response to high fat feeding and are able to augment inflammation in endothelial cells in a shear stress dependant manner. These finding implicate neutrophil microvesicles in the focal nature of atherosclerosis.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.739859
Depositing User: Mr. Ben Ward
Date Deposited: 08 May 2018 09:39
Last Modified: 01 May 2020 09:53
URI: http://etheses.whiterose.ac.uk/id/eprint/20092

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