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

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。从生理上讲，血管紧张素II(Ang II)在调节血压和体液平衡方面起着重要作用。在中风期间，血脑屏障(BBB)被破坏，导致紧密连接蛋白(occludin、claudin、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并不是很清楚。低氧(与卒中相关)通过改变紧密连接蛋白(occludin、claudin、ZO-1、ZO-2)增加血脑屏障通透性，这种血脑屏障通透性的变化被证明与一氧化氮和细胞内钙离子的变化有关。Ang II通过Ang II I型受体发挥作用，也被证明能引起血脑屏障通透性的增加。然而，这些效应背后的分子机制尚不清楚。经典的Ang II介导的反应利用PKC(α、β-I、β-II、伽马)，PKC可以修饰紧密连接。近年来，研究发现低氧可激活血脑屏障内皮细胞中的PKC。该方案的假设是Ang II上调血脑屏障内皮细胞的细胞内机制，改变细胞通透性，并加强低氧损伤引起的血脑屏障细胞旁通透性的变化。目的是研究血管紧张素转换酶II和低氧对PKC(α、βI、βII、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。

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.