Deletion of the von Hippel–Lindau gene causes sympathoadrenal cell death and impairs chemoreceptor‐mediated adaptation to hypoxia

Abstract

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. image Instead of tumorigenesis, Vhl inactivation in rodent catecholaminergic cells in vivo causes atrophy of the adrenal medulla, carotid body ( CB ) and sympathetic ganglia. Hypoxia‐induced adult CB neurogenesis is inhibited and Vhl‐ KO mice cannot acclimatize to hypoxia. Contrary to generally held beliefs Vhl is not a tumor suppressor gene in all cells. Vhl‐deficiency in mouse sympathoadrenal cells does not result in the appearance of tumors. Pheochromocytomas in man could be associated with gain‐of‐function mutations in VHL. Animals lacking Vhl exhibit atrophy of the CB and adrenal medulla and present a striking intolerance to systemic hypoxia that could give rise to death.