Divergent roles of reactive oxygen species in the responses of perinatal adrenal chromaffin cells to hypoxic challenges

Abstract The fetus and neonate experience variable patterns of low P O 2 (hypoxia) ranging from acute, sustained, and intermittent. Adaptation to hypoxia involves activation of key transcription factors, known as hypoxia-inducible factors (e.g. HIF-1α, HIF-2α), which regulate a number of genes in different cell types. This review focuses on the signaling pathways that mediate proper physiological responses of perinatal adrenomedullary chromaffin cells (AMC) to varying patterns of hypoxic challenges, and particularly on the controversial role of reactive oxygen species (ROS). At birth, acute hypoxia (seconds to minutes) directly stimulates catecholamine release from AMC via K+ channel inhibition, mediated by a decrease in mitochondrial-derived ROS. By contrast, exposure to chronic sustained hypoxia (CSH) induces HIF-2α in a fetal-derived chromaffin cell line independently of changes in ROS. Exposure to chronic intermittent hypoxia (CIH) activates antioxidant responses via the regulator Nrf-2, in association with an increase in ROS and the induction of HIF-1α. We propose that the physiological responses of perinatal AMC to hypoxia and the ensuing directional changes in ROS are dependent on the pattern and duration of the hypoxic exposure.