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Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha.


ABSTRACT: To investigate whether the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O(2)-regulated HIF-1 alpha subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a(+/-) mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wild-type mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded, whereas carotid bodies from Hif1a(+/-) mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a(+/-) mice. Wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a(+/-) mice. Thus partial HIF-1 alpha deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.

SUBMITTER: Kline DD 

PROVIDER: S-EPMC117389 | biostudies-literature | 2002 Jan

REPOSITORIES: biostudies-literature

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Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha.

Kline David D DD   Peng Ying-Jie YJ   Manalo Dominador J DJ   Semenza Gregg L GL   Prabhakar Nanduri R NR  

Proceedings of the National Academy of Sciences of the United States of America 20020115 2


To investigate whether the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O(2)-regulated HIF-1 alpha subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a(+/-) mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body ch  ...[more]