β1-integrin-matrix interactions modulate cerebral microvessel endothelial cell tight junction expression and permeability
Izawa, Y., Gu, Y-H., Osada, T., Kanazawa, M., Hawkins, B. T., Koziol, J. A., ... del Zoppo, G. J. (2018). β1-integrin-matrix interactions modulate cerebral microvessel endothelial cell tight junction expression and permeability. Journal of Cerebral Blood Flow and Metabolism, 38(4), 641-658. DOI: 10.1177/0271678X17722108
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.