AT 1 Receptor Blockade Regulates the Local Angiotensin II System in Cerebral Microvessels From Spontaneously Hypertensive Rats

Abstract

Background and Purpose— Blockade of angiotensin II AT ₁ receptors in cerebral microvessels protects against brain ischemia and inflammation. In this study, we tried to clarify the presence and regulation of the local renin-angiotensin system (RAS) in brain microvessels in hypertension. Methods— Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) controls were treated with an AT ₁ receptor antagonist (candesartan, 0.3 mg/kg per day) via subcutaneous osmotic minipumps for 4 weeks. The expression and localization of RAS components and the effect of AT ₁ receptor blockade were assessed by Affymetrix microarray, qRT-PCR, Western blots, immunohistochemistry and immunofluorescence. Results— We found transcripts of most of RAS components in our microarray database, and confirmed their expression by qRT-PCR. Angiotensinogen (Aogen), angiotensin-converting enzyme (ACE) and AT ₁ receptors were localized to the endothelium. There was no evidence of AT ₂ receptor localization in the microvascular endothelium. In SHR, (pro)renin receptor mRNA and AT ₁ receptor mRNA and protein expression were higher, whereas Aogen, ACE mRNA and AT ₂ receptor mRNA and protein expression were lower than in WKY rats. Candesartan treatment increased Aogen, ACE and AT ₂ receptor in SHR, and increased ACE and decreased Aogen in WKY rats, without affecting the (pro)renin and AT ₁ receptors. Conclusions— Increased (pro)renin and AT ₁ receptor expression in SHR substantiates the importance of the local RAS overdrive in the cerebrovascular pathophysiology in hypertension. AT ₁ receptor blockade and increased AT ₂ receptor stimulation after administration of candesartan may contribute to the protection against brain ischemia and inflammation.