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Abnormal Sympathoadrenal Development and Systemic Hypotension in PHD3^–/– Mice

Tammie Bishop,^1, Denis Gallagher,^2, Alberto Pascual,³ Craig A. Lygate,⁴ Joseph P. de Bono,⁴ Lynn G. Nicholls,¹ Patricia Ortega-Saenz,³ Henrik Oster,⁴ Bhathiya Wijeyekoon,¹ Andrew I. Sutherland,¹ Alexandra Grosfeld,¹ Julian Aragones,^5,6 Martin Schneider,^5,6 Katie van Geyte,^5,6 Dania Teixeira,² Antonio Diez-Juan,^5,6 Jose Lopez-Barneo,³ Keith M. Channon,⁴ Patrick H. Maxwell,⁷ Christopher W. Pugh,¹ Alun M. Davies,² Peter Carmeliet,^5,6 and Peter J. Ratcliffe^1*

The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington Campus, Roosevelt Drive, Oxford OX3 7BN, United Kingdom,¹ School of Biosciences, Cardiff University, Museum Avenue, P.O. Box 911, Cardiff CF10 3US, United Kingdom,² Laboratorio de Investigaciones Biomédicas, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, Spain,³ The Henry Wellcome Building for Genomic Medicine, University of Oxford, Headington Campus, Roosevelt Drive, Oxford OX3 7BN, United Kingdom,⁴ Department for Transgene Technology and Gene Therapy, VIB, 3000 Leuven, Belgium,⁵ The Center for Transgene Technology and Gene Therapy, K. U. Leuven, 3000 Leuven, Belgium,⁶ Renal Laboratory, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom⁷

Received 13 November 2007/ Returned for modification 19 December 2007/ Accepted 25 February 2008

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-2 but not HIF-1, supporting the nonredundant involvement of a PHD3-HIF-2 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.

Published ahead of print on 10 March 2008.

T.B. and D.G. contributed equally to this work.