PHD2 inactivation in Type I cells drives HIF-2α dependent multi-lineage hyperplasia and the formation of paraganglioma-like carotid bodies
The carotid body is a peripheral chemoreceptor that plays a central role in mammalian oxygen homeostasis. In response to sustained hypoxia, it manifests rapid cellular proliferation and an associated increase in responsiveness to hypoxia. Understanding the cellular and molecular mechanisms underlyin...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
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Physiological Society
2018
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| _version_ | 1797053074887409664 |
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| author | Fielding, J Hodson, E Cheng, X Ferguson, D Eckardt, L Adam, J Lip, P Maton-Howarth, M Ratnayak, I Pugh, C Buckle, K Ratcliff, P Bishop, T |
| author_facet | Fielding, J Hodson, E Cheng, X Ferguson, D Eckardt, L Adam, J Lip, P Maton-Howarth, M Ratnayak, I Pugh, C Buckle, K Ratcliff, P Bishop, T |
| author_sort | Fielding, J |
| collection | OXFORD |
| description | The carotid body is a peripheral chemoreceptor that plays a central role in mammalian oxygen homeostasis. In response to sustained hypoxia, it manifests rapid cellular proliferation and an associated increase in responsiveness to hypoxia. Understanding the cellular and molecular mechanisms underlying these processes is of interest both to specialised chemoreceptive functions of that organ and potentially to the general physiology and pathophysiology of cellular hypoxia. We have combined cell lineage tracing technology and conditionally inactivated alleles in recombinant mice to examine the role of components of the HIF hydroxylase pathway in specific cell types within the carotid body. We show that exposure to sustained hypoxia (10 % oxygen) drives rapid expansion of the Type I, tyrosine hydroxylase expressing cell lineage, with little transdifferentiation to or from that lineage. Inactivation of a specific HIF isoform, HIF-2α, in the Type I cells was associated with greatly reduced proliferation of Type I cells and hypoxic ventilatory responses, with ultrastructural evidence of an abnormality in the action of hypoxia on dense core secretory vesicles. We also show that inactivation of the principal HIF prolyl hydroxylase PHD2 within the Type I cell lineage is sufficient to cause multi-lineage expansion of the carotid body, with characteristics resembling paragangliomas. These morphological changes were dependent on the integrity of HIF-2α. These findings implicate specific components of the HIF hydroxylase pathway (PHD2 and HIF-2α) within Type I cells of the carotid body in the oxygen sensing and adaptive functions of that organ. This article is protected by copyright. All rights reserved. |
| first_indexed | 2024-03-06T18:38:57Z |
| format | Journal article |
| id | oxford-uuid:0c3cc40e-ff24-482d-8e19-756dcd8f9cb7 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T18:38:57Z |
| publishDate | 2018 |
| publisher | Physiological Society |
| record_format | dspace |
| spelling | oxford-uuid:0c3cc40e-ff24-482d-8e19-756dcd8f9cb72022-03-26T09:33:51ZPHD2 inactivation in Type I cells drives HIF-2α dependent multi-lineage hyperplasia and the formation of paraganglioma-like carotid bodiesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0c3cc40e-ff24-482d-8e19-756dcd8f9cb7Symplectic Elements at OxfordPhysiological Society2018Fielding, JHodson, ECheng, XFerguson, DEckardt, LAdam, JLip, PMaton-Howarth, MRatnayak, IPugh, CBuckle, KRatcliff, PBishop, TThe carotid body is a peripheral chemoreceptor that plays a central role in mammalian oxygen homeostasis. In response to sustained hypoxia, it manifests rapid cellular proliferation and an associated increase in responsiveness to hypoxia. Understanding the cellular and molecular mechanisms underlying these processes is of interest both to specialised chemoreceptive functions of that organ and potentially to the general physiology and pathophysiology of cellular hypoxia. We have combined cell lineage tracing technology and conditionally inactivated alleles in recombinant mice to examine the role of components of the HIF hydroxylase pathway in specific cell types within the carotid body. We show that exposure to sustained hypoxia (10 % oxygen) drives rapid expansion of the Type I, tyrosine hydroxylase expressing cell lineage, with little transdifferentiation to or from that lineage. Inactivation of a specific HIF isoform, HIF-2α, in the Type I cells was associated with greatly reduced proliferation of Type I cells and hypoxic ventilatory responses, with ultrastructural evidence of an abnormality in the action of hypoxia on dense core secretory vesicles. We also show that inactivation of the principal HIF prolyl hydroxylase PHD2 within the Type I cell lineage is sufficient to cause multi-lineage expansion of the carotid body, with characteristics resembling paragangliomas. These morphological changes were dependent on the integrity of HIF-2α. These findings implicate specific components of the HIF hydroxylase pathway (PHD2 and HIF-2α) within Type I cells of the carotid body in the oxygen sensing and adaptive functions of that organ. This article is protected by copyright. All rights reserved. |
| spellingShingle | Fielding, J Hodson, E Cheng, X Ferguson, D Eckardt, L Adam, J Lip, P Maton-Howarth, M Ratnayak, I Pugh, C Buckle, K Ratcliff, P Bishop, T PHD2 inactivation in Type I cells drives HIF-2α dependent multi-lineage hyperplasia and the formation of paraganglioma-like carotid bodies |
| title | PHD2 inactivation in Type I cells drives HIF-2α dependent multi-lineage hyperplasia and the formation of paraganglioma-like carotid bodies |
| title_full | PHD2 inactivation in Type I cells drives HIF-2α dependent multi-lineage hyperplasia and the formation of paraganglioma-like carotid bodies |
| title_fullStr | PHD2 inactivation in Type I cells drives HIF-2α dependent multi-lineage hyperplasia and the formation of paraganglioma-like carotid bodies |
| title_full_unstemmed | PHD2 inactivation in Type I cells drives HIF-2α dependent multi-lineage hyperplasia and the formation of paraganglioma-like carotid bodies |
| title_short | PHD2 inactivation in Type I cells drives HIF-2α dependent multi-lineage hyperplasia and the formation of paraganglioma-like carotid bodies |
| title_sort | phd2 inactivation in type i cells drives hif 2α dependent multi lineage hyperplasia and the formation of paraganglioma like carotid bodies |
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