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

David D. Kline, Ying Jie Peng, Dominador J. Manalo, Gregg L. Semenza, Nanduri R. Prabhakar

Research output: Contribution to journalArticlepeer-review

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 O2-regulated HIF-1α subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a+1- 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+1- mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a+1- 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+1- mice. Thus partial HIF-1 α deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.

Original languageEnglish (US)
Pages (from-to)821-826
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number2
DOIs
StatePublished - Jan 22 2002

ASJC Scopus subject areas

  • General

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