This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wagner, S. Articles by del Zoppo, G. J. Search for Related Content PubMed PubMed Citation Articles by Wagner, S. Articles by del Zoppo, G. J.

(Stroke. 1997;28:858-865.)
© 1997 American Heart Association, Inc.

Articles

Rapid Disruption of an Astrocyte Interaction With the Extracellular Matrix Mediated by Integrin ₆ß₄ During Focal Cerebral Ischemia/Reperfusion

Simone Wagner, MD; Masafumi Tagaya, MD; James A. Koziol, PhD; Vito Quaranta, MD Gregory J. del Zoppo, MD

From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, Calif.

Correspondence to Gregory J. del Zoppo, MD, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, SBR-17, La Jolla, CA 92037. E-mail GRGDLZOP{at}RISCSM.SCRIPPS.EDU

Background and Purpose Integrins participate in cerebral microvascular integrity and signaling during focal ischemia/reperfusion. The integrin subunits ₁, ₆, and ß₁ are distributed identically on normal cerebral microvessels. Studies in epithelium indicate that integrin ₆ß₄, which interacts with laminin-5 in the basal lamina/extracellular matrix, is unique. This study describes the exact location of ₆, ß₄, and ₆ß₄ 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 ₆ß₄ and laminin-5 in regions of cellular injury (dUTP incorporation) was examined in 15 nonhuman primates. Well-characterized antibodies against human ₆, ß₄, ₆ß₄, laminin-5 and laminin-1, endothelial CD31, and vascular markers were measured with computerized video imaging and laser confocal microscopy.

Results Integrin ₆ß₄ was localized on astrocytes where it connects with the extracellular matrix at the astrocyte-vessel interface. It represented 59.3±16.4% of ₆ antigen in cerebral microvessels <100 µm in diameter. By 2 hours of ischemia, the significant reduction in ₆ expression (2P<.001) was accompanied by decreases in ß₄/laminin-5 (0.76±0.03 to 0.20±0.09; 2P=.001) and ₆ß₄/laminin-5 (0.73±0.18 to 0.25±0.11; 2P=.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 ₆ß₄ in the brain, where it mediates astrocyte-matrix interactions. The dramatic disappearance of ₆ß₄ relative to its ligands reflects early loss of integrity between the astrocyte and the vessel wall in selected microvessels in response to ischemia.

Key Words: astrocytes • cell adhesion molecules • cerebral ischemia • microvascular injury • baboons

This article has been cited by other articles:

				J. An, C. Zhang, R. Polavarapu, X. Zhang, X. Zhang, and M. Yepes Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein induce Akt phosphorylation in the ischemic brain Blood, October 1, 2008; 112(7): 2787 - 2794. [Abstract] [Full Text] [PDF]

				B R Thanvi, S Treadwell, and T Robinson Haemorrhagic transformation in acute ischaemic stroke following thrombolysis therapy: classification, pathogenesis and risk factors Postgrad. Med. J., July 1, 2008; 84(993): 361 - 367. [Abstract] [Full Text] [PDF]

				R. Milner, S. Hung, X. Wang, G. I. Berg, M. Spatz, and G. J. del Zoppo Responses of Endothelial Cell and Astrocyte Matrix-Integrin Receptors to Ischemia Mimic Those Observed in the Neurovascular Unit Stroke, January 1, 2008; 39(1): 191 - 197. [Abstract] [Full Text] [PDF]

				G. J. del Zoppo, R. Milner, T. Mabuchi, S. Hung, X. Wang, G. I. Berg, and J. A. Koziol Microglial Activation and Matrix Protease Generation During Focal Cerebral Ischemia Stroke, February 1, 2007; 38(2): 646 - 651. [Abstract] [Full Text] [PDF]

				G. J. del Zoppo and R. Milner Integrin-Matrix Interactions in the Cerebral Microvasculature Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 1966 - 1975. [Abstract] [Full Text] [PDF]

				R. Veltkamp, D. A. Siebing, L. Sun, S. Heiland, K. Bieber, H. H. Marti, S. Nagel, S. Schwab, and M. Schwaninger Hyperbaric Oxygen Reduces Blood-Brain Barrier Damage and Edema After Transient Focal Cerebral Ischemia Stroke, August 1, 2005; 36(8): 1679 - 1683. [Abstract] [Full Text] [PDF]

				B. Bosche, C. Dohmen, R. Graf, M. Neveling, F. Staub, L. Kracht, J. Sobesky, F.-G. Lehnhardt, and W.-D. Heiss Extracellular Concentrations of Non-Transmitter Amino Acids in Peri-Infarct Tissue of Patients Predict Malignant Middle Cerebral Artery Infarction Stroke, December 1, 2003; 34(12): 2908 - 2913. [Abstract] [Full Text] [PDF]

				J. Montaner, J. Alvarez-Sabin, C.A. Molina, A. Angles, S. Abilleira, J. Arenillas, and J. Monasterio Matrix Metalloproteinase Expression Is Related to Hemorrhagic Transformation After Cardioembolic Stroke Stroke, December 1, 2001; 32(12): 2762 - 2767. [Abstract] [Full Text] [PDF]

				N. Hosomi, J. Lucero, J. H. Heo, J. A. Koziol, B. R. Copeland, and G. J. del Zoppo Rapid Differential Endogenous Plasminogen Activator Expression After Acute Middle Cerebral Artery Occlusion Stroke, June 1, 2001; 32(6): 1341 - 1348. [Abstract] [Full Text] [PDF]

				Z.-l. Chen, J. A. Indyk, T. H. Bugge, K. W. Kombrinck, J. L. Degen, and S. Strickland Neuronal Death and Blood-Brain Barrier Breakdown after Excitotoxic Injury Are Independent Processes J. Neurosci., November 15, 1999; 19(22): 9813 - 9820. [Abstract] [Full Text] [PDF]

				R Milner, X Huang, J Wu, S Nishimura, R Pytela, D Sheppard, and C ffrench-Constant Distinct roles for astrocyte alphavbeta5 and alphavbeta8 integrins in adhesion and migration J. Cell Sci., January 12, 1999; 112(23): 4271 - 4279. [Abstract] [PDF]

				J. A. Ellison, J. J. Velier, P. Spera, Z. L. Jonak, X. Wang, F. C. Barone, G. Z. Feuerstein, T. Abumiya, and G. J. del Zoppo Osteopontin and its Integrin Receptor {alpha}vß3 Are Upregulated During Formation of the Glial Scar After Focal Stroke • Editorial Comment Stroke, August 1, 1998; 29(8): 1698 - 1707. [Abstract] [Full Text] [PDF]

				G. J DEL ZOPPO, R. VON KUMMER, and G. F HAMANN Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke J. Neurol. Neurosurg. Psychiatry, July 1, 1998; 65(1): 1 - 9. [Full Text]

				L. Pantoni, C. Sarti, and D. Inzitari Cytokines and Cell Adhesion Molecules in Cerebral Ischemia : Experimental Bases and Therapeutic Perspectives Arterioscler Thromb Vasc Biol, April 1, 1998; 18(4): 503 - 513. [Abstract] [Full Text] [PDF]

				T. L. Davis, I. Rabinovitz, B. W. Futscher, M. Schnolzer, F. Burger, Y. Liu, M. Kulesz-Martin, and A. E. Cress Identification of a Novel Structural Variant of the alpha 6 Integrin J. Biol. Chem., July 6, 2001; 276(28): 26099 - 26106. [Abstract] [Full Text] [PDF]