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

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, signal transduction and the role of AMP-activated protein kinase (AMPK). Following stimulation with eithe...

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Autores principales: Dragoni, Silvia, Caridi, Bruna, Karatsai, Eleni, Burgoyne, Thomas, Sarker, Mosharraf H., Turowski, Patric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077405/
https://www.ncbi.nlm.nih.gov/pubmed/33712448
http://dx.doi.org/10.1242/jcs.253179
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author Dragoni, Silvia
Caridi, Bruna
Karatsai, Eleni
Burgoyne, Thomas
Sarker, Mosharraf H.
Turowski, Patric
author_facet Dragoni, Silvia
Caridi, Bruna
Karatsai, Eleni
Burgoyne, Thomas
Sarker, Mosharraf H.
Turowski, Patric
author_sort Dragoni, Silvia
collection PubMed
description 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, 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 Ca(2+). Accordingly, AMPK agonists potently induced acute retinal vascular leakage. AMPK activation led to phosphorylation of endothelial nitric oxide synthase (eNOS, also known as NOS3), which in turn increased VE-cadherin (CDH5) phosphorylation on Y685. In parallel, AMPK also mediated phosphorylation of p38 MAP kinases (hereafter p38) and HSP27 (HSPB1), 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 Ca(2+) 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 and agonists, as well as siRNA, the ex vivo retina model constitutes a reliable tool to identify and study regulators and mechanisms of acute neurovascular permeability.
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spelling pubmed-80774052021-05-06 AMP-activated protein kinase is a key regulator of acute neurovascular permeability Dragoni, Silvia Caridi, Bruna Karatsai, Eleni Burgoyne, Thomas Sarker, Mosharraf H. Turowski, Patric J Cell Sci Research Article 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, 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 Ca(2+). Accordingly, AMPK agonists potently induced acute retinal vascular leakage. AMPK activation led to phosphorylation of endothelial nitric oxide synthase (eNOS, also known as NOS3), which in turn increased VE-cadherin (CDH5) phosphorylation on Y685. In parallel, AMPK also mediated phosphorylation of p38 MAP kinases (hereafter p38) and HSP27 (HSPB1), 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 Ca(2+) 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 and agonists, as well as siRNA, the ex vivo retina model constitutes a reliable tool to identify and study regulators and mechanisms of acute neurovascular permeability. The Company of Biologists Ltd 2021-04-15 /pmc/articles/PMC8077405/ /pubmed/33712448 http://dx.doi.org/10.1242/jcs.253179 Text en © 2021. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Dragoni, Silvia
Caridi, Bruna
Karatsai, Eleni
Burgoyne, Thomas
Sarker, Mosharraf H.
Turowski, Patric
AMP-activated protein kinase is a key regulator of acute neurovascular permeability
title AMP-activated protein kinase is a key regulator of acute neurovascular permeability
title_full AMP-activated protein kinase is a key regulator of acute neurovascular permeability
title_fullStr AMP-activated protein kinase is a key regulator of acute neurovascular permeability
title_full_unstemmed AMP-activated protein kinase is a key regulator of acute neurovascular permeability
title_short AMP-activated protein kinase is a key regulator of acute neurovascular permeability
title_sort amp-activated protein kinase is a key regulator of acute neurovascular permeability
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077405/
https://www.ncbi.nlm.nih.gov/pubmed/33712448
http://dx.doi.org/10.1242/jcs.253179
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