Abstract

Key points The carotid body is a peripheral arterial chemoreceptor that regulates ventilation in response to both acute and sustained hypoxia.Type I cells in this organ respond to low oxygen both acutely by depolarization and dense core vesicle secretion and, over the longer term, via cellular proliferation and enhanced ventilatory responses.Using lineage analysis, the present study shows that the Type I cell lineage itself proliferates and expands in response to sustained hypoxia.Inactivation of HIF‐2α in Type I cells impairs the ventilatory, proliferative and cell intrinsic (dense core vesicle) responses to hypoxia.Inactivation of PHD2 in Type I cells induces multilineage hyperplasia and ultrastructural changes in dense core vesicles to form paraganglioma‐like carotid bodies.These changes, similar to those observed in hypoxia, are dependent on HIF‐2α.Taken together, these findings demonstrate a key role for the PHD2–HIF‐2α couple in Type I cells with respect to the oxygen sensing functions of the carotid body. The carotid body is a peripheral chemoreceptor that plays a central role in mammalian oxygen homeostasis. In response to sustained hypoxia, it manifests a rapid cellular proliferation and an associated increase in responsiveness to hypoxia. Understanding the cellular and molecular mechanisms underlying these processes is of interest both to specialized chemoreceptive functions of that organ and, potentially, to the general physiology and pathophysiology of cellular hypoxia. We have combined cell lineage tracing technology and conditionally inactivated alleles in recombinant mice to examine the role of components of the HIF hydroxylase pathway in specific cell types within the carotid body. We show that exposure to sustained hypoxia (10% oxygen) drives rapid expansion of the Type I, tyrosine hydroxylase expressing cell lineage, with little transdifferentiation to (or from) that lineage. Inactivation of a specific HIF isoform, HIF‐2α, in the Type I cells was associated with a greatly reduced proliferation of Type I cells and hypoxic ventilatory responses, with ultrastructural evidence of an abnormality in the action of hypoxia on dense core secretory vesicles. We also show that inactivation of the principal HIF prolyl hydroxylase PHD2 within the Type I cell lineage is sufficient to cause multilineage expansion of the carotid body, with characteristics resembling paragangliomas. These morphological changes were dependent on the integrity of HIF‐2α. These findings implicate specific components of the HIF hydroxylase pathway (PHD2 and HIF‐2α) within Type I cells of the carotid body with respect to the oxygen sensing and adaptive functions of that organ.

Highlights

  • Acclimatization is an important physiological response to low oxygen levels and the ventilatory component of this response is mediated by the carotid body (CB), a peripheral chemoreceptor (Bisgard, 2000; Robbins, 2007; Kumar & Prabhakar, 2012; Lopez-Barneo et al 2016)

  • Inducible Cre recombinase transgenes were selected to permit timed cell-specific expression following exposure to tamoxifen: a tyrosine hydroxylase (TH) promoter transgene (THCreER) whose expression is restricted within the CB to Type I cells (Rotolo et al 2008; Macias et al 2014) and a glial fibrillary acidic protein (GFAP) promoted transgene (GFAPCreER) whose expression is restricted to glia-like support cells (Hirrlinger et al 2006), such as the Type II cells of the CB (Kameda, 2005)

  • Because the TH gene has been reported to be induced by hypoxia (Czyzyk-Krzeska et al 1992), we examined the effect of the 28 day hypoxic exposure on tdTomatof/+;THCreER animals that had not received tamoxifen (Fig. 1A, far left)

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Summary

Introduction

Acclimatization is an important physiological response to low oxygen levels and the ventilatory component of this response is mediated by the carotid body (CB), a peripheral chemoreceptor (Bisgard, 2000; Robbins, 2007; Kumar & Prabhakar, 2012; Lopez-Barneo et al 2016). Previous work has implicated the HIF system in the modulation of CB function (Kline et al 2002; Peng et al 2011; Bishop et al 2013). HIF is regulated by a series of 2-oxoglutarate-dependent dioxygenases that generate an oxygen-dependent signal by the catalysis of hydroxylation on specific prolyl residues in HIFα subunits (Bishop & Ratcliffe, 2014). Mammalian cells express three closely related HIF prolyl hydroxylases: PHD1, 2 and 3, of which PHD2 is the most abundant and important regulator in most cells. We have observed that general inactivation of HIF-2α, but not HIF-1α, ablates the proliferation that occurs within days of exposure to hypoxia in adult mice (Hodson et al 2016)

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