Erythropoietin and the Sex-Dimorphic Chemoreflex Pathway

Abstract

During hypoxic or hypoxemic conditions, tissue oxygenation and arterial O(2) carrying capacity are upregulated by two complementary systems, namely the neural respiratory network (central and peripheral) that leads to increased minute ventilation thereby increasing tissue oxygenation, and erythropoietin (Epo) release by the kidney that activates erythropoiesis in bone marrow to augment arterial blood O(2) carrying capacity. Despite the fact that both neural respiratory control and Epo-mediated elevation of red blood cells are responsible for keeping arterial O(2) content optimal, no interaction between these systems has been described so far. Here we review data obtained in our laboratory demonstrating that ventilatory and erythropoietic systems are tightly connected. We found Epo is the key factor mediating this relationship through modulation of the chemoreflex pathway. Moreover, we showed that this interaction occurs in a sex-dependent manner.

Maternal nutrient restriction in guinea pigs leads to fetal growth restriction with evidence for chronic hypoxia

“…This cannot be attributed to less hypoxic stimulus since HP-1 tissue staining was similarly increased from control levels in both male and female FGR-MNR fetuses and growth and metabolite characteristics did not differ (18). More likely is the better adaptation to hypoxia in females than in males, including the tighter link between oxygenation and increased erythropoiesis as previously noted (29). The present findings thereby provide further support for chronic hypoxia as a primary signaling mechanism for the decreased fetal growth with moderate MNR in guinea pig pregnancies.…”

“…Mechanisms underlying these differences are not readily apparent, and Clemons et al (28) found no sexual dimorphism in the EPO response of fetal and neonatal rats to induced hypoxia. However, there are known to be sex-related differences in responses to hypoxia, with females showing better adaptation than males, including the ventilatory and erythropoietic system responses that are tightly linked in females but not in males (29). EPOR is a cell surface transmembrane protein to which EPO must bind in order to achieve signal transduction in both erythroid and non-erythroid tissues (19,30,31).…”

The Many Facets of Erythropoietin Physiologic and Metabolic Response

“…However, estrogen can affect EPO response and confer gender specific EPO action. In ventilatory response in mice, hypoxia induction of EPO modulates ventilatory response, which exhibits a sexdimorphic behavior mediated via interaction with carotid body cells that is also sensitive to ovarian steroids (Soliz et al, 2012). The sex-dependent EPO regulation of fat mass is demonstrated with EPO treatment during high fat diet feeding that reduces fat mass gain in male mice and in female ovariectomized mice but not in female non-ovariectomized mice and not in ovariectomized mice supplemented with estradiol pellets (Zhang et al, 2017).…”

“…For example, in adult female mice, estrogen dependent induction of EPO in the mouse uterus contributes to angiogenic activity and blood vessel formation in the uterine endometrium, contributing to the cyclic remodeling in the estrus cycle transition from diestrus to proestrus (Yasuda et al, 1998). With regards to environmental hypoxia, EPO affects the hypoxic ventilatory response via EPOR expression in brain and carotid body, and this response is increased in women and female mice compared with men and male mice (Soliz et al, 2012). This sexual dimorphism of EPO stimulated hypoxic ventilatory response is attributed, in part, to carotid body sensitivity to sex hormones, particularly estrogen.…”

The physiological determinants of Sudden Infant Death Syndrome

“…Several aspects of respiratory physiology have gender specific traits and such concepts have been extensively reviewed elsewhere (For reviews: (Behan et al, 2003; Behan and Wenninger, 2008; Soliz et al, 2012; Joseph et al, 2013; Kinkead et al, 2013)). Because SIDS appears to have a gender bias with a distinct developmental profile this section focuses on recent findings pertaining specifically to gender and developmental windows commonly used to investigate potential vulnerabilities that related to SIDS.…”