Erythropoietin and its antagonist regulate hypoxic fictive breathing in newborn mice

Khemiri, Hanan; Seaborn, Tommy; Gestreau, Christian; Soliz, Jorge

doi:10.1016/j.resp.2012.05.027

Cited by 17 publications

(13 citation statements)

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“…This is lower than in our previous study in which we injected 50 g over 3 days by an ICV infusion in adult mice (38). More recently, when recording the fictive breathing by using in vitro brain stem-spinal cord preparations, the samples were incubated in 3 g of sEpoR for 1 h (17). Based on these different studies and on the present results, it might be postulated that the dose injected was sufficient to obtain a reliable antagonization of the endogenous Epo in the brain stem region.…”

Section: Methodological Considerationsmentioning

confidence: 84%

“…While numerous studies describe the respiratory stimulant effect of Epo, most of them were conducted on transgenic animal models with constitutive overexpression of Epo (11,37,39,40), and only a limited number of studies addressed the respiratory effect of endogenous synthesized Epo in the CNS. We showed recently that incubation of the isolated brain stem-spinal cord preparations with sEpoR depresses neuronal respiratory activity in response to hypoxic exposure (17). However this experimental model can only be used in newborn rodents up to 4 days of age, when the respiratory control system is not fully mature.…”

Section: Cerebral Epo Is a Powerful Endogenous Respiratory Stimulantmentioning

confidence: 99%

“…Recent data obtained on the in vitro preparation of the isolated brain stem spinal cord preparation of newborn mice showed that the soluble Epo receptor (sEpoR, a competitive antagonist of Epo) changes the response to hypoxia, suggesting that endogenous synthesis of Epo might stimulate respiration, at least in response to hypoxia, in neonates by a direct effect on the central respiratory network (17). In the present study we used mice to ask whether similar effects of endogenous Epo are present in vivo, and if the effects of Epo are age-and sex-specific.…”

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confidence: 99%

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Endogenous brain erythropoietin is a potent sex-specific respiratory stimulant in adult and newborn mice

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Joseph

Soliz

2015

Journal of Applied Physiology

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We tested the hypothesis that endogenous brain Epo is a respiratory stimulant. Adult (3 mo) and newborn (10 days) male and female mice received an intracisternal (cisterna magna) injection of soluble Epo receptor (sEpoR; competes with EpoR to bind Epo; 50 μg/ml) or vehicle (0.1% BSA in PBS). Twenty-four hours after injection, we used whole body plethysmography to record minute ventilation (V̇e) tidal volume (VT), respiratory frequency (fR), O2 consumption (V̇o2), and CO2 production (V̇co2) under normoxia and progressive exposure to hypoxia (12-10-6% O2; 10 min each). In adult male and female mice sEpoR decreased normoxic V̇e (-25%), due to a decrease of VT in males and fR in females. Moreover, sEpoR injection decreased the ventilatory response to 12% O2, assessed as V̇e/V̇o2 or V̇e/V̇co2, in male but not in female mice. In newborn male and female mice sEpoR decreased V̇e (-37% in males, -59% in females) and VT (-38% in males, -47% in females) in normoxia and fR in females. During hypoxia, sEpoR decreased V̇e/V̇o2 and V̇e/V̇co2 in mice of both sexes. Upon extreme hypoxia (6% O2), the newborn mice treated with sEpoR showed respiratory depression, signs of asphyxia (gasping) and a high mortality rate in males and females. We concluded that endogenous brain Epo is a potent respiratory stimulant under normoxia and hypoxia in adult and newborn mice. Because sex-specific effects are different in newborn male and female, sex steroids secreted at different ages mice appear to modulate the effects of Epo on respiratory regulation in normoxia and in response to hypoxia.

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Section: Methodological Considerationsmentioning

confidence: 84%

Section: Cerebral Epo Is a Powerful Endogenous Respiratory Stimulantmentioning

confidence: 99%

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confidence: 99%

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Endogenous brain erythropoietin is a potent sex-specific respiratory stimulant in adult and newborn mice

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Joseph

Soliz

2015

Journal of Applied Physiology

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“…Epo increases the ventilatory response to hypoxia in both mice (60) and humans (17). The soluble EpoR, an endogenous Epo antagonist expressed in the mouse brain, regulates the ventilatory acclimatization to hypoxia (59,60) and decreases hypoxic respiratory activity in vitro (29). Although Epo contributes significantly to oxygen homeostasis, its potential role in modulating the ventilatory response to changes in Pa CO 2 has been little explored (1).…”

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confidence: 99%

Polycythemia and high levels of erythropoietin in blood and brain blunt the hypercapnic ventilatory response in adult mice

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Khemiri

d'Harambure

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Changes in arterial Po2, Pco2, and pH are the strongest stimuli sensed by peripheral and central chemoreceptors to adjust ventilation to the metabolic demand. Erythropoietin (Epo), the main regulator of red blood cell production, increases the hypoxic ventilatory response, an effect attributed to the presence of Epo receptors in both carotid bodies and key brainstem structures involved in integration of peripheral inputs and control of breathing. However, it is not known whether Epo also has an effect on the hypercapnic chemoreflex. In a first attempt to answer this question, we tested the hypothesis that Epo alters the ventilatory response to increased CO2 levels. Basal ventilation and hypercapnic ventilatory response (HCVR) were recorded from control mice and from two transgenic mouse lines constitutively expressing high levels of human Epo in brain only (Tg21) or in brain and plasma (Tg6), the latter leading to polycythemia. To tease apart the potential effects of polycythemia and levels of plasma Epo in the HCVR, control animals were injected with an Epo analog (Aranesp), and Tg6 mice were treated with the hemolytic agent phenylhydrazine after splenectomy. Ventilatory parameters measured by plethysmography in conscious mice were consistent with data from electrophysiological recordings in anesthetized animals and revealed a blunted HCVR in Tg6 mice. Polycythemia alone and increased levels of plasma Epo blunt the HCVR. In addition, Tg21 mice with an augmented level of cerebral Epo also had a decreased HCVR. We discuss the potential implications of these findings in several physiopathological conditions.

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“…Using brainstem-spinal cord preparations from mice, Soliz et al ( 25 ) reported that EPO and EPOR are present in the mouse brainstem. They also showed that EPO controls ventilation and that an EPO antagonist suppressed the frequency of nerve activity at C 4 ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin, a putative neurotransmitter during hypoxia, is produced in RVLM neurons and activates them in neonatal Wistar rats

Oshima

Onimaru

Yamagata

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent studies indicate that erythropoietin (EPO) is present in many areas of the brain and is active in the restoration of impaired neurons. In this study, we examined the presence of EPO and its role in bulbospinal neurons in the rostral ventrolateral medulla (RVLM). Hypoxia is often accompanied by a high blood pressure (BP). We hypothesized that EPO is produced in response to hypoxia in RVLM neurons and then activates them. To investigate whether RVLM neurons are sensitive to EPO, we examined the changes in the membrane potentials (MPs) of bulbospinal RVLM neurons using the whole cell patch-clamp technique during superfusion with EPO. A brainstem-spinal cord preparation was used for the experiments. EPO depolarized the RVLM neurons, and soluble erythropoietin receptor (SEPOR), an antagonist of EPO, hyperpolarized them. Furthermore, hypoxia-depolarized RVLM neurons were significantly hyperpolarized by SEPOR. In histological examinations, the EPO-depolarized RVLM neurons showed the presence of EPO receptor (EPOR). The RVLM neurons that possessed EPORs showed the presence of EPO and hypoxia-inducible factor (HIF)-2α. We also examined the levels of HIF-2α and EPO messenger RNA (mRNA) in the ventral sites of the medullas (containing RVLM areas) in response to hypoxia. The levels of HIF-2α and EPO mRNA in the hypoxia group were significantly greater than those in the control group. These results suggest that EPO is produced in response to hypoxia in RVLM neurons and causes a high BP via the stimulation of those neurons. EPO may be one of the neurotransmitters produced by RVLM neurons during hypoxia.

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Erythropoietin and its antagonist regulate hypoxic fictive breathing in newborn mice

Cited by 17 publications

References 47 publications

Endogenous brain erythropoietin is a potent sex-specific respiratory stimulant in adult and newborn mice

Endogenous brain erythropoietin is a potent sex-specific respiratory stimulant in adult and newborn mice

Polycythemia and high levels of erythropoietin in blood and brain blunt the hypercapnic ventilatory response in adult mice

Erythropoietin, a putative neurotransmitter during hypoxia, is produced in RVLM neurons and activates them in neonatal Wistar rats

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