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Sex-dependent regulation of hypoxic ventilation in mouse and man is mediated by erythropoietin


Soliz, J; Thomsen, J J; Soulage, C; Lundby, C; Gassmann, M (2009). Sex-dependent regulation of hypoxic ventilation in mouse and man is mediated by erythropoietin. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 296(6):1837-1846.

Abstract

Acclimatization to hypoxic exposure relies on an elevated ventilation and erythropoietic activity. We recently proposed that erythropoietin (Epo) links both responses: apart from red blood cell production, cerebral and plasma Epo interact with the central and peripheral respiratory centers. Knowing that women cope better than men with reduced oxygen supply (as observed at high altitude), we analyzed the hypoxic ventilatory response in Epo-overexpressing transgenic male and female mice with high Epo levels in brain and plasma (Tg6) or in wild type animals injected with recombinant human Epo (rhEpo). Exposure to moderate and severe hypoxia as well as to hyperoxia and injection of domperidone, a potent peripheral ventilatory stimulant, revealed that the presence of transgenic or rhEpo extensively increased the hypoxic ventilatory response in female mice compared to their corresponding male siblings. Alterations of catecholamines in the brainstem's respiratory centers were also sex-dependent. In a proof-of-concept study, human volunteers were i.v. injected 5000 U rhEpo and subsequently exposed to 10% oxygen. Compared to men, the hypoxic ventilatory response was significantly increased in women. We conclude that Epo exerts a sex-dependent impact on hypoxic ventilation improving the response in female mice and in women that most probably involves sexual hormones. Our data provides an explanation as to why women are less susceptibility to hypoxia-associated syndromes than men. Key words: carotid body, brainstem, sexual dimorphism.

Acclimatization to hypoxic exposure relies on an elevated ventilation and erythropoietic activity. We recently proposed that erythropoietin (Epo) links both responses: apart from red blood cell production, cerebral and plasma Epo interact with the central and peripheral respiratory centers. Knowing that women cope better than men with reduced oxygen supply (as observed at high altitude), we analyzed the hypoxic ventilatory response in Epo-overexpressing transgenic male and female mice with high Epo levels in brain and plasma (Tg6) or in wild type animals injected with recombinant human Epo (rhEpo). Exposure to moderate and severe hypoxia as well as to hyperoxia and injection of domperidone, a potent peripheral ventilatory stimulant, revealed that the presence of transgenic or rhEpo extensively increased the hypoxic ventilatory response in female mice compared to their corresponding male siblings. Alterations of catecholamines in the brainstem's respiratory centers were also sex-dependent. In a proof-of-concept study, human volunteers were i.v. injected 5000 U rhEpo and subsequently exposed to 10% oxygen. Compared to men, the hypoxic ventilatory response was significantly increased in women. We conclude that Epo exerts a sex-dependent impact on hypoxic ventilation improving the response in female mice and in women that most probably involves sexual hormones. Our data provides an explanation as to why women are less susceptibility to hypoxia-associated syndromes than men. Key words: carotid body, brainstem, sexual dimorphism.

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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:25 March 2009
Deposited On:07 Apr 2009 12:55
Last Modified:05 Apr 2016 13:12
Publisher:American Physiological Society
ISSN:0363-6119
Publisher DOI:10.1152/ajpregu.90967.2008
PubMed ID:19321698
Permanent URL: http://doi.org/10.5167/uzh-18142

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