Angiotensin II modulates BBB permeability via activation of the AT1 receptor in brain endothelial cells

被引:143
作者
Fleegal-DeMotta, Melissa A. [1 ,2 ]
Doghu, Shinya [1 ,2 ]
Banks, William A. [1 ,2 ]
机构
[1] St Louis Univ, Div Geriatr, Dept Internal Med, St Louis, MO 63106 USA
[2] VAMC, GRECC, St Louis, MO USA
关键词
angiotensin II; blood-brain barrier; endothelial; PKC; SPONTANEOUSLY HYPERTENSIVE-RATS; FLUID-PHASE ENDOCYTOSIS; MALIGNANT HYPERTENSION; BARRIER PERMEABILITY; PEPTIDE REGULATION; BINDING-SITES; MICROVESSELS; EMERGENCIES; MONOLAYERS; ENCEPHALOPATHY;
D O I
10.1038/jcbfm.2008.158
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:640 / 647
页数:8
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