Cerebral vascular effects of angiotensin II: new insights from genetic models

• Published in: Journal of cerebral blood flow and metabolism 2006-04, Vol.26 (4), p.449-455
• Main Authors: Faraci, Frank M, Lamping, Kathryn G, Modrick, Mary L, Ryan, Michael J, Sigmund, Curt D, Didion, Sean P
• Format: Article
• Language: English
• Subjects: Angiotensin II - pharmacology; Angiotensinogen - genetics; Animals; Antihypertensive agents; Biological and medical sciences; Cardiovascular system; Cerebral Arteries - drug effects; Cerebral Arteries - physiopathology; Cerebrovascular Circulation - drug effects; Endothelium, Vascular - pathology; Female; Humans; Hypertension - etiology; Hypertension - pathology; Hypertension - physiopathology; Intracellular Signaling Peptides and Proteins; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - physiology; Receptor, Angiotensin, Type 1 - physiology; Renin - genetics; rho-Associated Kinases; Sex Factors; Superoxides; Vascular diseases and vascular malformations of the nervous system; Vasoconstriction - drug effects
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/sj.jcbfm.9600204

Very little is known regarding the mechanisms of action of angiotensin II (Ang II) or the consequences of Ang II-dependent hypertension in the cerebral circulation. We tested the hypothesis that Ang II produces constriction of cerebral arteries that is mediated by activation of AT1A receptors and Rho-kinase. Basilar arteries (baseline diameter ~130 µm) from mice were isolated, cannulated and pressurized to measure the vessel diameter. Angiotensin II was a potent constrictor in arteries from male, but not female, mice. Vasoconstriction in response to Ang II was prevented by an inhibitor of Rho-kinase (Y-27632) in control mice, and was reduced by ~85% in mice deficient in expression of AT1A receptors. We also examined the chronic effects of Ang II using a model of Ang II-dependent hypertension, mice which overexpress human renin (R+) and angiotensinogen (A+). Responses to the endothelium-dependent agonist acetylcholine were markedly impaired in R+ A+ mice (P < 0.01) compared with controls, but were restored to normal by a superoxide scavenger (PEG-SOD). A-23187 (another endothelium-dependent agonist) produced vasodilation in control mice, but no response or vasoconstriction in R+ A+ mice. In contrast, dilation of the basilar artery in response to a NO donor (NONOate) was similar in R+ A+ mice and controls. Thus, Ang II produces potent constriction of cerebral arteries via activation of AT1A receptors and Rho-kinase. There are marked gender differences in cerebral vascular responses to Ang II. Endothelial function is greatly impaired in a genetic model of Ang II-dependent hypertension via a mechanism that involves superoxide.