ArticleThe Journal of physiology2016
Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway.
Article in The Journal of physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 85 citations in OpenAlex.
- Human hypoxic pulmonary vasoconstriction is unaltered by 8 h of preceding isocapnic hyperoxia.Physiological reports · 2017Trial
- SET1B Drives Sustained HIF Activity and Disease Progression in Clear-Cell Renal Cell Carcinoma.Cancer research · 2026Article
- HIF inhibition: Current strategies and clinical challenges.Redox biology · 2026Review
- The clinical landscape of HIF2α inhibitors in oncology.Nature reviews. Clinical oncology · 2026Review
- Exacerbated ATP transmission in the carotid body is linked to glomus cell expansion in spontaneously hypertensive rats.The Journal of physiology · 2026Article
- Targeting ecto-5'-nucleotidase (CD73) and cAMP alleviates carotid body hyperactivity and reduces blood pressure in chronically hypoxic rats.The Journal of physiology · 2026Article
- Age-dependent remodelling of arterial chemoafferent innervation in hypertension.Cardiovascular research · 2025Article
- Geographic Variation in Epigenetic Responses to Hypoxia in Deer Mice (Peromyscus maniculatus) Distributed Along an Elevational Gradient.Molecular ecology · 2025Article
- Higher oxygen content and transport characterize high-altitude ethnic Tibetan women with the highest lifetime reproductive success.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions.Pflugers Archiv : European journal of physiology · 2024Review
- Hif-2α programs oxygen chemosensitivity in chromaffin cells.The Journal of clinical investigation · 2024Article
- Oncogenic Cell Tagging and Single-Cell Transcriptomics Reveal Cell Type-Specific and Time-Resolved Responses to Vhl Inactivation in the Kidney.Cancer research · 2024Article
- Hypoxic pulmonary vasoconstriction does not limit maximal exercise capacity in healthy volunteers breathing 12% oxygen at sea level.Physiological reports · 2024Article
- Hypoxia Inducible Factor pathway proteins in high-altitude mammals.Trends in biochemical sciences · 2024Review
- Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity.BMJ oncology · 2024Review
- Commonalities and differences in carotid body dysfunction in hypertension and heart failure.The Journal of physiology · 2023Article
- Increased intrapulmonary shunt and alveolar dead space post-COVID-19.Journal of applied physiology (Bethesda, Md. : 1985) · 2023Article
- High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.Molecular biology and evolution · 2023Article
- The Brain at High Altitude: From Molecular Signaling to Cognitive Performance.International journal of molecular sciences · 2023Review
- Intra-carotid body inter-cellular communication.Journal of the Royal Society of New Zealand · 2023Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.