期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 38, 期 4, 页码 641-658出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X17722108
关键词
Cerebral microvessel endothelium; beta 1-integrin; intracellular signaling; permeability; tight junction proteins
资金
- National Institutes of Health [NS 053716, NS 038710]
- Astellas Foundation for Research on Metabolic Disorders
- Mochida Memorial Foundation
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS038710, R01NS053716] Funding Source: NIH RePORTER
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 beta 1-integrins. We extend previous findings to show that interference with endothelial beta 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 beta 1-integrin-matrix adhesion initiates F-actin conformational changes that coincide with claudin-5 redistribution. beta 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 6h after beta 1-integrin-matrix interference. These observations are supported by concordant observations in the cortex of a high-quality murine conditional beta 1-integrin deletion construct. Together they support the hypothesis that detachment of beta 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 beta 1-integrin-MLC signaling pathway is engaged when beta 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.
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