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Impaired ventilatory acclimatization to hypoxia in female mice overexpressing erythropoietin: unexpected deleterious effect of estradiol in carotid bodies


Gassmann, M; Pfistner, C; Doan, V D; Vogel, J; Soliz, J (2010). Impaired ventilatory acclimatization to hypoxia in female mice overexpressing erythropoietin: unexpected deleterious effect of estradiol in carotid bodies. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 299:R1511-R1520.

Abstract

Apart from enhancing the production of red blood cells, erythropoietin (Epo) alters the ventilatory response when oxygen supply is reduced. We recently demonstrated that Epo's beneficial effect on the ventilatory response to acute hypoxia is sex-dependent, with female mice being better able to cope with reduced oxygenation. In the present work we hypothesized that ventilatory acclimatization to chronic hypoxia (VAH) in transgenic female mice (Tg6) harboring high levels of Epo in the brain and blood will also be improved compared to wilde type (WT) animals. Surprisingly, VAH was blunted in Tg6 female mice. To define whether this phenomenon had a central (brainstem respiratory centers) and/or peripheral (carotid bodies) origin, a bilateral transection of carotid sinus nerve (chemodenervation) was performed. This procedure allowed the analysis of the central response in the absence of carotid body information. Interestingly, chemodenervation restored the VAH in Tg6 mice, suggesting that carotid bodies were responsible for the blunted response. Coherently with this observation, the sensitivity to oxygen alteration in arterial blood (Dejour test) after chronic hypoxia was lower in transgenic carotid bodies compared to the WT control. As blunted VAH occurred in female but not male transgenic mice, the involvement of sex female steroids was obvious. Indeed, measurement of sexual female hormones revealed that the estradiol serum level was 4 times higher in transgenic mice Tg6 than in WT animals. While ovariectomy decreased VAH in WT females, this treatment restored VAH in Tg6 female mice. In line with this observation, injections of estradiol in ovariectomized Tg6 females dramatically reduced the VAH. We concluded that during chronic hypoxia, estradiol in carotid bodies suppresses the Epo-mediated elevation of ventilation. Considering the increased application of recombinant Epo for a variety of disorders, our data implies the need to take the patient's hormonal status into consideration.

Abstract

Apart from enhancing the production of red blood cells, erythropoietin (Epo) alters the ventilatory response when oxygen supply is reduced. We recently demonstrated that Epo's beneficial effect on the ventilatory response to acute hypoxia is sex-dependent, with female mice being better able to cope with reduced oxygenation. In the present work we hypothesized that ventilatory acclimatization to chronic hypoxia (VAH) in transgenic female mice (Tg6) harboring high levels of Epo in the brain and blood will also be improved compared to wilde type (WT) animals. Surprisingly, VAH was blunted in Tg6 female mice. To define whether this phenomenon had a central (brainstem respiratory centers) and/or peripheral (carotid bodies) origin, a bilateral transection of carotid sinus nerve (chemodenervation) was performed. This procedure allowed the analysis of the central response in the absence of carotid body information. Interestingly, chemodenervation restored the VAH in Tg6 mice, suggesting that carotid bodies were responsible for the blunted response. Coherently with this observation, the sensitivity to oxygen alteration in arterial blood (Dejour test) after chronic hypoxia was lower in transgenic carotid bodies compared to the WT control. As blunted VAH occurred in female but not male transgenic mice, the involvement of sex female steroids was obvious. Indeed, measurement of sexual female hormones revealed that the estradiol serum level was 4 times higher in transgenic mice Tg6 than in WT animals. While ovariectomy decreased VAH in WT females, this treatment restored VAH in Tg6 female mice. In line with this observation, injections of estradiol in ovariectomized Tg6 females dramatically reduced the VAH. We concluded that during chronic hypoxia, estradiol in carotid bodies suppresses the Epo-mediated elevation of ventilation. Considering the increased application of recombinant Epo for a variety of disorders, our data implies the need to take the patient's hormonal status into consideration.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Physiology
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:22 September 2010
Deposited On:08 Oct 2010 12:21
Last Modified:05 Apr 2016 14:16
Publisher:American Physiological Society
ISSN:0363-6119
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1152/ajpregu.00205.2010
PubMed ID:20861276

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