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AMP-activated protein kinase is a key regulator of acute neurovascular permeability

Dragoni, S; Caridi, B; Karatsai, E; Burgoyne, T; Sarker, MH; Turowski, P; (2021) AMP-activated protein kinase is a key regulator of acute neurovascular permeability. Journal of Cell Science 10.1242/jcs.253179. (In press). Green open access

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Abstract

Many neuronal and retinal disorders are associated with pathological hyperpermeability of the microvasculature. We have used explants of rodent retinae to study acute neurovascular permeability and signal transduction and the role of AMP-activated protein kinase (AMPK). Following stimulation with either vascular endothelial growth factor (VEGF-A) or bradykinin (BK), AMPK was rapidly and strongly phosphorylated and acted as a key mediator of permeability downstream of Ca2+ Accordingly, AMPK agonists potently induced acute retinal vascular leakage. AMPK activation led to phosphorylation of endothelial nitric oxide synthase (eNOS), which in turn increased VE-cadherin phosphorylation on Y685. In parallel, AMPK also mediated phosphorylation of p38 MAP kinase and HSP27, indicating that it regulated paracellular junctions and cellular contractility, both previously associated with endothelial permeability. Endothelial AMPK provided a missing link in neurovascular permeability, connecting Ca2+ transients to the activation of eNOS and p38, irrespective of the permeability-inducing factor used. Collectively, we find that, due to its compatibility with small molecule antagonists/agonists and siRNA, the ex-vivo retina model constitutes a reliable tool to identify and study regulators and mechanism of acute neurovascular permeability.

Type: Article
Title: AMP-activated protein kinase is a key regulator of acute neurovascular permeability
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/jcs.253179
Publisher version: https://doi.org/10.1242/jcs.253179
Language: English
Additional information: © 2021. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0).
Keywords: AMP-activated protein kinase, Endothelial nitric oxide synthase, Retina, VE-cadherin, VEGF-A, bradykinin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10125025
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