Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms

To the majority of the population, recurrent episodes of hypoxia are more likely encountered in life than sustained hypoxia. Until recently, much of the information on the long-term effects of intermittent hypoxia has come from studies on human subjects experiencing chronic recurrent apneas. Recent development of animal models of intermittent hypoxia and techniques for exposing cell cultures to alternating cycles of hypoxia have led to new information on the effects of episodic hypoxia on oxygen-sensing mechanisms in the carotid body chemoreceptors and regulation of gene expression. The purpose of this review is to highlight some recent studies on the effects of intermittent hypoxia on oxygen sensing at the carotid bodies and regulation of gene expression. In a rodent model, chronic intermittent hypoxia selectively enhances hypoxic sensitivity of the carotid body chemoreceptors. More interestingly, chronic intermittent hypoxia also induces a novel form of plasticity in the carotid body, leading to long-term facilitation in the sensory discharge. Studies on cell cultures reveal that intermittent hypoxia is more potent in activating activator protein-1 and hypoxia-inducible factor-1 transcription factors than sustained hypoxia. Moreover, some evidence suggests that intermittent hypoxia utilizes intracellular signaling pathways distinct from sustained hypoxia. Reactive oxygen species generated during the reoxygenation phase of intermittent hypoxia might play a key role in the effects of intermittent hypoxia on carotid body function and gene expression. Global gene profile analysis in cell cultures suggests that certain genes are selectively affected by intermittent hypoxia, some upregulated and some downregulated. It is suggested that, in intact animals, coordinated gene regulation of gene expression might be critical for eliciting phenotypic changes in the cardiorespiratory systems in response to intermittent hypoxia. It is hoped that future studies will unravel new mechanisms that are unique to intermittent hypoxia that may lead to a better understanding of the changes in the cardiorespiratory systems and new therapies for diseases associated with chronic recurrent episodes of hypoxia.