Wagner S, Tagaya M, Koziol J A, Quaranta V, del Zoppo G J
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, Calif. 92037, USA.
Stroke. 1997 Apr;28(4):858-65. doi: 10.1161/01.str.28.4.858.
Integrins participate in cerebral microvascular integrity and signaling during focal ischemia/ reperfusion. The integrin subunits alpha 1, alpha 6, and beta 1 are distributed identically on normal cerebral microvessels. Studies in epithelium indicate that integrin alpha 6 beta 4, which interacts with laminin-5 in the basal lamina/extracellular matrix, is unique. This study describes the exact location of alpha 6, beta 4, and alpha 6 beta 4 and that their responses in focal cerebral ischemia are relevant to astrocyte-matrix interactions.
The effect of middle cerebral artery occlusion and subsequent reperfusion on the microvascular expression of alpha 6 beta 4 and laminin-5 in regions of cellular injury (dUTP incorporation) was examined in 15 nonhuman primates. Well-characterized antibodies against human alpha 6, beta 4, alpha 6 beta 4, laminin-5 and laminin-1, endothelial CD31, and vascular markers were measured with computerized video imaging and laser confocal microscopy.
Integrin alpha 6 beta 4 was localized on astrocytes where it connects with the extracellular matrix at the astrocyte-vessel interface. It represented 59.3 +/- 16.4% of alpha 6 antigen in cerebral microvessels < 100 microns in diameter. By 2 hours of ischemia, the significant reduction in alpha 6 expression (2P < .001) was accompanied by decreases in beta 4/laminin-5 (0.76 +/- 0.03 to 0.20 +/- 0.09; 2P = .001) and alpha 6 beta 4/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.
This is the first description of a potential role of integrin alpha 6 beta 4 in the brain, where it mediates astrocyte-matrix interactions. The dramatic disappearance of alpha 6 beta 4 relative to its ligands reflects early loss of integrity between the astrocyte and the vessel wall in selected microvessels in response to ischemia.
整合素在局灶性缺血/再灌注期间参与脑微血管完整性及信号传导。整合素亚基α1、α6和β1在正常脑微血管上分布相同。上皮细胞研究表明，与基底膜/细胞外基质中的层粘连蛋白-5相互作用的整合素α6β4具有独特性。本研究描述了α6、β4和α6β4的确切定位，以及它们在局灶性脑缺血中的反应与星形胶质细胞-基质相互作用相关。
在15只非人灵长类动物中，研究大脑中动脉闭塞及随后再灌注对细胞损伤区域（dUTP掺入）微血管α6β4和层粘连蛋白-5表达的影响。使用计算机视频成像和激光共聚焦显微镜检测针对人α6、β4、α6β4、层粘连蛋白-5和层粘连蛋白-1、内皮细胞CD31以及血管标志物的特异性抗体。
整合素α6β4定位于星形胶质细胞，在星形胶质细胞-血管界面处与细胞外基质相连。在直径小于100微米的脑微血管中，它占α6抗原的59.3±16.4%。缺血2小时时，α6表达显著降低（P<0.001），同时dUTP掺入区域的β4/层粘连蛋白-5（从0.76±0.03降至0.20±0.09；P = 0.001）和α6β4/层粘连蛋白-5（从0.73±0.18降至0.25±0.11；P = 0.001）也降低。层粘连蛋白-5和层粘连蛋白-1的平行变化不太明显，在24小时时一致。
这是首次描述整合素α6β4在脑中的潜在作用，它介导星形胶质细胞-基质相互作用。相对于其配体，α6β4的显著消失反映了在缺血时特定微血管中星形胶质细胞与血管壁之间早期完整性的丧失。
