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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:826.)
© 2006 American Heart Association, Inc.

Vascular Biology

Angiotensin II Attenuates Endothelium-Dependent Responses in the Cerebral Microcirculation Through Nox-2–Derived Radicals

Helene Girouard; Laibaik Park; Josef Anrather; Ping Zhou; Costantino Iadecola

From the Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY.

Correspondence to Costantino Iadecola, MD, Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69^th Street; KB410, New York, NY 10021. E-mail coi2001{at}med.cornell.edu

Objective— Angiotensin II (Ang II) exerts deleterious effect on the cerebral circulation through production of reactive oxygen species (ROS). However, the enzymatic source of the ROS has not been defined. We tested the hypothesis that Ang II impairs endothelium-dependent responses in the cerebral microcirculation through ROS generated in cerebrovascular cells by the enzyme NADPH oxidase.

Methods and Results— Cerebral blood flow (CBF) was monitored by laser Doppler flowmetry in anesthetized mice equipped with a cranial window. Ang II (0.25±0.02 µg/kg per minute for 30 to 45 minutes) attenuated the CBF increase produced by the endothelium-dependent vasodilators acetylcholine (–42±5%; P<0.05), bradykinin (–53±5%; P<0.05), and A23187 (–43±4%; P<0.05), and induced cerebrovascular ROS production, assessed by hydroethidine fluoromicrography. These actions of Ang II were prevented by losartan, by the ROS scavenger Mn(III) tetrakis (4-benzoic acid) porphyrin chloride (100 µmol/L), or by the NADPH oxidase peptide inhibitor gp91ds-tat (1 µmol/L), and were not observed in mice lacking the NADPH oxidase subunit gp91^phox (nox-2).

Conclusions— Ang II impairs the endothelial regulation of the cerebral microcirculation through AT1 receptor-mediated cerebrovascular oxidative stress. The source of the ROS is a nox-2-containing NADPH oxidase. These effects of Ang II could threaten the cerebral blood supply and contribute to the increased susceptibility to stroke and dementia associated with hypertension.

We investigated the mechanism of the effect of angiotensin II on the increase in cerebral blood flow (CBF) produced by endothelium-dependent vasodilators. We found that the attenuation of endothelium-dependent responses induced by Ang II is mediated by free radicals produced by a NADPH oxidase containing nox-2 as the catalytic subunit.

Key Words: cerebral blood flow • gp91^phox • laser Doppler flowmetry • NADPH oxidase • reactive oxygen species

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