Expression mechanism and pathophysiology of the blood brain barier related membrane protein in cerebral capillary endothelial cells

本课题旨在阐明血脑屏障(BBB)特异性膜蛋白的生理作用和表达机制，并进一步探讨其在治疗BBB病理状态中的作用。采用大鼠脑肿瘤模型、人脑肿瘤标本和大鼠脑梗塞模型，应用免疫组织化学和生化方法研究血脑屏障特异性膜蛋白、P-糖蛋白和多种血管生成因子的表达。BBB相关蛋白在正常血管内皮细胞和脑胶质瘤血肿瘤屏障中均有表达。非胶质瘤的肿瘤血管不表达BBB相关蛋白。这些结果解释了胶质瘤化疗的困难。为了克服这些情况，几种血管活性药物，如钙拮抗剂和缓激肽，在通过颈动脉给药时，分别有助于选择性地增加胶质瘤的局部血流量和毛细血管通透性。我们还研究了…更多的血管生成因子，尤其是血管内皮生长因子(VEGF)参与了肿瘤的血管生成。在胶质瘤和脑膜瘤中，血管内皮生长因子的表达与血管密度呈正相关。对大鼠脑梗塞的时间学研究表明，BBB相关蛋白在脑梗塞后3天内消失，并随着内皮细胞的成熟而重新出现，并伴随着反应性胶质细胞增厚。巨噬细胞、神经胶质细胞和有趣的神经元可能是血管内皮生长因子分泌的来源。这些结果表明，新生毛细血管在病理条件下是未成熟的，具有通透性。梗死灶愈合过程表明神经胶质细胞对BBB相关蛋白表达的重要性。BBB的成熟需要内皮细胞和胶质细胞的接触，进而需要BBB相关蛋白的表达，这些表达的调节可能有助于控制脑水肿的形成和肿瘤的生长。较少

This project was planned to clarify the physiological roles and expression mechanis of the blood brain barrier (BBB) specific membrane proteins, and further to implicate them for the treatment of pathological conditions of BBB.Using rat brain tumor model, human brain tumor samples, and rat brain infarct model, the expression of gamma-glutamyl transpeptidase (gamma-GTP), P-glycoprotein, and several angiogenic factors was investigated immunohistochemically and biochemically. BBB related proteins were expressed in the normal capillary endothelial cells and blood tumor barrier in gliomas. Tumor vessels in non-glial tumor did not express BBB related proteins. These results explained difficulty of the chemotherapy of gliomas.To overcome these condition, several vasoactive agents, such as calcium antagonists and bradykinin, were useful to selectively increase regional blood flow and capillary permeability in gliomas, respectiverly, when administered through the carotid artery.We also investig … More ated angiogenic factors, especially vascular endothelial growth factor (VEGF) , which had been involved in tumor angiogenesis. In glioma and meningioma, the expression of VEGF was statistically corelated with vascularity. Chronological investigation of rat brain infarct revealed that BBB-related proteins were disappear wihtin 3 days after infarct and reappeared in endothelial cells with their maturation in conjunction with reactive gliosis. Macrophages, glial cells, and interestingly neurons could be the sourse of VEGF secretion. These results suggested that newly formed capillaries were immature and permeable in pathological condition. The healing process of infarct cleary showed the importance of glial cells for the expression of BBB related proteins. The maturation of BBB requires the contact between endothelial cells and glial cells, and further requres the expression of BBB related proteins.The modulation of these expression might be useful to control brain edema formation and tumor growth. Less