Adrenal epinephrine facilitates erythropoietin gene activation by hypoxia through β2 adrenergic receptor interaction with Hif-2α

Hypobaric hypoxia (HH) occurring at high altitudes activates the sympathetic nervous system (SNS) and increases circulating erythropoietin (EPO) levels. EPO stimulates red blood cell production (erythropoiesis), enhancing oxygen transport in arterial blood to counteract hypoxemia. The present study tested the hypothesis that SNS contributes to EPO activation by HH through epinephrine (EPI) release from the adrenal medullae. Adult male C57B6 mice were exposed to 18 h of HH (0.4 atm), and renal <i>EPO</i> mRNA and plasma EPO levels were measured. HH increased <i>EPO</i> mRNA and plasma EPO levels, and SNS activation, as indicated by elevated plasma norepinephrine (NE) and EPI levels. In adrenal-medullectomized mice, HH-induced EPO response was reduced, correlating with decreased circulating NE and absence of EPI elevation. EPI, but not NE infusion, mimicked the effects of HH in room air-breathing mice. EPO responses to HH were reduced with β-adrenergic receptor (AR) blockade using dl-propranolol and in β2 adrenergic receptor knockout mice. Mice with heterozygous Hif-2α deficiency (<i>Hif-2α</i>^+/-), but not <i>Hif-1α</i>^+/-, showed attenuated <i>EPO</i> gene activation and elevated plasma EPO levels in response to HH and EPI infusion. These results demonstrate that adrenal EPI facilitates the <i>EPO</i> gene activation by HH through the interaction of β2 AR with HIF-2α.<b>NEW & NOTEWORTHY</b> Hypobaric hypoxia activates the sympathetic nervous system (SNS) and the erythropoietin (<i>EPO</i>) gene. Whether SNS activation by hypoxia influences the <i>EPO</i> gene activation is an unresolved question. The present study demonstrates that adrenal epinephrine facilitates hypoxia-induced <i>EPO</i> gene activation through the interaction of β2 adrenergic receptors (β2 ARs) with the transcriptional activator HIF-2α.