Nox2 Deficiency Prevents Hypertension-Induced Vascular Dysfunction and Hypertrophy in Cerebral Arterioles

Siu-Lung Chan,Gary L Baumbach

doi:10.1155/2013/793630

Abstract

Oxidative stress is involved in many hypertension-related vascular diseases in the brain, including stroke and dementia. Thus, we examined the role of genetic deficiency of NADPH oxidase subunit Nox2 in the function and structure of cerebral arterioles during hypertension. Arterial pressure was increased in right-sided cerebral arterioles with transverse aortic banding for 4 weeks in 8-week-old wild-type (WT) and Nox2-deficient (-/y) mice. Mice were given NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or vehicle to drink. We measured the reactivity in cerebral arterioles through open cranial window in anesthetized mice and wall cross-sectional area and superoxide levels ex vivo. Aortic constriction increased systolic and pulse pressures in right-sided carotid arteries in all groups of mice. Ethidium fluorescence showed increased superoxide in right-sided cerebral arterioles in WT, but not in Nox2-/y mice. Dilation to acetylcholine, but not sodium nitroprusside, was reduced, and cross-sectional areas were increased in the right-sided arterioles in WT, but were unchanged in Nox2-/y mice. L-NAME reduced dilation to acetylcholine but did not result in hypertrophy in right-sided arterioles of Nox2-/y mice. In conclusion, hypertension-induced superoxide production derived from Nox2-containing NADPH oxidase promotes hypertrophy and causes endothelial dysfunction in cerebral arterioles, possibly involving interaction with nitric oxide.

Highlights

Chronic hypertension is a major risk factor of vascular disorders
To determine if Nox2containing NADPH oxidase is responsible for hypertensioninduced superoxide production, levels of superoxide were determined in cerebral arterioles from WT and Nox2-/y mice by ethidium fluorescence
These findings suggest that Nox2 is the major source of hypertension-induced superoxide in cerebral arterioles

Summary

Introduction

Chronic hypertension is a major risk factor of vascular disorders. Profound vascular functional and structural changes occur in many disease states, and emerging evidence suggests that oxidative stress has a major role in mediating these changes [1]. While functional forms of NADPH oxidase have been demonstrated throughout the vasculature, there are subtle, but important, structural differences with respect to its subunits depending on vessel size and region It appears that Nox may play a role in NADPH oxidase activity in vascular muscle of small resistance arteries, whereas homologues of Nox, such as Nox and Nox, may be more important in large cerebral arteries [8, 9]. A number of studies showed that angiotensin II-induced impairment of endothelial function and reduced cerebral blood flow are restored in Nox2-deficient (-/y) mice [10, 11] These findings highlight the importance of Nox2-containing NADPH oxidase in the pathology of hypertension in the cerebral circulation

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