Ischemic stroke produces rapid profound loss of microvascular integrity. Early following focal ischemia detectable disruption in the permeability barrier of cerebral microvessels, and rapid changes in the matrix composition of their basal lamina occur. The hypotheses to be tested by this Proposal state i) that the interaction of matrix receptors on microvessel endothelial cells and astrocytes with the matrix components of the basal lamina are a major determinant of the blood-brain barrier phenotype, ii) that focal ischemia by middle cerebral artery occlusion (MCA:O) disrupts receptor-matrix interactions, and iii) that interruptions of the receptor-matrix interaction results in loss of the blood brain barrier phenotype. The phenotype of the permeability barrier involves the inter-endothelial tight junctions. But, adhesion of endothelial cells and astrocytes to the intact basal lamina matrix is also likely to be important. The vascular matrix is generated by endothelial cells and astrocytes in concert during development, and is maintained by both endothelial cells and astrocytes through their matrix adhesion receptors. Adhesion receptors which could bind cerebral microvascular endothelial cells and astrocytes to the basal lamina matrix include specific integrins and the a- and (3-dystroglycans. Based upon previous work and preliminary data, we propose that both integrins and dystroglycans are central to the integrity of the blood-brain and matrix barriers. The goal of this Project is to demonstrate that the action of specific members of these two adhesion receptor families is required for the integrity of the microvessel barrier functions, and that focal ischemia, hypoxia, and specific inhibitors that disrupt these receptor - matrix interactions, produce barrier failure.
The Specific Aims are to: 1) Demonstrate that cell adhesion via cell receptors (integrins and dystroglycans) determine endothelial cell-matrix-astrocyte and blood brain barrier integrity;2) Demonstrate that MCA:O or hypoxia significantly alter integrin-matrix and dystroglycan-matrix interactions at the endothelial cell-astrocyte interface;and 3) Demonstrate that the disruption of the cell adhesion receptor-matrix interactions occur independent of metalloproteinase expression. These studies provide a novel plausible explanation for the disruption of both the cerebral endothelial cell barrier to small molecules and the microvascular integrity immediately following focal ischemia. The specific use of select integrins and dystroglycans by astrocyte end-feet, and of PHntegrins by endothelial cells suggests the novel premise that their early disruption by focal ischemia is responsible for loss of the blood- brain barrier. Understanding the mechanisms of their expression and disruption is likely to lead to new testable approaches to preserve or selectively alter barrier function and microvessel integrity in other neurovascular degenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053716-06
Application #
7738486
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (91))
Program Officer
Jacobs, Tom P
Project Start
2005-12-16
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
6
Fiscal Year
2010
Total Cost
$337,412
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Gu, Yu-Huan; Kanazawa, Masato; Hung, Stephanie Y et al. (2015) Cathepsin L acutely alters microvessel integrity within the neurovascular unit during focal cerebral ischemia. J Cereb Blood Flow Metab 35:1888-900
Hawkins, Brian Thomas; Gu, Yu-Huan; Izawa, Yoshikane et al. (2015) Dabigatran abrogates brain endothelial cell permeability in response to thrombin. J Cereb Blood Flow Metab 35:985-92
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Degos, Vincent; Westbroek, Erick M; Lawton, Michael T et al. (2013) Perioperative management of coagulation in nontraumatic intracerebral hemorrhage. Anesthesiology 119:218-27
del Zoppo, Gregory J (2013) Plasminogen activators and ischemic stroke: conditions for acute delivery. Semin Thromb Hemost 39:406-25

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