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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2021
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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. |
format | Online Article Text |
id | pubmed-8077405 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
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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