ArticleThe Journal of physiology2013
Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2.
Article in The Journal of physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 67 citations in OpenAlex.
- Elevation of iron storage in humans attenuates the pulmonary vascular response to hypoxia.Journal of applied physiology (Bethesda, Md. : 1985) · 2016Trial
- HIF inhibition: Current strategies and clinical challenges.Redox biology · 2026Review
- 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
- 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
- Sex andJournal of neurophysiology · 2024Article
- Alveolar hypoxia induces organ-specific inflammasome-related inflammation in male mouse lungs.Physiological reports · 2024Article
- Hypoxic Signaling Pathways in Carotid Body Tumors.Cancers · 2024Review
- Hypoxia Inducible Factor pathway proteins in high-altitude mammals.Trends in biochemical sciences · 2024Review
- Commonalities and differences in carotid body dysfunction in hypertension and heart failure.The Journal of physiology · 2023Article
- Intra-carotid body inter-cellular communication.Journal of the Royal Society of New Zealand · 2023Review
- Isoform-specific Roles of Prolyl Hydroxylases in the Regulation of Pancreatic β-Cell Function.Endocrinology · 2022Article
- Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma.Endocrine-related cancer · 2021Article
- Oxygen-dependent regulation of ion channels: acute responses, post-translational modification, and response to chronic hypoxia.Pflugers Archiv : European journal of physiology · 2021Review
- High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology.Molecular biology and evolution · 2021Review
- Perinatal Hypoxemia and Oxygen Sensing.Comprehensive Physiology · 2021Article
- Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- TibetanProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control.The Journal of clinical investigation · 2020Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
Oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor (HIF) by a set of closely related prolyl hydroxylase domain enzymes (PHD1, 2 and 3) regulates a range of transcriptional responses to hypoxia. This raises important questions about the role of these oxygen-sensing enzymes in integrative physiology. We investigated the effect of both genetic deficiency and pharmacological inhibition on the change in ventilation in response to acute hypoxic stimulation in mice. Mice exposed to chronic hypoxia for 7 days manifest an exaggerated hypoxic ventilatory response (HVR) (10.8 ± 0.3 versus 4.1 ± 0.7 ml min(-1) g(-1) in controls; P < 0.01). HVR was similarly exaggerated in PHD2(+/-) animals compared to littermate controls (8.4 ± 0.7 versus 5.0 ± 0.8 ml min(-1) g(-1); P < 0.01). Carotid body volume increased (0.0025 ± 0.00017 in PHD2(+/-) animals versus 0.0015 ± 0.00019 mm(3) in controls; P < 0.01). In contrast, HVR in PHD1(-/-) and PHD3(-/-) mice was similar to littermate controls. Acute exposure to a small molecule PHD inhibitor (PHI) (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid) did not mimic the ventilatory response to hypoxia. Further, 7 day administration of the PHI induced only modest increases in HVR and carotid body cell proliferation, despite marked stimulation of erythropoiesis. This was in contrast with chronic hypoxia, which elicited both exaggerated HVR and cellular proliferation. The findings demonstrate that PHD enzymes modulate ventilatory sensitivity to hypoxia and identify PHD2 as the most important enzyme in this response. They also reveal differences between genetic inactivation of PHDs, responses to hypoxia and responses to a pharmacological inhibitor, demonstrating the need for caution in predicting the effects of therapeutic modulation of the HIF hydroxylase system on different physiological responses.
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