Angiotensin II Modulates BBB Permeability via Activation of the AT1 Receptor in Brain Endothelial Cells

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 125 I-albumin and transendothelial electrical resistance (TEER) were assessed. Angiotensin II (100 nmol/L) caused significant time-dependent changes in both 125 I-albumin permeability (25%) at 2 h and TEER (−8.87 Ω·cm 2 ) at 6 h. Next, MECs were pretreated with the Ang II type 1 (AT 1 ) receptor blocker telmisartan (1 μmol/L) or the Ang II type 2 (AT 2 ) receptor blocker PD123,319 (1 μmol/L) followed by treatment with Ang II (100 nm). Telmisartan completely inhibited the Ang II-induced increase in 125 I-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.