Erythropoietin regulates hypoxic ventilation in mice by interacting with brainstem and carotid bodies
Résumé
Apart from its role in elevating red blood cell number, erythropoietin (Epo) exerts protective functions in brain, retina and heart upon ischemic injury. However, physiological non-erythroid functions of Epo remain unclear. Here we use a transgenic mouse line (Tg21) constitutively overexpressing human Epo in brain to investigate Epo's impact on ventilation upon hypoxic exposure. Tg21 mice showed improved ventilatory response to severe acute hypoxia and moreover improved ventilatory acclimatization to chronic hypoxic exposure. Furthermore, following bilateral transection of carotid sinus nerves that uncouples the brain from the carotid body, Tg21 mice adapted their ventilation to acute severe hypoxia while chemodenervated wild type (WT) animals developed a life-threatening apnea. These results imply that Epo in brain modulates ventilation. Additional analysis revealed that Epo receptor (EpoR) is expressed in the main brainstem respiratory centers and suggested that Epo stimulates breathing control by alteration of catecholaminergic metabolism in brainstem. The modulation of hypoxic pattern of ventilation after i.v. injection of recombinant human Epo in WT mice and the dense EpoR immunosignal observed in carotid bodies showed that these chemoreceptors are sensitive to plasma levels of Epo. In summary, our results suggest that Epo controls ventilation at central (brainstem) and peripheral (carotid body) levels. The physiological relevance of these novel findings are useful to better understand respiratory disorders including those occurring at high altitude