Erythropoietin regulates hypoxic ventilation in mice by interacting with brainstem and carotid bodies

Abstract

Apart from its role in elevating red blood cell number, erythropoietin (Epo) exerts protective functions in brain, retina and heart upon ischaemic injury. However, the 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 apnoea. These results imply that Epo in brain modulates ventilation. Additional analysis revealed that the Epo receptor (EpoR) is expressed in the main brainstem respiratory centres 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 the central (brainstem) and peripheral (carotid body) levels. These novel findings are relevant to understanding better respiratory disorders including those occurring at high altitude.

Preserved placental oxygenation and development during severe systemic hypoxia

“…Finally, hypoxic changes in metabolic parameters such as glucose levels or acid-base status might have influenced placental oxygenation as well. We observed reduced food intake and activity of hypoxic mice, including a decrease in ventilatory oxygen consumption and carbon dioxide production (43). Furthermore, tissue glycogen levels have been shown to be decreased in hypoxic rats (36), and inhibition of brown adipose tissue sympathetic nerve activity during hypoxia has been suggested to directly contribute to the hypoxia-evoked reduction in body temperature and oxygen consumption serving as adaptive responses to decreased oxygen availability (28).…”

Role of erythropoietin in the brain

“…In cultures of rat hippocampal neurons, EPO can directly increase BDNF expression [94]. Increase in EPO bioavailability by over expression in brain or by intravenous injection can also modulate ventilatory response to hypoxia [95]. In experimental subarachnoid hemorrhage in rats, subcutaneously administered EPO provided protection preserving cerebral blood flow autoregulation [96].…”

Combination of Erythropoietin and Sildenafil Can Effectively Attenuate Hypoxia‐Induced Pulmonary Hypertension in Mice

“…27,28 Briefly, mice were placed in a 600-mL chamber continuously supplied with a 0.7-0.8 L/ min airflow controlled by flow restrictors. The ventilation of mice was recorded twice, before the interventions (exposure to hypoxia/drug treatment) and thereafter according to a standardized protocol: at least 5 minutes of recording at rest under normoxic conditions before the oxygen content within the chamber was gradually decreased (within 5 minutes) from room air to 10% oxygen, after which ventilation was recorded for another 10 minutes.…”