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. Author manuscript; available in PMC: 2017 Jan 1.
Published in final edited form as: Pflugers Arch. 2015 Aug 13;468(1):71–75. doi: 10.1007/s00424-015-1719-z

Regulation of Carotid Body Oxygen Sensing by Hypoxia-Inducible Factors

Nanduri R Prabhakar 1, Gregg L Semenza 2
PMCID: PMC4548826  NIHMSID: NIHMS715081  PMID: 26265380

Abstract

Oxygen (O2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Carotid body responses to hypoxia are not uniform but instead exhibit remarkable inter-individual variations. The molecular mechanisms underlying variations in carotid body O2 sensing are not known. Hypoxia-inducible factor-1 (HIF-1) and HIF-2 mediate transcriptional responses to hypoxia. This article reviews the emerging evidence that proper expression of the HIF-α isoforms is a key molecular determinant for carotid body O2 sensing. HIF-1α deficiency leads to a blunted carotid body hypoxic response, which is due to increased abundance of HIF-2α, elevated anti-oxidant enzyme activity, and a reduced intracellular redox state. Conversely, HIF-2α deficiency results in augmented carotid body sensitivity to hypoxia, which is due to increased abundance of HIF-1α, elevated pro-oxidant enzyme activity, and an oxidized intracellular redox state. Double heterozygous mice with equally reduced HIF-1α and HIF-2α showed no abnormality in redox state or carotid body O2 sensing. Thus, mutual antagonism between HIF-α isoforms determines the redox state and thereby establishes the set point for hypoxic sensing by the carotid body.

Keywords: sleep apnea, NADPH oxidase 2, superoxide dismutase 2, hypertension, sympathetic nerve activity

Carotid bodies are sensory organs for detecting reduced arterial blood O2 levels and the ensuing chemosensory reflex maintains cardio-respiratory homeostasis during hypoxemia [10]. However, the carotid body response to hypoxia is not uniform, but instead exhibits remarkable variation among different strains of rodents [20]. Consequently, the chemosensory reflex exhibits inter-individual variation, which has important physiological consequences [35]. Diminished hypoxic sensing results in poor adaptation to low O2 environments and high-altitude pulmonary edema, whereas heightened carotid body sensitivity to hypoxia leads to increased sympathetic nerve activation and hypertension [20]. Despite the physiological significance, molecular mechanisms underlying the inherent variation in carotid body O2 sensing are not known.

The hypoxia-inducible factor (HIF) family of transcriptional activators is critical for maintaining homeostasis under hypoxic conditions [31]. HIF-1 and HIF-2, which are the two best studied members of the HIF family, are heterodimers comprised of an O2-regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit. While HIF-1α is expressed in all cells of all metazoan species, HIF-2α is only expressed in certain cell types of vertebrate species [23]. In this article, we will summarize the emerging evidence demonstrating that proper expression of the HIF-α isoforms is a key molecular determinant for carotid body O2 sensing, discuss the underlying cellular mechanisms, and consider the physiological relevance of these findings.

HIF-α isoform expression in the carotid body

The carotid body is comprised of two major cell types, including the Type 1 or glomus cells, which are of neuronal phenotype, and the glia-like Type II or sustentacular cells. Type I cells are the primary site of O2 sensing and they work in concert with the nearby afferent nerve ending as a sensory unit [10]. Both Type I and Type II cells express HIF-1α [27], whereas HIF-2α expression is restricted to Type I cells [27, 34].

HIF-1α deficiency impairs carotid body O2 sensing

Complete deficiency of HIF-1α leads to embryonic lethality, whereas mice with partial deficiency of HIF-1α develop normally [6, 9]. The importance of HIF-1α was assessed in mice with partial deficiency of HIF-1α (Hif1a+/−). The carotid body response to hypoxia was impaired in Hif1a+/− mice, whereas chemoreceptor activation evoked either by cyanide or by CO2 was unaltered [8,16,37]. Analysis of carotid body histology revealed no significant difference between Hif1a+/− mice and wild-type littermates with respect to the number of Type I cells, mean Type I cell volume, or the ratio of Type I cell volume to total volume [8]. Digoxin is a potent inhibitor of HIF-1α protein expression [39]. Wild-type mice treated with digoxin showed selective impairment of the carotid body response to hypoxia, similar to that observed in Hif1a+/− mice [37].

The defective carotid body O2 sensing caused by HIF-1α deficiency has important consequences for cardio-respiratory homeostasis. Chronic hypoxia induces carotid body-dependent ventilatory adaptation that is manifested by an augmented response to subsequent acute hypoxia [10]. Hif1a+/− mice, as well as wild-type littermates treated with digoxin, showed severely impaired ventilatory adaptation to chronic hypoxia and reduced sympathetic activation, which was manifested by low plasma norepinephrine levels [8, 37]. These findings demonstrate that HIF-1α deficiency resulting either from genetic or pharmacological intervention leads to selective impairment of carotid body O2 sensing and disrupted cardio-respiratory homeostasis.

HIF-2α deficiency augments carotid body response to hypoxia

HIF-2α, also known as endothelial PAS domain protein-1 (EPAS-1), shares 48% amino acid sequence identity with HIF-1α [33]. Similar to HIF-1α, continuous hypoxia leads to HIF-2α accumulation and subsequent dimerization with HIF-1β. Transcriptional activation by HIF-2 regulates some target genes in common with HIF-1 as well as other genes that are uniquely regulated by HIF-2 [3, 5, 29]. Despite the similarities between HIF-1α and HIF-2α, Hif2a+/− mice exhibit a remarkable increase in carotid body sensitivity to hypoxia [19,37]. The heightened carotid body response to hypoxia was associated with increased sympathetic nerve activation as evidenced by elevated plasma norepinephrine levels, hypertension and irregular breathing with increased number of spontaneous apneas (transient cessation of breathing) [19, 37]. Similar to Hif2a+/− mice, wild type mice treated with 2-methoxyestradiol (2ME2), an inhibitor of HIF-2α protein expression, increased carotid body sensitivity to hypoxia and cardio-respiratory abnormalities, including increased plasma catecholamines, hypertension and irregular breathing [37]. These observations suggest that despite being an orthologue of HIF-1α, HIF-2α deficiency results in the opposite physiological effect of HIF-1α deficiency, with augmented rather than impaired carotid body responses to hypoxia.

Reciprocal regulation of HIF-α isoforms in Hif1a+/− and Hif2a+/− mice

Hif1α+/− mice and digoxin-treated wild-type mice showed increased abundance of HIF-2α protein in Type I cells. The elevated HIF-2α protein accumulation was due to decreased degradation of HIF-2α protein by calpain proteases, with no change in HIF-2α mRNA levels [37]. 2ME2 treatment normalized HIF-2α protein levels in the carotid bodies of Hif1α+/− mice and restored the carotid body hypoxic sensitivity as well as the ventilatory adaptation to chronic hypoxia.

In contrast, Hif2a+/− mice and 2ME2-treated wild-type mice showed increased abundance of HIF-1α protein in Type I cells, which was due to increased protein synthesis involving mammalian target of rapamycin (mTOR) and increased protein stability resulting from inhibition of prolyl hydroxylases [37]. Digoxin treatment normalized HIF-1α protein levels, carotid body hypoxic sensing, plasma catecholamine levels, blood pressure, and breathing patterns. These findings establish that partial deficiency of HIF-1α leads to increased HIF-2α levels and reduced carotid body responses to hypoxia; whereas partial deficiency of HIF-2α results in increased HIF-1α levels and augmented carotid body sensitivity to hypoxia.

On the other hand, Hif1a+/−;Hif-2a+/− double heterozygous mice, which exhibited equally reduced levels of HIF-1α and HIF-2α, showed carotid body responses to hypoxia, blood pressure, plasma catecholamine levels, and ventilatory adaptation to chronic hypoxia that were indistinguishable from wild-type mice [37], suggesting that imbalanced levels of HIF-1α and HIF-2α, rather than absolute reductions in HIF-α isoform levels, lead to alterations in carotid body O2 sensing with profound impact on cardio-respiratory homeostasis.

HIF-α isoforms affect carotid body O2 sensing through redox regulation

Recent studies demonstrated that HIF-1 and HIF-2 regulate gene products with opposing effects on the cellular redox state. While HIF-1 regulates expression of genes encoding pro-oxidant enzymes, such as NADPH oxidase 2 (Nox2) [2, 36], HIF-2 is a potent activator of genes encoding anti-oxidant enzymes including superoxide dismutase 1 (Sod1), Sod2, and catalase [12, 29].

The blunted hypoxic sensitivity of the carotid bodies in Hif1a+/− mice was associated with decreased pro-oxidant capacity as evidenced by low abundance of Nox2 mRNA and enzyme activity, and high abundance of Sod2 mRNA and enzyme activity. As a result, the carotid bodies in Hif1a+/− mice exhibited a reduced cellular redox state. Normalizing HIF-2α levels by 2ME2 administration decreased Sod2 mRNA and enzyme activity and corrected the redox state [37]. In contrast, the augmented carotid body hypoxic sensitivity in Hif2a+/− mice was associated with an oxidized redox state, decreased Sod2 mRNA and enzyme activity, and increased Nox2 mRNA and pro-oxidant enzyme activity. Digoxin treatment, which normalized HIF-1α levels, alleviated oxidative stress by restoring Nox2 enzyme activity, and abrogated the carotid body hypersensitivity to hypoxia [37]. These findings demonstrate that dysregulation of HIF-α isoform expression in the carotid body leads to imbalanced expression of pro-oxidant and anti-oxidant enzymes that alter the cellular redox state and thereby affect response of the carotid body to hypoxia.

Studies from an experimental model of sleep apnea establish the clinical significance of dysregulated HIF-α isoform expression

Sleep-disordered breathing with obstructive sleep apnea (OSA) is a major clinical disorder that is reaching epidemic proportions [13, 32]. In severely affected patients, the frequency of apnea may exceed 60 episodes/h and arterial blood O2 saturation can be reduced to as low as 50%. Patients with sleep apnea exhibit elevated sympathetic nerve activity, as well as increased plasma and urinary catecholamines, and are prone to develop hypertension. Emerging evidence suggests that a heightened carotid body chemosensory reflex mediates autonomic dysfunction in sleep apnea patients [7, 22].

Chronic intermittent hypoxia (IH) is a hallmark manifestation of sleep apnea. Rodents exposed to chronic IH exhibit selective augmentation of the carotid body response to hypoxia [14-16, 25, 26], and sensory long-term facilitation (LTF) manifested by a long-lasting increase in baseline sensory activity [14, 16]. Carotid bodies from chronic IH-exposed rodents show increased HIF-1α [11, 16, 36] and decreased HIF-2α levels [12]. The increased HIF-1α levels were due to increased HIF-1α protein synthesis, which was mediated by Ca2+- and protein kinase C-dependent activation of mTOR, and decreased HIF-1α degradation as a result of impaired prolyl hydroxylation [36]. The decreased HIF-2α levels in the carotid bodies of mice exposed to chronic IH were due to increased degradation of HIF-2α protein by Ca2+-activated calpain proteases [12].

HIF-1 activation by chronic IH was associated with increased abundance of Nox2 mRNA, protein and enzyme activity in the carotid body [17]. The decreased HIF-2 activation was associated with reduced abundance of Sod2 mRNA, protein, and enzyme activity [12]. ROS levels were elevated in chronic IH-exposed carotid bodies [12, 17]. The following findings suggest that HIF-mediated ROS contribute to altered carotid body function by chronic IH: 1) anti-oxidant treatment prevented chronic-IH-induced carotid body sensitization to hypoxia and sensory LTF [14]; 2) carotid body responses to chronic IH were absent in Hif1a+/− mice [16]; and 3) Hif2a+/− mice exhibited augmented hypoxic carotid body sensitivity, which was similar to chronic IH-exposed mice and could also be prevented by anti-oxidant treatment [19].

HIF-mediated changes in the carotid body contribute to cardio-respiratory pathology associated with chronic IH. Following each episode of apnea, the increased carotid body sensitivity to hypoxia results in a greater magnitude of hyperventilation, thus driving the respiratory controller below the apneic threshold for CO2, leading to a greater number of apneas [21]. Thus, the heightened hypoxic sensitivity of the carotid body might act as a “positive feedback,” leading to greater incidence of apneas. Indeed, chronic IH-exposed rats with intact carotid bodies exhibit greater incidence of spontaneous apneas and this effect was absent in carotid body-ablated rats exposed to chronic IH [24]. Patients with OSA exhibit elevated sympathetic nerve activity even during the day-time when apneas are absent [7]. Since chronic IH-induces sensory LTF of the carotid body, it is likely that increased sensory nerve activity by activating the chemo-sensory reflex mediates the elevated sympathetic nerve activity. Supporting this possibility is the finding that following bilateral sectioning of the carotid sinus nerves, chronic IH-exposed rats no longer showed elevated sympathetic nerve activity [24]. Hif1a+/− mice, whose carotid bodies are insensitive to hypoxia, exhibit a remarkable absence of hypertension and elevated plasma catecholamines in response to chronic IH. Hif2a +/− mice, on the other hand, like chronic IH-exposed mice, exhibit an increased number of apneas, hypertension and elevated plasma catecholamine levels. Taken together, these findings suggest that dysregulation of HIF-α isoform expression contributes to cardio-respiratory pathology in the setting of chronic IH through a heightened chemosensory reflex arising from augmented carotid body sensitivity to hypoxia.

Perspective and future directions

HIFs regulate hundreds of genes, including those encoding ion channels and enzymes associated with neurotransmitter synthesis or degradation [23, 30], which have been implicated in the carotid body response to hypoxia [10]. Dysregulation of HIF-α isoform expression affects the transcription of genes other than those associated with redox regulation remains to be investigated. While ROS resulting from imbalanced expression of HIF-α isoforms mediate the carotid body response to hypoxia, the downstream targets of ROS signaling have not yet been identified. Recent studies implicate carbon monoxide (CO)-sensitive hydrogen sulfide (H2S) generation as critical mediators of the carotid body response to hypoxia [18, 38]. Whether altered ROS levels result from dysregulated HIF-α isoform expression target CO and H2S signaling in the carotid body remains to be studied. In addition to sleep apnea, a hyperactive carotid body chemosensory reflex is implicated in autonomic dysfunction associated with congestive heart failure [28] and neurogenic hypertension [1]. The blunted hypoxic sensitivity of the carotid body has adverse physiological consequences, including impaired ventilatory adaptation to high altitude hypoxia that is manifested by pulmonary edema [4]. Whether imbalanced expression of HIF-α isoforms in the carotid body also contributes to these pathologies remains an interesting possibility. Studies described above utilized digoxin and 2ME-2 to block the HIF-1α and HIF-2α protein accumulation, respectively. However, the precise mechanism of action and the specificity of these compounds to HIF-α isoforms have not been determined. Exposure to continuous hypobaric hypoxia results in initial augmentation, followed by desensitization of the carotid body to hypoxia [10]. Whether differential regulation of HIF-α isoforms contribute to the diametrically opposed carotid body responses during the initial and late phase of continuous hypobaric hypoxia remains to be studied.

Figure 1.

Figure 1

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Chronic intermittent hypoxia associated with obstructive sleep apnea dysregulates HIF-α isoform expression, leading to increased ROS, carotid body activation, increased sympathetic activation, and systemic hypertension. NOX2, NADPH oxidase 2; ROS, reactive oxygen species; SOD2, superoxide dismutase 2 ; PKC, protein kinase C; mTOR, mammalian target of rapamycin; [Ca2+]i , intracellular calcium ion concentration. HIF-1α and HIF-2α are mutually antagonistic: HIF-1α deficiency results in decreased NOX2, decreased ROS, decreased [Ca2+]i, and decreased calpain activity, which leads to increased HIF-2α levels; HIF-2α deficiency causes decreased SOD2 activity, increased ROS, increased [Ca2+]i, and increased mTOR activity, which leads to increased HIF-1α levels.

Acknowledgements

The authors’ research is supported by Public Health Service Grants PO1-HL90554 and UH2-HL123610 to N.R.P. G.L.S is the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine.

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