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β1- integrin: An endothelial mechanoreceptor distinguishing force direction

Xanthis, Ioannis (2017) β1- integrin: An endothelial mechanoreceptor distinguishing force direction. PhD thesis, University of Sheffield.

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Abstract

Endothelial cell (EC) function is affected by forces generated by flowing blood on the arterial wall (wall shear stress, WSS). Unidirectional WSS and laminar flow occurs in unbranched areas of the arteries, which are protected from atherosclerosis, whereas oscillatory WSS and “disturbed flow” occurs at branch points, where the majority of atherosclerotic plaques are initiated. EC can sense forces via multiple mechanoreceptors including β1- integrin, which induces downstream signalling in response to WSS. Although EC can distinguish between unidirectional and oscillatory WSS, the mechanisms that control this are unknown. We hypothesized that mechanoreceptors are activated by specific mechanical conditions which trigger downstream signalling, i.e. some mechanoreceptors are activated by unidirectional WSS whereas others are activated by bidirectional force. We examined the effect of flow direction and frequency of oscillation on calcium signalling and how the mechanical activation of β1- integrin contributes to these responses. We found significant differences in calcium dynamics in ECs exposed to different flow conditions. Using magnetic beads, unidirectional force but not bidirectional force applied directly to apical β1- integrin induced its conversion from a bent inactive to an extended active form. Furthermore, application of unidirectional force to β1- integrin induced calcium release from the inner stores of the endoplasmic reticulum. Finally, studies using pharmacological inhibitors revealed that phospholipase C and ROCK regulate the calcium responses triggered by mechanostimulation of β1- integrin. These results are consistent with the hypothesis that distinct endothelial mechanoreceptors respond to different flow patterns. My work suggests that β1- integrin functions as a mechanoreceptor that can distinguish between different force directions.

Item Type: Thesis (PhD)
Keywords: shear stress mechanoreceptors
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Depositing User: Mr Ioannis Xanthis
Date Deposited: 30 Oct 2017 13:48
Last Modified: 30 Oct 2017 13:48
URI: http://etheses.whiterose.ac.uk/id/eprint/18461

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