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

被引：168

作者：

Bishop, Tammie ^{[1
]}

Gallagher, Denis ^{[2
]}

Pascual, Alberto ^{[3
]}

Lygate, Craig A. ^{[1
]}

de Bono, Joseph P. ^{[1
]}

Nicholls, Lynn G. ^{[1
]}

Ortega-Saenz, Patricia ^{[3
]}

Oster, Henrik ^{[1
]}

Wijeyekoon, Bhathiya ^{[1
]}

Sutherland, Andrew I. ^{[1
]}

Grosfeld, Alexandra ^{[1
]}

Aragones, Julian ^{[4
,6
]}

Schneider, Martin ^{[4
,6
]}

van Geyte, Katie ^{[4
,6
]}

Teixeira, Dania ^{[2
]}

Diez-Juan, Antonio ^{[4
,6
]}

Lopez-Barneo, Jose ^{[3
]}

Channon, Keith M. ^{[1
]}

Maxwell, Patrick H. ^{[5
]}

Pugh, Christopher W. ^{[1
]}

Davies, Alun M. ^{[2
]}

Carmeliet, Peter ^{[4
,6
]}

Ratcliffe, Peter J. ^{[1
]}

机构：

[1] Univ Oxford, Henry Wellcome Bldg Mol Physiol, Oxford OX3 7BN, England

[2] Cardiff Univ, Sch Biosci, Cardiff CF10 3US, S Glam, Wales

[3] Univ Seville, Hosp Univ Virgen Rocio, Lab Invest Biomed, Seville, Spain

[4] VIB, Dept Transgene Technol & Gene Therapy, Louvain 3000, Belgium

[5] Univ London Imperial Coll Sci Technol & Med, Renal Lab, London W12 0NN, England

[6] Katholieke Univ Leuven, Ctr Transgene Technol & Gene Therapy, Louvain 3000, Belgium

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2008年 / 28卷 / 10期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

D O I：

10.1128/MCB.02041-07

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 alpha, supporting the nonredundant involvement of a PHD3-HIF-2 alpha 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.

引用

页码：3386 / 3400

页数：15

共 44 条

[1] Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor [J].