The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis

The respiratory response to hypoxia in mammals develops from an inhibition of breathing movements in utero into a sustained increase in ventilation in the adult. This ventilatory response to hypoxia (HVR) in mammals is the subject of this review. The period immediately after birth contains a critical time window in which environmental factors can cause long-term changes in the structural and functional properties of the respiratory system, resulting in an altered HVR phenotype. Both neonatal chronic and chronic intermittent hypoxia, but also chronic hyperoxia, can induce such plastic changes, the nature of which depends on the time pattern and duration of the exposure (acute or chronic, episodic or not, etc.). At adult age, exposure to chronic hypoxic paradigms induces adjustments in the HVR that seem reversible when the respiratory system is fully matured. These changes are orchestrated by transcription factors of which hypoxia-inducible factor 1 has been identified as the master regulator. We discuss the mechanisms underlying the HVR and its adaptations to chronic changes in ambient oxygen concentration, with emphasis on the carotid bodies that contain oxygen sensors and initiate the response, and on the contribution of central neurotransmitters and brain stem regions. We also briefly summarize the techniques used in small animals and in humans to measure the HVR and discuss the specific difficulties encountered in its measurement and analysis.