Breathing and the circulation are rapidly adjusted in response to changes in metabolic demands and the requirements for gas exchange. The hypoxic chemoreflex is a physiological control system that regulates breathing and blood flow in response to hypoxia. The reflex is initiated by a reduction in O2 in arterial blood, which is sensed by the carotid bodies — the body’s key O2 chemoreceptors. When stimulated, the carotid bodies send afferent information to the brain that leads to an increase in pulmonary ventilation termed the hypoxic ventilatory response (HVR). Carotid body stimulation also activates the sympathetic nervous system and leads to the release of catecholamines (epinephrine, norepinephrine, etc.) into the circulation from the adrenal medulla. This sympathoadrenal response to hypoxia can have a significant effect on the circulation — increasing cardiac output, inducing vasoconstriction in many tissues, and increasing systemic vascular resistance — with the net effect being that blood flow is preferentially redistributed toward core hypoxia-sensitive organs such as the brain and heart. The hypoxic chemoreflex is critical to surviving acute exposure to severe hypoxia, but its advantages during chronic hypoxia are less clear. In some cases, there can be a trade-off associated with the hypoxic chemoreflex between physiological changes that are beneficial to pulmonary O2 uptake and tissue O2 supply (e.g., increases in ventilation), and other changes (e.g., persistent sympathoadrenal activation) that may compromise long-term O2 supply to some tissues. Such trade-offs could represent a significant challenge to high-altitude natives, for which long-term reductions in blood flows to digestive, reproductive, and other tissues could have detrimental consequences for fitness. We are examining control of breathing and the circulation in high-altitude mammals and birds to gain insight into how they have overcome this challenge.
The hypoxic chemoreflex is a key control system regulating the ventilatory and circulatory responses to hypoxia (Storz and Scott, 2019). The carotid bodies detect a reduction in the O2 tension in arterial blood and send afferent information to respiratory and cardiovascular control centres in the brain. This leads to the stimulation of pulmonary ventilation, and to sympathetic activation that has various effects on the heart and vasculature.
Our work in deer mice has shown that high-altitude populations have evolved changes to many aspects of the hypoxic chemoreflex. In low-altitude mice, chronic hypoxia enlarges the carotid bodies, increases total ventilation and the HVR, reduces catecholamine release from the adrenal medulla, and reduces the sensitivity of the systemic vasculature to stimulation by catecholamines. In contrast, chronic hypoxia does not increase ventilation or carotid body size in high-altitude mice, but they tend to breathe much deeper than low-altitude mice to maintain pulmonary O2 uptake. Furthermore, catecholamine release from the adrenal medulla is even lower in highlanders than in lowlanders in chronic hypoxia. We are also exploring the genetic bases for these evolved changes in the hypoxic chemoreflex, which include coding sequence changes in the genes encoding hypoxia inducible factor 2ɑ (Epas1) and haemoglobin.
Our work in birds has shown that there can be distinct evolutionary paths in different high-altitude lineages. Ventilation and the HVR is greater in some high-altitude taxa compared to their low-altitude counterparts (e.g., bar-headed geese, yellow-billed pintail), suggesting that the hypoxic chemoreflex has evolved to augment pulmonary O2 uptake in these species. In contrast, ventilation and the HVR is attenuated in some other high-altitude taxa (e.g., Andean geese), suggesting that they have evolved to minimize the detrimental consequences of having high ventilation (e.g., respiratory CO2 and water loss) and a pronounced hypoxic chemoreflex.
Scott Lab @ McMaster 