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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Izawa, Y; Gu, Y-H; Osada, T; Kanazawa, M; Hawkins, BT; Koziol, JA; Papayannopoulou, T; Spatz, M; Del Zoppo, GJ

Published Date

  • April 2018

Published In

Volume / Issue

  • 38 / 4

Start / End Page

  • 641 - 658

PubMed ID

  • 28787238

Pubmed Central ID

  • 28787238

Electronic International Standard Serial Number (EISSN)

  • 1559-7016

International Standard Serial Number (ISSN)

  • 0271-678X

Digital Object Identifier (DOI)

  • 10.1177/0271678x17722108

Language

  • eng