Journal
EMBO MOLECULAR MEDICINE
Volume 6, Issue 12, Pages 1577-1592Publisher
WILEY-BLACKWELL
DOI: 10.15252/emmm.201404153
Keywords
adult carotid body neurogenesis; intolerance to hypoxia; sympathoadrenal tumorigenesis; Vhl-deficient mouse model; von Hippel-Lindau protein
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Funding
- Botin Foundation
- Spanish Ministry of Science and Innovation (SAF program)
- Spanish Ministry of Science and Innovation (FPI program)
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Mutations of the von Hippel-Lindau (VHL) gene are associated with pheochromocytomas and paragangliomas, but the role of VHL in sympathoadrenal homeostasis is unknown. We generated mice lacking Vhl in catecholaminergic cells. They exhibited atrophy of the carotid body (CB), adrenal medulla, and sympathetic ganglia. Vhl-null animals had an increased number of adult CB stem cells, although the survival of newly generated neuron-like glomus cells was severely compromised. The effects of Vhl deficiency were neither prevented by pharmacological inhibition of prolyl hydroxylases or selective genetic down-regulation of prolyl hydroxylase-3, nor phenocopied by hypoxia inducible factor overexpression. Vhl-deficient animals appeared normal in normoxia but survived for only a few days in hypoxia, presenting with pronounced erythrocytosis, pulmonary edema, and right cardiac hypertrophy. Therefore, in the normal sympathoadrenal setting, Vhl deletion does not give rise to tumors but impairs development and plasticity of the peripheral O-2-sensing system required for survival in hypoxic conditions.
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