Hif-2α programs oxygen chemosensitivity in chromaffin cells
Maria Prange-Barczynska, … , Thomas P. Keeley, Tammie Bishop
Maria Prange-Barczynska, … , Thomas P. Keeley, Tammie Bishop
Published August 6, 2024
Citation Information: J Clin Invest. 2024;134(18):e174661. https://doi.org/10.1172/JCI174661.
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Hif-2α programs oxygen chemosensitivity in chromaffin cells

Abstract

The study of transcription factors that determine specialized neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electrophysiologically excitable cells that link the oxygen concentration of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by type I cells of the carotid body, and recent work has revealed one isoform of the hypoxia-inducible transcription factor (HIF), HIF-2α, as having a nonredundant role in the development and function of that organ. Here, we show that activation of HIF-2α, including isolated overexpression of HIF-2α but not HIF-1α, is sufficient to induce oxygen chemosensitivity in adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues resembling the fetal organ of Zuckerkandl, which also manifests oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of gene classes that are ordinarily characteristic of the carotid body, including G protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking 2 major oxygen-sensing systems.

Authors

Maria Prange-Barczynska, Holly A. Jones, Yoichiro Sugimoto, Xiaotong Cheng, Joanna D.C.C. Lima, Indrika Ratnayaka, Gillian Douglas, Keith J. Buckler, Peter J. Ratcliffe, Thomas P. Keeley, Tammie Bishop

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Figure 2

Ca2+ imaging showing oxygen chemosensitivity in Phd2KO (Phd2fl/fl;Ai95fl/+;ThCre), but not WT (Ai95fl/+;ThCre), AM from young adult mice.

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Ca2+ imaging showing oxygen chemosensitivity in Phd2KO (Phd2fl/fl;Ai95fl...
(A) Representative image showing GFP fluorescence in an AM slice from a mouse expressing genetically encoded calcium indicator (GCaMP6f), the expression of which is restricted to TH+ cells (Ai95fl/+;ThCre, referred to as WT in Figures 5, 6, and 8) and perfused with 45 mM K+. Red outline shows an example of the K+-responsive region of interest from which fluorescence is quantified. Scale bar: 0.2 mm. (B) Average AUC corresponding to each hypoxic (or sham, 18% O2) stimulus in C. Figures are normalized as percentages of AUC under 45 mM K+ signal. Data are represented as mean ± SEM with individual data points overlaid in this and subsequent figures. Data were analyzed by a mixed-effects 2-way ANOVA, with 18% O2 excluded from analysis: variation due to change in oxygen tension, P < 0.0001; variation due to Phd2 inactivation, P = 0.0004, followed by Šidák’s multiple-comparisons test on pairwise comparisons at each oxygen level. *P < 0.05; **P < 0.01. (C) Representative traces showing fluorescence (F) in the AM (averaged across the K+-responsive region as per red outline in image A), background corrected, and normalized to the fluorescence at the beginning of the recording (F0) to give F/F0; shaded areas highlight the time for which the indicated stimuli are applied: hypoxia (18%–0% O2) or 45 mM K+ (in this and all subsequent figures depicting GCaMP6f recordings).