β1-integrin-matrix interactions modulate cerebral microvessel endothelial cell tight junction expression and permeability.
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 zonula occludens-1 (ZO-1) from inter-endothelial borders. Interference with β1-integrin-matrix adhesion initiates F-actin conformational changes that coincide with claudin-5 redistribution. β1-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 β1-integrin-matrix interference. These observations are supported by concordant observations in the cortex of a high-quality murine conditional β1-integrin deletion construct. Together they support the hypothesis that detachment of β1-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 β1-integrin-MLC signaling pathway is engaged when β1-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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Related Subject Headings
- Tight Junctions
- Tight Junction Proteins
- Protein Conformation
- Neurology & Neurosurgery
- Myosin Light Chains
- Microvessels
- Mice, Knockout
- Mice, Inbred C57BL
- Mice
- Integrin beta1
Citation
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Tight Junctions
- Tight Junction Proteins
- Protein Conformation
- Neurology & Neurosurgery
- Myosin Light Chains
- Microvessels
- Mice, Knockout
- Mice, Inbred C57BL
- Mice
- Integrin beta1