Neurovascular Adhesion Receptors and Barrier Integrity

缺血性卒中会导致微血管完整性的迅速严重丧失。局灶性脑缺血后早期 可检测到的脑微血管通透性屏障的破坏和基质的快速变化 它们的基板的组成出现了。这项提议要检验的假设是：i) 微血管内皮细胞和星形胶质细胞上的基质受体与基质的相互作用 基底膜的成分是血脑屏障表型的主要决定因素，ii) 大脑中动脉闭塞(MCA：O)所致局灶性脑缺血对受体基质的破坏作用 相互作用，以及iii)受体-基质相互作用的中断导致失血 脑屏障表型。通透性屏障的表型涉及内皮细胞间的紧密联系 交汇点。但是，内皮细胞和星形胶质细胞与完整的基底板基质的粘连也可能 做一个重要的人。血管基质是由血管内皮细胞和星形胶质细胞在 发育，由内皮细胞和星形胶质细胞通过基质黏附维持 感受器。可与脑微血管内皮细胞和星形胶质细胞结合的黏附受体 基底板基质包括特定的整合素和α-和(3-)-营养不良多糖。基于以前的工作 和初步数据，我们认为整合素和营养不良多糖都是细胞完整性的核心。 血脑屏障和基质屏障。该项目的目标是证明特定的行动 这两个黏附受体家族的成员对于微血管屏障的完整性是必需的 功能，以及局部缺血、缺氧和破坏这些受体基质的特定抑制物 相互作用，产生障碍失效。具体目的是：1)证明细胞通过细胞黏附 受体(整合素和营养不良多糖)决定内皮细胞-基质-星形胶质细胞和血脑屏障 完整性；2)证明MCA：O或低氧显著改变整合素基质和营养不良糖链基质 内皮细胞-星形胶质细胞界面的相互作用；以及3)细胞的破坏 黏附受体与基质的相互作用不依赖于金属蛋白酶的表达。 这些研究为大脑内皮细胞的破坏提供了一种新的可信的解释 对小分子的屏障和局部缺血后微血管的完整性。具体的 星形胶质细胞末端足部利用精选整合素和营养不良多糖，内皮细胞利用内皮化整合素 提出了一个新的前提，即它们早期被局灶性缺血破坏是导致失血的原因- 大脑屏障。了解它们的表达和破坏机制可能会导致新的 保留或选择性改变其他血管屏障功能和微血管完整性的可测试方法 神经血管退行性疾病。

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.