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

Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):821-6. doi: 10.1073/pnas.022634199. Epub 2002 Jan 15.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Afferent Pathways / physiopathology
  • Animals
  • Carotid Body / pathology
  • Carotid Body / physiopathology*
  • Chemoreceptor Cells / physiopathology
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Female
  • Gene Expression
  • Heterozygote
  • Hypoxia / genetics
  • Hypoxia / pathology
  • Hypoxia / physiopathology*
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / deficiency*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Respiratory Physiological Phenomena*
  • Transcription Factors*
  • Vagus Nerve / physiopathology


  • DNA-Binding Proteins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors