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PMID: 18332118 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice.

Molecular and cellular biology ·Vol. 28 ·No. 10 ·2008-05-00 ·Pages 3386-400

Bishop T, Gallagher D, Pascual A, Lygate CA, de Bono JP, Nicholls LG, Ortega-Saenz P, Oster H, Wijeyekoon B, Sutherland AI, Grosfeld A, Aragones J, Schneider M, van Geyte K, Teixeira D, Diez-Juan A, Lopez-Barneo J, Channon KM, Maxwell PH, Pugh CW, Davies AM, Carmeliet P, Ratcliffe PJ

Abstract

Cell culture studies have implicated the oxygen-sensitive hypoxia-inducible factor (HIF) prolyl hydroxylase PHD3 in the regulation of neuronal apoptosis. To better understand this function in vivo, we have created PHD3(-/-) mice and analyzed the neuronal phenotype. Reduced apoptosis in superior cervical ganglion (SCG) neurons cultured from PHD3(-/-) mice is associated with an increase in the number of cells in the SCG, as well as in the adrenal medulla and carotid body. Genetic analysis by intercrossing PHD3(-/-) mice with HIF-1a(+/-) and HIF-2a(+/-) mice demonstrated an interaction with HIF-2alpha but not HIF-1alpha, supporting the nonredundant involvement of a PHD3-HIF-2alpha pathway in the regulation of sympathoadrenal development. Despite the increased number of cells, the sympathoadrenal system appeared hypofunctional in PHD3(-/-) mice, with reduced target tissue innervation, adrenal medullary secretory capacity, sympathoadrenal responses, and systemic blood pressure. These observations suggest that the role of PHD3 in sympathoadrenal development extends beyond simple control of cell survival and organ mass, with functional PHD3 being required for proper anatomical and physiological integrity of the system. Perturbation of this interface between developmental and adaptive signaling by hypoxic, metabolic, or other stresses could have important effects on key sympathoadrenal functions, such as blood pressure regulation.

MeSH Terms
Adaptation, Physiological Adrenal Glands/abnormalities,pathology,physiopathology Animals Apoptosis Base Sequence Basic Helix-Loop-Helix Transcription Factors/deficiency,genetics,physiology DNA Primers/genetics Female Gene Targeting Hypotension/etiology,genetics,pathology,physiopathology Hypoxia-Inducible Factor 1, alpha Subunit/deficiency,genetics,physiology Male Mice Mice, Knockout Pregnancy Procollagen-Proline Dioxygenase/deficiency,genetics,physiology Superior Cervical Ganglion/abnormalities,pathology,physiopathology Sympathetic Nervous System/abnormalities,pathology,physiopathology
Chemicals
Basic Helix-Loop-Helix Transcription Factors DNA Primers Hif1a protein, mouse Hypoxia-Inducible Factor 1, alpha Subunit endothelial PAS domain-containing protein 1 PHD3 protein, mouse Procollagen-Proline Dioxygenase
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Bishop Tammie
The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington Campus, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
Gallagher Denis
Pascual Alberto
Lygate Craig A
de Bono Joseph P
Nicholls Lynn G
Ortega-Saenz Patricia
Oster Henrik
Wijeyekoon Bhathiya
Sutherland Andrew I
Grosfeld Alexandra
Aragones Julian
Schneider Martin
van Geyte Katie
Teixeira Dania
Diez-Juan Antonio
Lopez-Barneo Jose
Channon Keith M
Maxwell Patrick H
Pugh Christopher W
Davies Alun M
Carmeliet Peter
Ratcliffe Peter J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.02041-07
Published
2008-05-00
Epub
2008-00-10
Pages
3386-400
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2423159
Subset
IM
Grants
Wellcome Trust · 071251 · United Kingdom
Medical Research Council · G0200482 · United Kingdom
British Heart Foundation · United Kingdom
External Links
PubMed source DOI: 10.1128/MCB.02041-07 PMC Full Text View journal details
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