Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway.
Ventilatory sensitivity to hypoxia increases in response to continued hypoxic exposure as part of acute acclimatisation. Although this process is incompletely understood, insights have been gained through studies of the hypoxia-inducible factor (HIF) hydroxylase system. Genetic studies implicate these pathways widely in the integrated physiology of hypoxia, through effects on developmental or adaptive processes. In keeping with this, mice that are heterozygous for the principal HIF prolyl hydroxylase, PHD2, show enhanced ventilatory sensitivity to hypoxia and carotid body hyperplasia. Here we have sought to understand this process better through comparative analysis of inducible and constitutive inactivation of PHD2 and its principal targets HIF-1α and HIF-2α. We demonstrate that general inducible inactivation of PHD2 in tamoxifen-treated Phd2(f/f);Rosa26(+/CreERT2) mice, like constitutive, heterozygous PHD2 deficiency, enhances hypoxic ventilatory responses (HVRs: 7.2 ± 0.6 vs. 4.4 ± 0.4 ml min(-1) g(-1) in controls, P < 0.01). The ventilatory phenotypes associated with both inducible and constitutive inactivation of PHD2 were strongly compensated for by concomitant inactivation of HIF-2α, but not HIF-1α. Furthermore, inducible inactivation of HIF-2α strikingly impaired ventilatory acclimatisation to chronic hypoxia (HVRs: 4.1 ± 0.5 vs. 8.6 ± 0.5 ml min(-1) g(-1) in controls, P < 0.0001), as well as carotid body cell proliferation (400 ± 81 vs. 2630 ± 390 bromodeoxyuridine-positive cells mm(-2) in controls, P < 0.0001). The findings demonstrate the importance of the PHD2/HIF-2α enzyme-substrate couple in modulating ventilatory sensitivity to hypoxia.
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.
Emma J
EJ
Hodson
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.
Lynn G
LG
Nicholls
Department of Physiology, Anatomy and Genetics, Sherrington Building, South Parks Road, University of Oxford, Oxford, OX1 3PT, UK.
Philip J
PJ
Turner
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.
Ronan
R
Llyr
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.|Ludwig Institute for Cancer Research, Roosevelt Drive, University of Oxford, Oxford, OX3 7DQ, UK.
James W
JW
Fielding
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.
Gillian
G
Douglas
Ludwig Institute for Cancer Research, Roosevelt Drive, University of Oxford, Oxford, OX3 7DQ, UK.
Indrika
I
Ratnayaka
Department of Physiology, Anatomy and Genetics, Sherrington Building, South Parks Road, University of Oxford, Oxford, OX1 3PT, UK.
Peter A
PA
Robbins
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.
Christopher W
CW
Pugh
Department of Physiology, Anatomy and Genetics, Sherrington Building, South Parks Road, University of Oxford, Oxford, OX1 3PT, UK.
Keith J
KJ
Buckler
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.|Ludwig Institute for Cancer Research, Roosevelt Drive, University of Oxford, Oxford, OX3 7DQ, UK.
Peter J
PJ
Ratcliffe
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.
Tammie
T
Bishop
D000818:Animals; D002344:Carotid Body / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012123:Pulmonary Ventilation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C485502:HIF-2 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases