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

被引:50
|
作者
Izawa, Yoshikane [1 ,2 ]
Gu, Yu-Huan [1 ]
Osada, Takashi [1 ,2 ]
Kanazawa, Masato [1 ,3 ]
Hawkins, Brian T. [1 ,4 ]
Koziol, James A. [5 ]
Papayannopoulou, Thalia [1 ]
Spatz, Maria [6 ]
del Zoppo, Gregory J. [1 ,7 ]
机构
[1] Univ Washington, Sch Med, Dept Med, Div Hematol, Seattle, WA 98195 USA
[2] Keio Univ, Sch Med, Dept Neurol, Tokyo, Japan
[3] Niigata Univ, Brain Res Inst, Dept Neurol, Niigata, Japan
[4] RTI Int, Discovery Sci & Technol, Res Triangle Pk, NC USA
[5] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
[6] NINDS, Stroke Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA
[7] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA
来源
基金
美国国家卫生研究院;
关键词
Cerebral microvessel endothelium; beta; 1-integrin; intracellular signaling; permeability; tight junction proteins; BLOOD-BRAIN-BARRIER; LIGHT-CHAIN PHOSPHORYLATION; LINKED KINASE ILK; HEMORRHAGIC TRANSFORMATION; NEUROVASCULAR UNIT; DISTINCT ROLES; RHO-KINASE; ISCHEMIA; INTEGRIN; MATRIX;
D O I
10.1177/0271678X17722108
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:641 / 658
页数:18
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