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

Abstract

To investigate whether the transcriptional activator hypoxiainducible 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␣ subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a ϩ/Ϫ 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 ϩ/Ϫ mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a ϩ/Ϫ 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 ϩ/Ϫ mice. Thus partial HIF-1␣ deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.O xygen homeostasis is mediated by the combined physiologic functioning of the circulatory and respiratory systems. Recent studies have demonstrated that the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for both the establishment of the circulatory system during embryonic development and physiologic responses in postnatal life. Analysis of Hif1a Ϫ/Ϫ knockout mice, which are homozygous for a lossof-function mutation in the Hif1a gene encoding the O 2 -regulated HIF-1␣ subunit, revealed that complete HIF-1␣ deficiency results in embryonic lethality at midgestation with major malformations of the heart and vasculature (1-3). Hif1a ϩ/Ϫ heterozygous mice, which are partially HIF-1␣ deficient, develop normally and are indistinguishable from their wild-type littermates under normoxic conditions. However, adult Hif1a ϩ/Ϫ mice manifest impaired physiological responses to chronic hypoxia including significantly reduced rates of erythropoiesis and pulmonary vascular remodeling (4). Thus HIF-1␣ plays essential roles in cardiac, erythroid, and vascular development and physiology, i.e., all three major components of the circulatory system.An essential adaptation to both acute and chronic hypoxia is an increase in ventilation that depends on the activity of peripheral chemoreceptors, particularly those within the carotid body, which detect changes in arterial blood O 2 concentration and relay sensory information to the brainstem neurons that regulate breathing (reviewed in ref. 5). Altered ventilatory responses to hypoxia may play a critical role in asthma, diabetes, Parkinson's disease, sleep-related breathing disorders, and sudden infant death syndrome (6-8). We hypothesized that HIF-1␣ is required for carotid body function and ventilatory adaptation to chronic hypoxia. To test this hyp...

H 2 S mediates O 2 sensing in the carotid body

“…CSE immunoreactivity was seen in glomus cells of carotid bodies from CSE +/+ mice as evidenced by colocalization with tyrosine hydroxylase (TH), an established marker of glomus cells (11,12). CSE expression was absent in carotid bodies from CSE −/− mice (Fig.…”

“…3 and 11. For assessing CSE immunoreactivity, sections (8 μm thick) were incubated at room temperature for 2 h with polyclonal rabbit anti-CSE antibody (1:400), this antibody was raised using bacterially purified full-length His-tagged CSE as antigen, and monoclonal mouse anti-tyrosine hydroxylase (1:2,000; Sigma), an established marker of glomus and chromaffin cells (11,12), followed by Texas red-conjugated goat anti-rabbit IgG and FITC-conjugated goat anti-mouse IgG (1:250; Molecular Probes) in PBS with 1% normal goat serum and 0.2% Triton X-100. After washing with PBS, sections were mounted in DAPI-containing media and visualized using a fluorescent microscope (Eclipse E600; Nikon).…”

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

“…The HIF1a/ARNT dimer activates transcription through the hypoxia response element (HRE: TACGTG) in the promoter or enhancer region of target genes that include vascular endothelial growth factor (VEGF), erythropoietin and phosphoglycerate kinase (PGK). In mammals, HIF1 is required for the establishment and utilization of the placenta, cartilage, erythroid, vascular, cardiac and respiratory systems (Maltepe et al, 1997;Iyer et al, 1998;Ryan et al, 1998;Kotch et al, 1999;Kline et al, 2002;Kojima et al, 2002;Ramirez-Bergeron et al, 2004). In keeping with this fundamental role in normal development, HIF1 activity has also been associated with human diseases.…”

Gas biology: small molecular medicine

“…Glomus cells within the carotid body sense the arterial O 2 concentration and transduce neural signals to the brain centers that control respiration and blood pressure in order to increase tissue oxygenation. Remarkably, carotid bodies from mice that are heterozygous for a knockout allele at the locus encoding HIF-1α do not respond to hypoxia [15], whereas carotid bodies from mice that are heterozygous for a knockout allele at the locus encoding HIF-2α show exaggerated responses to hypoxia [16], providing evidence that the homeostatic responses mediated by the carotid body are dependent upon a balance between HIF-1 and HIF-2. Glomus cells express CSE and carotid bodies from mice lacking CSE also do not respond to hypoxia [17], whereas NOS1-deficient mice exhibit exaggerated ventilatory responses to hypoxia [18].…”