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: 6834745
• 负责人: MELISSA A FLEEGAL-DeMOTTA
• 金额: $ 4.3万
• 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 2007-07-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6834745
• 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，中风是死亡的第三大主要原因，高血压是中风严重性和发生的主要危险因素。在生理上，血管紧张素II（ANG II）对于调节血压和液体稳态很重要。在中风期间，血脑屏障（BBB）发生了破坏，这会导致紧密连接蛋白（Occludin，claudin，ZO-1，ZO-2）和脑血管生成性水肿的变化。但是，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）来增加BBB的渗透性，并且已证明BBB渗透率的这种变化涉及一氧化氮和细胞内Ca 2+的变化。 ANG II通过ANG II型受体作用，也已显示出可引起BBB渗透性的增加。但是，这些作用背后的分子机制尚不清楚。经典ANG II介导的反应利用PKC（Alpha，Beta-I，Beta-II，Gamma）和PKC可以修改紧密的连接。最近，已经证明缺氧在BBB内皮细胞中激活PKC。该提议的假设是，在BBB的内皮细胞中，Ang II的细胞内机制上调会改变细胞的通透性，并增强由于低氧损伤引起的BBB旁细胞通透性的变化。目的是研究ANG II和缺氧对PKC（Alpha，Beta-I，Beta-II，Gamma）的表达和活性及其对紧密连接和BBB渗透率的影响。