Angiotensin II modulates BBB permeability via activation of the AT1 receptor in brain endothelial cells
Angiotensin II modulates BBB permeability via activation of the AT1 receptor in brain endothelial cells
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DOI：
10.1038/jcbfm.2008.158
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发表时间：
2009-03-01
影响因子：
6.3
通讯作者：
Banks, William A.
中科院分区：
文献类型：
--
作者：
Fleegal-DeMotta, Melissa A.;Doghu, Shinya;Banks, William A.
高血压性脑病发生时，血压的急性变化导致血脑屏障（BBB）的破坏。血管紧张素II（Ang II）在这种病理生理学中起作用。我们确定血管紧张素II是否直接调节血脑屏障内皮细胞功能。在BBB微血管内皮细胞（MEC），血管紧张素II（100 nmol/L; 0至6小时）对I-125-白蛋白的渗透性和跨内皮电阻（TEER）的影响进行了评估。血管紧张素II（100 nmol/L）在2 h时引起I-125-白蛋白渗透性（25%）和6 h时TEER（-8.87 Omega.cm（2））的显著时间依赖性变化。接着，用Ang II 1型（AT（1））受体阻断剂替米沙坦（1 μ mol/L）或Ang II 2型（AT（2））受体阻断剂PD 123，319（1 μ mol/L）预处理MEC，然后用Ang II（100 nm）处理。替米沙坦完全抑制血管紧张素II诱导的MEC中I-125-白蛋白渗透性增加，而PD 123，319无影响。Western印迹分析显示，MEC表达AT（1）受体，但不表达AT（2）受体。Ang Ⅱ（100 nmol/L; 0 ~ 6 h）处理也增加了总蛋白激酶C活性。与此相反，血管紧张素II的表达occludin，claudin 5，或肌动蛋白没有影响。这些结果表明，血管紧张素Ⅱ直接调节血脑屏障内皮细胞的跨细胞和细胞旁通透性，并可能有助于高血压脑病的病理生理。
Hypertensive encephalopathy occurs when acute changes in blood pressure cause breakdown of the blood-brain barrier (BBB). Angiotensin II (Ang II) plays a role in this pathophysiology. We determined whether Ang II directly regulates endothelial cell function at the BBB. In BBB microvessel endothelial cells (MECs), the Ang II (100 nmol/L; 0 to 6 h) effects on permeability to I-125-albumin and transendothelial electrical resistance (TEER) were assessed. Angiotensin II (100 nmol/L) caused significant time-dependent changes in both I-125-albumin permeability (25%) at 2 h and TEER (-8.87 Omega.cm(2)) at 6 h. Next, MECs were pretreated with the Ang II type 1 (AT(1)) receptor blocker telmisartan (1 mu mol/L) or the Ang II type 2 (AT(2)) receptor blocker PD123,319 (1 mu mol/L) followed by treatment with Ang II (100 nm). Telmisartan completely inhibited the Ang II-induced increase in I-125-albumin permeability in MECs whereas PD123,319 had no effect. Using western blot analysis, we showed that MECs express AT(1) receptors but not AT(2) receptors. Treatment with Ang II (100 nmol/L; 0 to 6 h) also increased total protein kinase C activity. In contrast, Ang II had no effect on the expression of occludin, claudin 5, or actin. These results show that Ang II directly modulates transcytotic and paracellular permeability in BBB endothelial cells and could contribute to the pathophysiology of hypertensive encephalopathy.