Sex-dependent regulation of hypoxic ventilation in mice and humans is mediated by erythropoietin

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 with their corresponding male siblings. Alterations of catecholamines in the brain stem's respiratory centers were also sex dependent. In a proof-of-concept study, human volunteers were intravenously injected with 5,000 units rhEpo and subsequently exposed to 10% oxygen. Compared with 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 susceptible to hypoxia-associated syndromes than men.