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?1-integrin-matrix interactions modulate cerebral microvessel endothelial cell tight junction expression and permeability.


ABSTRACT: Acutely following focal cerebral ischemia disruption of the microvessel blood-brain barrier allows transit of plasma proteins into the neuropil as edema formation that coincides with loss of microvessel endothelial ?1-integrins. We extend previous findings to show that interference with endothelial ?1-integrin-matrix adhesion by the monoclonal IgM Ha2/5 increases the permeability of primary cerebral microvascular endothelial cell monolayers through reorganization of claudin-5, occludin, and zonula occludens-1 (ZO-1) from inter-endothelial borders. Interference with ?1-integrin-matrix adhesion initiates F-actin conformational changes that coincide with claudin-5 redistribution. ?1-integrin-matrix interference simultaneously increases phosphorylation of myosin light chain (MLC), while inhibition of MLC kinase (MLCK) and Rho kinase (ROCK) abolishes the Ha2/5-dependent increased endothelial permeability by 6?h after ?1-integrin-matrix interference. These observations are supported by concordant observations in the cortex of a high-quality murine conditional ?1-integrin deletion construct. Together they support the hypothesis that detachment of ?1-integrins from abluminal matrix ligands increases vascular endothelial permeability through reorganization of tight junction (TJ) proteins via altered F-actin conformation, and indicate that the ?1-integrin-MLC signaling pathway is engaged when ?1-integrin detachment occurs. These findings provide a novel approach to the research and treatment of cerebral disorders where the breakdown of the blood-brain barrier accounts for their progression and complication.

SUBMITTER: Izawa Y 

PROVIDER: S-EPMC5888854 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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β1-integrin-matrix interactions modulate cerebral microvessel endothelial cell tight junction expression and permeability.

Izawa Yoshikane Y   Gu Yu-Huan YH   Osada Takashi T   Kanazawa Masato M   Hawkins Brian T BT   Koziol James A JA   Papayannopoulou Thalia T   Spatz Maria M   Del Zoppo Gregory J GJ  

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20170808 4


Acutely following focal cerebral ischemia disruption of the microvessel blood-brain barrier allows transit of plasma proteins into the neuropil as edema formation that coincides with loss of microvessel endothelial β1-integrins. We extend previous findings to show that interference with endothelial β1-integrin-matrix adhesion by the monoclonal IgM Ha2/5 increases the permeability of primary cerebral microvascular endothelial cell monolayers through reorganization of claudin-5, occludin, and zonu  ...[more]

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