Abstract
The hypoxia-inducible factor (HIF) family of transcription factors coordinates diverse cellular and systemic responses to hypoxia. Chuvash polycythemia (CP) is an autosomal recessive disorder in humans in which there is impaired oxygen-dependent degradation of HIF, resulting in long-term systemic elevation of HIF levels at normal oxygen tensions. CP patients demonstrate the characteristic features of ventilatory acclimatization to hypoxia, namely, an elevated baseline ventilation and enhanced acute hypoxic ventilatory response (AHVR). We investigated the ventilatory and carotid-body phenotype of a mouse model of CP, using whole-body plethysmography, immunohistochemistry, and electron microscopy. In keeping with studies in humans, CP mice had elevated ventilation in euoxia and a significantly exaggerated AHVR when exposed to 10% oxygen, with or without the addition of 3% carbon dioxide. Carotid-body immunohistochemistry demonstrated marked hyperplasia of the oxygen-sensing type I cells, and the cells themselves appeared enlarged with more prominent nuclei. This hypertrophy was confirmed by electron microscopy, which also revealed that the type I cells contained an increased number of mitochondria, enlarged dense-cored vesicles, and markedly expanded rough endoplasmic reticulum. The morphological and ultrastructural changes seen in the CP mouse carotid body are strikingly similar to those observed in animals exposed to chronic hypoxia. Our study demonstrates that the HIF pathway plays a major role, not only in regulating both euoxic ventilatory control and the sensitivity of the response to hypoxia, but also in determining the morphology of the carotid body.
Highlights
THE ACUTE HYPOXIC VENTILATORY response (AHVR) describes the rapid increase in ventilation that occurs upon exposure to hypoxia
If the hypoxic stimulus continues for more than several minutes, ventilation decreases toward, but does not reach, prehypoxic levels. This hypoxic ventilatory decline (HVD) cannot be explained by the respiratory alkalosis resulting from the initial, rapid increase in ventilation, since it has been demonstrated under conditions of isocapnia [21]
This study demonstrates that the Chuvash mutation in mice results in features that are characteristic of ventilatory acclimatization to hypoxia, namely, an elevated baseline ventilation and enhanced AHVR
Summary
THE ACUTE HYPOXIC VENTILATORY response (AHVR) describes the rapid increase in ventilation that occurs upon exposure to hypoxia. If the hypoxic stimulus continues for more than several minutes, ventilation decreases toward, but does not reach, prehypoxic levels This hypoxic ventilatory decline (HVD) cannot be explained by the respiratory alkalosis resulting from the initial, rapid increase in ventilation, since it has been demonstrated under conditions of isocapnia [21]. Patients with CP have elevated baseline ventilation (with consequent respiratory alkalosis) and an abnormally high AHVR [40] In other words, they demonstrate the characteristic features of individuals acclimatized to hypoxia. We demonstrate striking morphological and ultrastructural changes within the carotid body that are similar to those observed after exposure to chronic hypoxia These findings together indicate the major role that HIF has to play in the calibration and homeostasis of the respiratory system and in determining the morphology of the carotid body.
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