Response to Sex of the Animal Impacts Responses to Angiotensin II, Oxidative Stress Levels, and Nitric Oxide Bioavailability
We appreciate the interest and the thoughtful letter by Brinson and Sullivan1 on our recent article.2 In experiments using a combination of male and female superoxide dismutase 1 (SOD1)-knockout or transgenic mice, we showed that SOD1 limits renal microvascular remodeling and attenuates arteriole and blood pressure responses to angiotensin (Ang) II via modulation of NO bioavailability. Considering emerging evidence for sex differences in Ang II–induced hypertension, Brinson and Sullivan1 encouraged us to examine potential sex differences. They hypothesized that the inclusion of both sexes in our study may be a confounding factor and that blood pressure and vascular responses to Ang II could have been even more dramatic if only males were included. This is an interesting and important question; however, we were limited by the availability of a suitable number of animals to perform a robust sex analysis. Telemetry data in Figure 2 of our article, with prolonged Ang II infusion, included 3 male and 2 female SOD1-knockouts. Interestingly, when separating the Ang II responses based on sex, male mice had a more dramatic response (113±5 to 151±6 mm Hg) than females (105±12 to 120±8 mm Hg). Further investigations are planned to address this observation in more detail. In contrast to blood pressure results, reanalysis of afferent arteriolar responses to Ang II did not reveal any sex differences. A previous study showed that renal afferent arteriolar vasoconstriction to Ang II, and the combination with NG-nitro-l-arginine methyl ester, was not different between males and females.3 Similar to this study, our in vitro approach with isolated afferent arterioles is free from circulating hormonal influence, and sex differences may exist if hormones (eg, estrogen) were added to the perfusion solutions.
Renal oxidative stress and NO deficiency have been linked to hypertension and cardiovascular disease4; however, neither clinical trials nor experimental studies are consistent in terms of whether oxidative stress levels are higher in males than females.5 Discrepancies likely involve age and sex hormone levels, cardiovascular-renal health, and genetics of the individuals. Studies in spontaneously hypertensive rats showed that antioxidant treatment with Tempol or apocynin reduced levels of reactive oxygen species in the kidney and lowered blood pressure in male but not in female rats.5 In addition, stimulation of oxidative stress increased blood pressure only in male spontaneously hypertensive rats.5 These findings, together with our observations in SOD1-deficient mice, would indicate that females have lower production of reactive oxygen species or better antioxidant capacity than males.
Imbalance between production of reactive oxygen species and NO has also been implicated in microvascular remodeling and endothelial dysfunction. Vascular remodeling was demonstrated in cerebral arterioles from SOD1-knockout mice, regardless of sex.6 Our study showed that renal afferent arterioles from SOD1-knockouts displayed hypertrophic changes compared with SOD1-transgenic mice.2 Analysis of media:lumen ratios did not show any sex differences in knockouts (males: 2.45±0.22; females: 2.92±0.18) or transgenic mice (males: 1.29±0.19; females: 1.28±0.11), but it is possible that sex differences exist in conditions with prolonged Ang II treatment.
We thank Drs Brinson and Sullivan for their valuable comments1 and agree that sex analysis should be included in coming studies, as this may render novel information.
Department of Medical Cell Biology
Department of Medicine
Georgetown University Medical Center
Department of Physiology and Pharmacology
Sources of Funding
This study was financially supported by the Swedish Research Council (K2009-64X-03522-38-2 and K2009-54X-21117-01-3); the Wallenberg Foundation; the Swedish Heart and Lung Foundation (20090264); Wenner-Gren Foundation; the Swedish Society of Medicine; the Magnus Bergvall Foundation; the Swedish Society of Medical Research; the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL68686); and the National Institute of Diabetes and Digestive and Kidney Diseases (DK-036079 and DK-049870) of the National Institutes of Health.
Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.
- © 2011 American Heart Association, Inc.
- Brinson KN,
- Sullivan JC
- Carlstrom M,
- Lai EY,
- Ma Z,
- Steege A,
- Patzak A,
- Eriksson UJ,
- Lundberg JO,
- Wilcox CS,
- Persson AE
- Patzak A,
- Mrowka R,
- Storch E,
- Hocher B,
- Persson PB
- Wilcox CS
- Baumbach GL,
- Didion SP,
- Faraci FM