Effects of Ang II and hypoxia on the blood-brain barrier

Ang II和缺氧对血脑屏障的影响

• 批准号: 6929271
• 负责人: MELISSA A FLEEGAL-DeMOTTA
• 金额: $ 4.83万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2006-07-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929271
• 关键词: angiotensin II; biological signal transduction; blood brain barrier; cell component structure /function; cellular pathology; cerebral ischemia /hypoxia; gene expression; hormone regulation /control mechanism; laboratory rat; postdoctoral investigator; protein kinase C; tight junctions; vascular endothelium; vascular endothelium permeability

DESCRIPTION (provided by applicant): In the United States, stroke is the third leading cause of death and hypertension is a major risk factor for the severity and occurrence of stroke. Physiologically, angiotensin II (Ang II) is important in regulating blood pressure and fluid homeostasis. During stroke there is a disruption of the blood-brain barrier (BBB), which leads to changes in tight junction proteins (occludin, claudin, ZO-1, ZO-2) and cerebral vasogenic edema. However, the cellular mechanisms leading to this disruption are not well known. Hypoxia (associated with stroke) increases BBB permeability by altering the tight junction proteins (occludin, claudin, ZO-1, ZO-2), and this change in BBB permeability has been shown to involve nitric oxide and changes in intracellular Ca 2+. Ang II, acting via the Ang II type I receptor, has also been shown to cause increases in BBB permeability. However, the molecular mechanisms behind these effects are unknown. Classic Ang II-mediated responses utilize PKC (alpha, beta-I ,beta-II, gamma) and PKC can modify the tight junctions. Recently, it has been demonstrated that hypoxia activates PKC in BBB endothelial cells. The hypothesis of this proposal is that upregulation of intracellular mechanisms by Ang II in endothelial cells of the BBB alters cell permeability and potentiates changes in BBB paracellular permeability due to hypoxic insult. The goal is to investigate the effects of Ang II and hypoxia on PKC(alpha, beta-I, beta-II, gamma) expression and activity and its effects on tight junctions and BBB permeability.

描述（由申请人提供）： 在美国，中风是第三大死亡原因，高血压是中风严重程度和发生的主要危险因素。在生理学上，血管紧张素II（Ang II）在调节血压和流体稳态中是重要的。在中风期间，存在血脑屏障（BBB）的破坏，这导致紧密连接蛋白（闭合蛋白、紧密连接蛋白、ZO-1、ZO-2）的变化和脑血管源性水肿。然而，导致这种破坏的细胞机制尚不清楚。缺氧（与中风相关）通过改变紧密连接蛋白（occludin，claudin，ZO-1，ZO-2）增加BBB通透性，并且这种BBB通透性的变化已被证明涉及一氧化氮和细胞内Ca 2+的变化。通过Ang II I型受体起作用的Ang II也已显示引起BBB通透性的增加。然而，这些影响背后的分子机制是未知的。经典的Ang II介导的反应利用PKC（α、β-I、β-II、γ），并且PKC可以修饰紧密连接。最近的研究表明，缺氧可激活血脑屏障内皮细胞中的PKC。该建议的假设是，在BBB的内皮细胞中通过Ang II的细胞内机制的上调改变了细胞通透性，并增强了由于缺氧损伤而引起的BBB细胞旁通透性的变化。目的是研究血管紧张素II和缺氧对PKC（α，β-I，β-II，γ）表达和活性的影响及其对紧密连接和血脑屏障通透性的影响。