Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice
Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice
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DOI：
10.1128/mcb.02041-07
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发表时间：
2008-05-01
影响因子：
5.3
通讯作者：
Ratcliffe, Peter J.
中科院分区：
文献类型：
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作者：
Bishop, Tammie;Gallagher, Denis;Ratcliffe, Peter J.
细胞培养研究表明，氧敏感性缺氧诱导因子（HIF）脯氨酰羟化酶PHD 3参与神经元凋亡的调节。为了更好地了解体内的这种功能，我们创建了PHD 3（-/-）小鼠并分析了神经元表型。从PHD 3（-/-）小鼠培养的上级颈神经节（SCG）神经元中的细胞凋亡减少与SCG以及肾上腺髓质和颈动脉体中的细胞数量增加相关。通过将PHD 3（-/-）小鼠与HIF-1a（+/-）和HIF-2a（+/-）小鼠杂交进行的遗传分析证明了与HIF-2而不是HIF-1 α的相互作用，支持PHD 3-HIF-2 α通路在交感肾上腺发育的调节中的非冗余参与。尽管细胞数量增加，但PHD 3（-/-）小鼠的交感肾上腺系统功能减退，靶组织神经支配、肾上腺髓质分泌能力、交感肾上腺反应和全身血压降低。这些观察结果表明，PHD 3在交感肾上腺发育中的作用超出了细胞存活和器官质量的简单控制，系统的适当解剖和生理完整性需要功能性PHD 3。缺氧、代谢或其他应激对发育和适应性信号传导之间的这种界面的干扰可能对关键的交感肾上腺功能（如血压调节）产生重要影响。
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.