Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 31, Issue 10, Pages 1972-1985Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2011.99
Keywords
beta(1)-integrins; cerebral endothelial cells; claudin-5; extracellular matrix; matrix adhesion receptors; microvessel permeability
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Funding
- NIH [NS 053716, NS 038710, NS 036945]
- Kanae Foundation for the Promotion of Medical Science
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The hypothesis tested by these studies states that in addition to interendothelial cell tight junction proteins, matrix adhesion by beta(1)-integrin receptors expressed by endothelial cells have an important role in maintaining the cerebral microvessel permeability barrier. Primary brain endothelial cells from C57 BL/6 mice were incubated with beta(1)-integrin function-blocking antibody (Ha2/5) or isotype control and the impacts on claudin-5 expression and microvessel permeability were quantified. Both flow cytometry and immunofluorescence studies demonstrated that the interendothelial claudin-5 expression by confluent endothelial cells was significantly decreased in a time-dependent manner by Ha2/5 exposure relative to isotype. Furthermore, to assess the barrier properties, transendothelial electrical resistance and permeability measurements of the monolayer, and stereotaxic injection into the striatum of mice were performed. Ha2/5 incubation reduced the resistance of endothelial cell monolayers significantly, and significantly increased permeability to 40 and 150 kDa dextrans. Ha2/5 injection into mouse striatum produced significantly greater IgG extravasation than the isotype or the control injections. This study demonstrates that blockade of beta(1)-integrin function changes interendothelial claudin-5 expression and increases microvessel permeability. Hence, endothelial cell-matrix interactions via beta(1)-integrin directly affect interendothelial cell tight junction claudin-5 expression and brain microvascular permeability. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1972-1985; doi:10.1038/jcbfm.2011.99; published online 20 July 2011
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