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

Yoshikane Izawa, Yu Huan Gu, Takashi Osada, Masato Kanazawa, Brian T. Hawkins, James A. Koziol, Thalia Papayannopoulou, Maria Spatz, Gregory J. del Zoppo

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)641-658
Number of pages18
JournalJournal of Cerebral Blood Flow and Metabolism
Volume38
Issue number4
DOIs
Publication statusPublished - 2018 Apr 1

Keywords

  • Cerebral microvessel endothelium
  • intracellular signaling
  • permeability
  • tight junction proteins
  • β1-integrin

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Izawa, Y., Gu, Y. H., Osada, T., Kanazawa, M., Hawkins, B. T., Koziol, J. A., Papayannopoulou, T., Spatz, M., & 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. https://doi.org/10.1177/0271678X17722108