Neurovascular Adhesion Receptors and Barrier Integrity

缺血性中风导致微血管完整性的迅速严重丧失。局灶性缺血后早期 脑微血管通透性屏障的可检测破坏，以及基质的快速变化 其基底层的组成发生。本提案所要检验的假设是：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 基底层的组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）引起的局灶性缺血破坏了受体基质， 相互作用，和iii）受体-基质相互作用的中断导致血液损失 脑屏障表型通透性屏障的表型涉及内皮细胞间的紧密连接， 交叉点但是，内皮细胞和星形胶质细胞与完整的基底层基质的粘附也可能是 变得重要血管基质是由内皮细胞和星形胶质细胞协同产生的， 发育，并通过内皮细胞和星形胶质细胞通过其基质粘附来维持 受体。脑微血管内皮细胞和星形胶质细胞粘附受体 基底层基质包括特异性整联蛋白和α-和β-肌营养不良聚糖。根据以前的工作 和初步的数据，我们提出，整合素和肌营养不良蛋白聚糖是核心的完整性， 血脑和基质屏障。该项目的目标是证明，具体的行动 这两个粘附受体家族的成员是微血管屏障完整性所必需的 局部缺血、缺氧和破坏这些受体基质的特异性抑制剂， 相互作用，导致屏障失效。具体目的是：1）证明细胞粘附通过细胞粘附分子的作用， 受体（整合素和肌营养不良蛋白聚糖）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或缺氧显著改变整合素-基质和肌营养不良聚糖-基质 内皮细胞-星形胶质细胞界面的相互作用;和3）证明细胞的破坏 粘附受体-基质相互作用的发生不依赖于金属蛋白酶的表达。 这些研究提供了一种新的合理的解释，脑内皮细胞的破坏， 局灶性缺血后即刻对小分子的屏障和微血管完整性的影响。具体 通过星形胶质细胞末端足使用选择的整合素和肌营养不良蛋白聚糖，以及通过内皮细胞使用PHntegrin 提出了一个新的假设，即局部缺血引起的早期破坏是造成失血的原因， 脑屏障了解它们的表达和破坏机制可能会导致新的 在其他组织中，可测试的方法来保持或选择性地改变屏障功能和微血管完整性 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.