Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles

Siu-Lung Chan,Gary L Baumbach

doi:10.3389/fphys.2013.00133

Abstract

Angiotensin II is an important determinant of inward remodeling in cerebral arterioles. Many of the vascular effects of angiotensin II are mediated by reactive oxygen species (ROS) generated from homologs of NADPH oxidase with Nox2 predominating in small arteries and arterioles. Therefore, we tested the hypothesis that superoxide generated by Nox2 plays a role in angiotensin II-induced cerebral arteriolar remodeling. We examined Nox2-deficient and wild-type (WT) mice in which a pressor or a non-pressor dose of angiotensin II (1000 or 200 ng/kg/day) or saline was infused for 4 weeks via osmotic minipumps. Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of cerebral arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area (by histology) and superoxide level (by hydroethidine staining) of cerebral arterioles were determined ex vivo. The pressor, but not the non-pressor, dose of angiotensin II significantly increased systolic arterial pressure in both WT and Nox2-deficient mice. Both doses of angiotensin II increased superoxide levels and significantly reduced external diameter in maximally dilated cerebral arterioles in WT mice. Increased superoxide and inward remodeling were prevented in Nox2-deficient mice. Moreover, only the pressor dose of AngII increased cross-sectional area of arteriolar wall in WT mice and was prevented in Nox2-deficient mice. In conclusion, superoxide derived from Nox2-containing NADPH oxidase plays an important role in angiotensin II-mediated inward remodeling in cerebral arterioles. This effect appears to be independent of pressure and different from that of hypertrophy.

Highlights

Stroke is a common cause of death and disability in developed countries and it is estimated that about 800,000 people have stroke each year in the United States (Goldstein et al, 2011)
Increases in cerebral arteriolar superoxide in WT mice were greater with the pressor dose of Angiotensin II (AngII) than with the nonpressor dose
The non-pressor dose of AngII caused inward remodeling of cerebral arterioles in WT mice that was prevented in Nox2−/− mice

Summary

Introduction

Stroke is a common cause of death and disability in developed countries and it is estimated that about 800,000 people have stroke each year in the United States (Goldstein et al, 2011). An important risk factor of stroke, causes profound changes in cerebral vascular structure, such as hypertrophy and inward remodeling (Heagerty et al, 1993). To distinguish it from hypertrophy, we define inward remodeling as a reduction in external diameter due to rearrangement of existing components around a smaller lumen that cannot be accounted for by a reduction in vessel distensibility (Baumbach and Heistad, 1989). The renin-angiotensin system plays an important role in regulating cerebral vascular structure. Angiotensin II (AngII) is one of several determinants, along with other humoral factors, sympathetic nerves and increases in arterial pressure per se, that may result in hypertrophy of cerebral arterioles (Baumbach et al, 1989, 1991, 2003). The molecular mechanisms activated by AngII that lead to inward remodeling remain largely unknown

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