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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 and Turowski, P (2021) AMP-activated protein kinase is a key regulator of acute neurovascular permeability. Journal of Cell Science, 134 (7). jcs253179. ISSN 0021-9533

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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 Ca2+. 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 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 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.

Item Type: Article
Uncontrolled Keywords: Vascular Endothelial Growth Factor A; Signal Transduction; Phosphorylation; Permeability; AMP-Activated Protein Kinases; AMP-activated protein kinase; Bradykinin; Endothelial nitric oxide synthase; Retina; VE-cadherin; VEGF-A; AMP-Activated Protein Kinases; Permeability; Phosphorylation; Signal Transduction; Vascular Endothelial Growth Factor A; 06 Biological Sciences; 11 Medical and Health Sciences; Developmental Biology
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Publisher: The Company of Biologists
SWORD Depositor: A Symplectic
Date Deposited: 14 Feb 2024 15:06
Last Modified: 14 Feb 2024 15:06
DOI or ID number: 10.1242/jcs.253179
URI: https://researchonline.ljmu.ac.uk/id/eprint/22620
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