HIF-1 and ventilatory acclimatization to chronic hypoxia

Ventilatory acclimatization to hypoxia (VAH) is a time-dependent increase in ventilation and ventilatory O(2)-sensitivity that involves plasticity in carotid body chemoreceptors and CNS respiratory centers. Hypoxia inducible factor-1 alpha (HIF-1 alpha) controls the expression of several genes that increase physiological O(2) supply. Studies using transgenic mice show HIF-1 alpha expression in the carotid bodies and CNS with chronic sustained and intermittent hypoxia is important for VAH. Other O(2)-sensitive transcription factors such as HIF-2 alpha may be important for VAH by reducing metabolic O(2) demands also. Specific gene targets of HIF-1 alpha shown to be involved in VAH include erythropoietin, endothelin-1, neuronal nitric oxide synthase and tyrosine hydroxylase. Other HIF-1 alpha targets that may be involved in VAH include vascular endothelial growth factor, heme oxygenase 1 and cytoglobin. Interactions between these multiple pathways and feedback control of HIF-1 alpha expression from some of the targets support a complex and powerful role for HlF-1 alpha in neural plasticity of physiological control circuits with chronic hypoxia. (C) 2008 Elsevier B.V. All rights reserved.