Rapid Disruption of an Astrocyte Interaction With the Extracellular Matrix Mediated by Integrin α 6 β 4 During Focal Cerebral Ischemia/Reperfusion

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Abstract
Background and Purpose Integrins participate in cerebral microvascular integrity and signaling during focal ischemia/reperfusion. The integrin subunits α 1 , α 6 , and β 1 are distributed identically on normal cerebral microvessels. Studies in epithelium indicate that integrin α 6 β 4 , which interacts with laminin-5 in the basal lamina/extracellular matrix, is unique. This study describes the exact location of α 6 , β 4 , and α 6 β 4 and that their responses in focal cerebral ischemia are relevant to astrocyte-matrix interactions. Methods The effect of middle cerebral artery occlusion and subsequent reperfusion on the microvascular expression of α 6 β 4 and laminin-5 in regions of cellular injury (dUTP incorporation) was examined in 15 nonhuman primates. Well-characterized antibodies against human α 6 , β 4 , α 6 β 4 , laminin-5 and laminin-1, endothelial CD31, and vascular markers were measured with computerized video imaging and laser confocal microscopy. Results Integrin α 6 β 4 was localized on astrocytes where it connects with the extracellular matrix at the astrocyte-vessel interface. It represented 59.3±16.4% of α 6 antigen in cerebral microvessels 6 expression (2 P <.001) was accompanied by decreases in β 4 /laminin-5 (0.76±0.03 to 0.20±0.09; 2 P =.001) and α 6 β 4 /laminin-5 (0.73±0.18 to 0.25±0.11; 2 P =.001) in the region of dUTP incorporation. Parallel changes in laminin-5 and laminin-1 were less pronounced and coincided by 24 hours. Conclusions This is the first description of a potential role of integrin α 6 β 4 in the brain, where it mediates astrocyte-matrix interactions. The dramatic disappearance of α 6 β 4 relative to its ligands reflects early loss of integrity between the astrocyte and the vessel wall in selected microvessels in response to ischemia.

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