Estradiol in carotid bodies impairs the ventilatory acclimatization to hypoxia in Epo overexpressing female mice

Erythropoietin (Epo) impacts the ventilatory response to acute hypoxia in a sex‐dependent manner, with female mice having better capability to cope with reduced oxygenation. Here we hypothesized that ventilatory acclimatization to chronic hypoxia (VAH) in transgenic female mice showing high levels of Epo in brain and blood (Tg6) will be improved compared to WT animals. The data obtained by plethysmography showed the opposite: VAH was blunted in Tg6 female mice. To define whether this phenomenon had central and/or peripheral origin, a bilateral chemodenervation was performed. This procedure allowed testing the central response in absence of carotid body information. Interestingly, chemodenervated Tg6 and WT female mice had similar VAH, thus suggesting that carotid bodies were responsible for the blunted response. Accordingly, the sensitivity to oxygen alteration in arterial blood (Dejour test) was impaired in Tg6 carotid bodies. As blunted VAH occurred in female but not male Tg6 mice, the involvement of female steroids was suspected. Indeed, estradiol serum level was 4‐folds higher in Tg6 mice compared to WT animals. In addition, ovarectomy decreased VAH in WT animals, but restored VAH in Tg6 female mice, while estradiol treatment in ovarectomiced Tg6 females suppressed VAH. We concluded that under chronic hypoxia, estradiol in carotid bodies blunts the VAH of Tg6 female mice overexpressing Epo.