Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 35, Issue 10, Pages 1648-1656Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2015.102
Keywords
blood-brain barrier; cerebrovascular disease; endothelium; free radicals
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Funding
- National Development Plan/Higher Education Authority of Ireland, Programme for Research in Third Level Institute-HEA/PRTLI Cycle 4 (Targeted Therapeutics & Theranostics-T3)
- National Development Plan/Higher Education Authority of Ireland, Programme for Research in Third Level Institute-HEA/PRTLI Cycle 5 (BioAT-BioAnalysis and Therapeutics)
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The regulatory interplay between laminar shear stress and proinflammatory cytokines during homeostatic maintenance of the brain microvascular endothelium is largely undefined. We hypothesized that laminar shear could counteract the injurious actions of proinflammatory cytokines on human brain microvascular endothelial cell (HBMvEC) barrier properties, in-part through suppression of cellular redox signaling. For these investigations, HBMvECs were exposed to either shear stress (8 dynes/cm(2), 24 hours) or cytokines (tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6), 0 to 100 ng/mL, 6 or 18 hours). Human brain microvascular endothelial cell 'preshearing' +/- cytokine exposure was also performed. Either cytokine dose-dependently decreased expression and increased phosphorylation (pTyr/pThr) of interendothelial occludin, claudin-5, and vascular endothelial-cadherin; observations directly correlating to endothelial barrier reduction, and in precise contrast to effects seen with shear. We further observed that, relative to unsheared cells, HBMvECs presheared for 24 hours exhibited significantly reduced reactive oxygen species production and barrier permeabilization in response to either TNF-alpha or IL-6 treatment. Shear also downregulated NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) activation in HBMvECs, as manifested in the reduced expression and coassociation of gp91phox and p47phox. These findings lead us to conclude that physiologic shear can protect the brain microvascular endothelium from injurious cytokine effects on interendothelial junctions and barrier function by regulating the cellular redox state in-part through NADPH oxidase inhibition.
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