Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology

BACKGROUND: The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. METHODS AND FINDINGS: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. CONCLUSIONS: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF

Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology

Background: The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF)pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. Methods and Findings: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. Conclusions: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF

Systemic Vascular Responses to Mild and Moderate Hypoxia

<div><p>(A and B) Heart rate. Mild hypoxia provoked a rise of 11.7 beats/min in the CP patient group, compared with 3.6 beats/min in normal control participants ( <i>p</i> < 0.05). No other statistically significant differences in systemic vascular responses were detected between these two groups. </p> <p>(C and D) Blood pressure, showing systolic pressure (upper plot) and diastolic pressure (lower plot).</p> <p>(E and F) Cardiac output, assessed non-invasively using Doppler echocardiography.</p> <p>All responses are shown during mild (A, C, and E) and moderate (B, D, and F) hypoxia. Values are mean ± standard error of the mean.</p></div

Aldolase C and <i>VEGF</i> mRNA Expression at Different Oxygen Tensions

<p>Lymphocytes were isolated from venous blood taken from CP patients and normal control participants, and incubated at eight different levels of oxygen tension prior to RNA isolation. Gene expression is shown relative to a standard calibrator sample. Basal gene expression at 20% oxygen was significantly higher in CP patients for both <i>Aldolase C</i> (A) and <i>VEGF</i> (B) ( <i>p</i> < 0.05). Both genes were induced by hypoxia, and at the lowest oxygen tension (0.1%) expression was no longer significantly different for either gene. Values are mean ± standard error of the mean. Asterisks indicate <i>p</i> < 0.05 (unpaired <i>t</i>-test). </p

Sensitivities to Hypoxia for Individual Participants

<p>Results are shown in terms of the number of (normal control group) standard deviations by which each participant's response differed from the mean response of the normal control participants. The patients with CP were significantly different from the normal control group in their ventilatory and pulmonary vascular responses to both mild and moderate hypoxia, and in their heart rate responses to mild hypoxia. BP, blood pressure.</p

End-Tidal Gas Control, Ventilatory, and Pulmonary Vascular Responses to Mild and Moderate Hypoxia

<div><p>(A and B) End-tidal gas control. </p><p>Pet_O₂</p> and Pet_CO₂ were well controlled. <p>Pet_O₂</p> was well matched between all groups. Pet_CO₂ was lower in the CP patient group, reflecting this group's lower baseline air-breathing Pet_CO₂. <p></p> <p>(C and D) Ventilation, given at body temperature and pressure, saturated with water vapour. Mild hypoxia provoked an increase in ventilation of 4.4 l/min in the CP patients versus 1.6 l/min in normal controls ( <i>p</i> < 0.05), while moderate hypoxia induced increases of 24.5 versus 10.0 l/min in these two groups, respectively ( <i>p</i> < 0.05). </p> <p>(E and F) Pulmonary vascular tone. This was assessed using Doppler echocardiography to determine ΔP_max, a standard non-invasive index of pulmonary vascular tone. With mild hypoxia, ΔP_max increased by 11.5 mm Hg in the CP patient group compared with only 1.1 mm Hg in the normal control group ( <i>p</i> < 0.05). Moderate hypoxia stimulated a rise in ΔP_max of 35.3 mm Hg compared with 6.1 mm Hg in these two groups, respectively ( <i>p</i> < 0.001). </p> <p>All responses are shown during mild (A, C, and E) and moderate (B, D, and F) hypoxia. Values are mean ± standard error of the mean.</p></div