The von Hippel-Lindau Chuvash mutation in mice causes carotid-body hyperplasia and enhanced ventilatory sensitivity to hypoxia

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.

The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism

“…Polycythemia in the CP mice was confirmed by demonstrating a modest increase in both hemoglobin and hematocrit, consistent with previous reports (18, 19, 64). No differences were seen in nonfasting plasma metabolites.…”

“…Studies on patients and mice have demonstrated that perturbations in the HIF pathway, such as CP or HIF-2α gain-of-function mutations, result in profound abnormalities in systemic and cellular processes that are usually under tight control. Marked changes in skeletal muscle metabolism, ventilation, pulmonary vascular tone, and glucose homeostasis are all observed in both humans and animals with disorders of the HIF pathway (2, 13–16, 18, 19, 37, 39, 46, 48, 50–53, 57, 64–66, 68, 69). We now demonstrate that chronic modest upregulation of HIF due to the Chuvash VHL mutation results in altered cardiac metabolism and energetics in the mouse heart.…”

“…Patients with CP develop polycythemia, pulmonary hypertension, increased ventilatory and pulmonary vascular sensitivity to hypoxia, and altered skeletal muscle metabolism and energetics (14, 65) although any effects on cardiac function remain unidentified. Many aspects of the human disease have been shown to be faithfully recapitulated in the mouse model (18, 19, 39, 64). …”

Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF‐2 pathway

“…; Slingo et al . ), and based on published data which show that adding 3% carbon dioxide prevents a major rise in arterial pH or fall in when mice are exposed to 7% oxygen (Ishiguro et al . ), exhibited a more sustained HVR (Fig.…”

Impact of sleep disordered breathing on carotid body size

“…While our understanding of the precise mechanisms that initiate and control cellular hypertrophy and hyperplasia in the carotid body are limited, previous work in animal models has implicated important roles for cAMP (Nurse, 1995). More recent work has highlighted the hypoxia-inducible factor pathway (Slingo et al, 2014) and an O 2 -sensitive glomus cell-stem cell synapse (Platero-Luengo et al, 2014) as potential contributors. Whether such mechanisms can be isolated to one or both carotid bodies has yet to be examined.…”