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

J Cereb Blood Flow Metab. 2018 Apr;38(4):641-658. doi: 10.1177/0271678X17722108. Epub 2017 Aug 8.

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.

Keywords: Cerebral microvessel endothelium; intracellular signaling; permeability; tight junction proteins; β1-integrin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Blood-Brain Barrier
  • Brain Ischemia / metabolism
  • Cell Membrane Permeability
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / physiology
  • Cerebrovascular Circulation / physiology*
  • Endothelial Cells / physiology*
  • Immunoglobulin M / immunology
  • Integrin beta1 / biosynthesis*
  • Integrin beta1 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels / physiology*
  • Myosin Light Chains / metabolism
  • Protein Conformation
  • Tight Junction Proteins / biosynthesis*
  • Tight Junction Proteins / physiology
  • Tight Junctions / physiology*

Substances

  • Actins
  • Immunoglobulin M
  • Integrin beta1
  • Myosin Light Chains
  • Tight Junction Proteins