In Transgenic Erythropoietin Deficient Mice, an Increase in Respiratory Response to Hypercapnia Parallels Abnormal Distribution of CO2/H+-Activated Cells in the Medulla Oblongata

Abstract

Erythropoietin (Epo) and its receptor are expressed in central respiratory areas. We hypothesized that chronic Epo deficiency alters functioning of central respiratory areas and thus the respiratory adaptation to hypercapnia. The hypercapnic ventilatory response (HcVR) was evaluated by whole body plethysmography in wild type (WT) and Epo deficient (Epo-TAgh) adult male mice under 4%CO2. Epo-TAgh mice showed a larger HcVR than WT mice because of an increase in both respiratory frequency and tidal volume, whereas WT mice only increased their tidal volume. A functional histological approach revealed changes in CO2/H+-activated cells between Epo-TAgh and WT mice. First, Epo-TAgh mice showed a smaller increase under hypercapnia in c-FOS-positive number of cells in the retrotrapezoid nucleus/parafacial respiratory group than WT, and this, independently of changes in the number of PHOX2B-expressing cells. Second, we did not observe in Epo-TAgh mice the hypercapnic increase in c-FOS-positive number of cells in the nucleus of the solitary tract present in WT mice. Finally, whereas hypercapnia did not induce an increase in the c-FOS-positive number of cells in medullary raphe nuclei in WT mice, chronic Epo deficiency leads to raphe pallidus and magnus nuclei activation by hyperacpnia, with a significant part of c-FOS positive cells displaying an immunoreactivity for serotonin in the raphe pallidus nucleus. All of these results suggest that chronic Epo-deficiency affects both the pattern of ventilatory response to hypercapnia and associated medullary respiratory network at adult stage with an increase in the sensitivity of 5-HT and non-5-HT neurons of the raphe medullary nuclei leading to stimulation of fR for moderate level of CO2.

Chronic pulmonary fibrosis alters the functioning of the respiratory neural network

“…As previously described ( Voituron et al, 2009 ; Niane et al, 2011 ; Samillan et al, 2013 ; Jeton et al, 2022 ), breathing variables were measured non-invasively in unanesthetized and unrestrained animals using whole-body flow barometric plethysmograph (Emka technologies, Paris, France). This method consists of measuring the pressure variations in a recording chamber during spontaneous ventilation.…”

Does fetal growth restriction induce neuropathology within the developing brainstem?

“…The internal cellular sensors may include hypoxia and CO 2 ‐sensitive astrocytes and cardiorespiratory neurons (Patterson et al., 2021 ), although this has recently been questioned (Li et al., 2023 ). Classically, the CNS was believed to lack hypoxia sensors, but work in rodents (Herlenius, 2011 ; Hofstetter & Herlenius, 2005 ; Hofstetter et al., 2007 ; Sheikhbahaei et al., 2018 ) has shown that (1), mitochondria within astrocytes (for example, within the preBötC) are susceptible to local hypoxia (Sheikhbahaei et al., 2018 ); (2), astrocytes at multiple sites, including in the NTS, MRN and RTN/pFRG, are sensitive to the brain's parenchymal levels of metabolites (pH, glucose, O 2 and CO 2 ), to prostaglandin E2 (PGE2), and to certain hormones and neurotransmitters (Forsberg & Herlenius, 2019 ; Funk, 2010 ; Marina et al., 2018 ); and (3), the cardiorespiratory neurons in the NTS, MRN and RTN act as central pH sensors through a complex mechanism including Ca 2+ channels and connexin‐mediated ATP release (Forsberg et al., 2016 ; Funk, 2010 ; Gourine et al., 2010 ; Jeton et al., 2022 ). In the two putative chemoreceptive sites, the MRN and RTN, elevation of CO 2 , independent of pH change, mediates chemosensation following a connexin‐mediated release of ATP (Funk, 2010 ), and hypercapnia has been shown to induce connexin‐mediated ATP and PGE2 release from pFRG/RTN astrocytes, which in turn increases the activity of pFRG/RTN neurons and subsequent inspiratory frequency (Forsberg et al., 2016 ; Forsberg et al., 2017 ; Gourine et al., 2010 ; Huxtable et al., 2010 ).…”