Published Online
on October 21, 2002

A more recent version of this article appeared on November 5, 2002

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Submitted on May 15, 2002
Revised on August 13, 2002
Accepted on August 16, 2002

Perivascular Superoxide Anion Contributes to Impairment of Endothelium-Dependent Relaxation. Role of gp91^phox

Federico E. Rey , Xiao-Chun Li MD, Oscar A. Carretero MD, Jeffrey L. Garvin PhD, and Patrick J. Pagano PhD^*

From the Hypertension & Vascular Research Division, Henry Ford Hospital, Detroit, Mich.

^* To whom correspondence should be addressed. E-mail: ppagano1{at}hfhs.org.

Background—Like endothelial and smooth muscle cells, vascular adventitial fibroblasts contain a substantial NAD(P)H oxidase superoxide anion (O₂^-)-generating system activated by angiotensin II (Ang II). Based on the ability of nitric oxide (NO·) to diffuse rapidly through tissue and the fast reaction rate of NO· and O₂^-, we postulated that the interaction between NO· and adventitial NAD(P)H oxidase-derived O₂^- contributes to impairment of endothelium-dependent relaxation (EDR).

Methods and Results—C57Bl/6 mouse abdominal aortas were simultaneously perfused intraluminally and suffused adventitially with physiological buffer at 37°C. After constricting the vessels with phenylephrine, an acetylcholine dose-response curve was obtained while monitoring changes in diameter by videomicroscopy. Endogenous O₂^- was increased by treating the adventitial side of the aortas with Ang II (10 pmol/L), leading to impairment of EDR. EDR impairment was reversed by adventitial suffusion of superoxide dismutase (SOD) of aortas from wild-type mice. Ang II-treated aortas from gp91^phox-/- mice, which lack significant adventitial O₂^-, exhibited greater EDR and were not affected by SOD. Adventitially suffused SOD failed to penetrate the media, indicating that the effects of SOD were localized to the adventitia. Adventitial application of the O₂^--generating system xanthine/xanthine oxidase or the potent NO scavenger oxyhemoglobin impaired EDR.

Conclusions—O₂^- derived from adventitial gp91^phox-based NAD(P)H oxidase contributes to impairment of the action of endothelium-derived NO·.

Key words: aorta • endothelium-derived factors • angiotensin • nitric oxide • free radicals

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