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Pressure-dependent regulation of Ca2+ signalling in the vascular endothelium.

Wilson, Calum and Saunter, Christopher D. and Girkin, John M. and McCarron, John G. (2015) 'Pressure-dependent regulation of Ca2+ signalling in the vascular endothelium.', The journal of physiology., 593 (24). pp. 5231-5253.

Abstract

The endothelium is an interconnected network upon which haemodynamic mechanical forces act to control vascular tone and remodelling in disease. Ca2+ signalling is central to the endothelium's mechanotransduction and networked activity. However, challenges in imaging Ca2+ in large numbers of endothelial cells under conditions that preserve the intact physical configuration of pressurized arteries have limited progress in understanding how pressure-dependent mechanical forces alter networked Ca2+ signalling. We developed a miniature wide-field, gradient-index (GRIN) optical probe designed to fit inside an intact pressurized artery that permitted Ca2+ signals to be imaged with subcellular resolution in a large number (∼200) of naturally connected endothelial cells at various pressures. Chemical (acetylcholine) activation triggered spatiotemporally complex, propagating inositol trisphosphate (IP3)-mediated Ca2+ waves that originated in clusters of cells and progressed from there across the endothelium. Mechanical stimulation of the artery, by increased intraluminal pressure, flattened the endothelial cells and suppressed IP3-mediated Ca2+ signals in all activated cells. By computationally modelling Ca2+ release, endothelial shape changes were shown to alter the geometry of the Ca2+ diffusive environment near IP3 receptor microdomains to limit IP3-mediated Ca2+ signals as pressure increased. Changes in cell shape produce a geometric microdomain regulation of IP3-mediated Ca2+ signalling to explain macroscopic pressure-dependent, endothelial mechanosensing without the need for a conventional mechanoreceptor. The suppression of IP3-mediated Ca2+ signalling may explain the decrease in endothelial activity as pressure increases. GRIN imaging provides a convenient method that gives access to hundreds of endothelial cells in intact arteries in physiological configuration.

Item Type:Article
Full text:(AM) Accepted Manuscript
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Status:Peer-reviewed
Publisher Web site:http://dx.doi.org/10.1113/JP271157
Publisher statement:© 2015 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Date accepted:19 October 2015
Date deposited:18 January 2016
Date of first online publication:28 October 2015
Date first made open access:No date available

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