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. Author manuscript; available in PMC: 2009 Dec 10.
Published in final edited form as: Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):282–287. doi: 10.1016/j.resp.2008.07.017

HIF-1 and ventilatory acclimatization to chronic hypoxia

Frank L Powell 1, Zhenxing Fu 1
PMCID: PMC2700119  NIHMSID: NIHMS78658  PMID: 18708172

Abstract

Ventilatory acclimatization to hypoxia (VAH) is a time-dependent increase in ventilation and ventilatory O2-sensitivity that involves plasticity in carotid body chemoreceptors and CNS respiratory centers. Hypoxia inducible factor-1α (HIF-1α) controls the expression of several genes that increase physiological O2 supply. Studies using transgenic mice show HIF-1α expression in the carotid bodies and CNS with chronic sustained and intermittent hypoxia is important for VAH. Other O2-sensitive transcription factors such as HIF-2α may be important for VAH by reducing metabolic O2 demands also. Specific gene targets of HIF-1α shown to be involved in VAH include erythropoietin, endothelin-1, neuronal nitric oxide synthase and tyrosine hydroxylase. Other HIF-1α targets that may be involved in VAH include vascular endothelial growth factor, heme oxygenase 1 and cytoglobin. Interactions between these multiple pathways and feedback control of HIF-1α expression from some of the targets support a complex and powerful role for HIF-1α in neural plasticity of physiological control circuits with chronic hypoxia.

Keywords: carotid body, endothelin-1, erythropoietin, gene expression, heme oxygenase, neural plasticity, nitric oxide, transgenic mice, vascular endothelial growth factor

1. Introduction

Ventilatory acclimatization to hypoxia (VAH) is a time-dependent increase in ventilation that occurs in humans and animals exposed to chronic hypoxia (Powell et al., 1998). VAH involves an increase in the acute hypoxic ventilatory response (HVR) that is most clearly demonstrated when hypocapnia is prevented during hypoxic hyperventilation, i.e. isocapnic hypoxia (Powell et al., 2000). The increased HVR results from both enhanced carotid body O2-sensitivity (Bisgard, 2000) and plasticity in CNS integration and processing of arterial chemoreceptor afferent input (Dwinell and Powell, 1999). Another feature of plasticity in ventilatory control with chronic hypoxia is ventilatory deacclimatization to hypoxia (VDH), which is a persistent hyperventilation when normoxia is restored after chronic hypoxia (Powell et al., 1998). The mechanisms for VDH are unknown but it cannot be simply explained by a metabolic acidosis in the cerebrospinal fluid stimulating ventral medullary CO2-sensitive chemoreceptors as originally hypothesized in the 1960s (Dempsey and Forster, 1982). VAH and VDH require hours to days of hypoxic exposure so it is reasonable to hypothesize they involve changes in gene expression in the neural circuits controlling breathing. A likely factor controlling changes in the expression of genes involved in VAH is Hypoxia Inducible Factor 1 (HIF-1), which was discovered as an important transcription factor for erythropoietin (EPO) and has been described as a master regulator for O2 homeostasis (Semenza, 1998). Since this discovery, HIF-1 has been shown to increase expression of a wide variety of genes besides EPO that are involved in O2 delivery and metabolism (Semenza, 1999).

1.1. HIF-1 molecular biology and physiology

This topic has been covered in detail in other recent reviews (e.g. Weidemann and Johnson, 2008). HIF-1 induces physiological responses to hypoxia by binding to an 8 base pair hypoxia response element (HRE) in hypoxia responsive genes and activating transcription. HIF-1 activity depends on phosphorylation and its binding in the DNA major groove is redox-sensitive. HIF-1 is a heterodimer composed of HIF-1α and HIF-1β. HIF-1β is also known as the aryl hydrocarbon receptor nuclear translocator, ARNT. Both HIF-1 subunits are expressed constitutively but HIF-1α is subject to degradation under normoxic conditions. Prolyl hydroxylases (PHDs) act on two specific prolyl residues in the oxygen-dependent-degradation domains (ODD) of HIF-1α subunits in the presence of oxygen, Fe2+ and 2-oxogluterate. Under normoxic conditions, PHD is hydroxylated and the ODD binds the Von Hippel-Lindau protein. This provides recognition for the E3 ubiquitin ligase complex and leads to proteasomal degradation of HIF-1α. Other hydroxylases modify asparagine residues in the carboxy-terminal-trans-activation domain of HIF-1α and modulate HIF-1α activity instead of stability in response to oxygen.

The first correlation demonstrated between a physiological stimulus, increased HIF-1 and an adaptive physiological response was increased vascular endothelial growth factor (VEGF) expression and increased cardiac vascularization in fetal lambs subjected to chronic anemia (Martin et al., 1998). HIF-1α is also essential for vascularization during normal embryonic development and homozygous deletion of the HIF-1α gene in mice is embryonic lethal (Ryan et al., 1998). Although the regression of blood vessels and massive cell death in cephalic mesenchyme of homozygous HIF-1α knockout mice is similar to that of homozygous VEGF knockout mice, homozygous HIF-1α knockout mice actually show increased VEGF (reviewed by Semenza, 1999). Therefore, HIF-1α exerts important developmental effects by other non-VEGF pathways too. HIF-1 gene products that are relevant to ventilatory acclimatization to hypoxia are considered in Section 5.

1.2. Other O2-sensitive Transcription Factors

Besides HIF-1α, other transcription factors in the basic helix-loop-helix/PAS superfamily include HIF-2α and HIF-3α. HIF-2α is also referred to as endothelial PAS domain protein-1 (EPAS-1) and like HIF-1α, it is stabilized by hypoxia (Wiesener et al., 1998). Gene expression studies show relatively few target genes for HIF-2α versus HIF-1α and even fewer of these are uniquely controlled by HIF-2α (Warnecke et al., 2008). The effects of HIF-1α knockdown are generally larger than those of HIF-2α knockdown on genes controlled by both factors (Warnecke et al., 2008). However, a notable exception is EPO and there is evidence that HIF-2α may be the most important factor controlling erythropoiesis in hypoxia, at least in mice (Gruber et al., 2007).

Involvement of HIF-2α in VAH remains to be demonstrated but it appears likely. EPO is produced in the brain and is important for CNS mechanisms of VAH as described later. The effect of HIF-2α on EPO in the brain is not known yet but is reasonable to hypothesize that it may be stimulatory, as it is for systemic EPO (Gurber et al., 2007). A role for HIF-2α in carotid body mechanisms of VAH has also been suggested, as discussed later. Finally HIF-2α appears to be more important than HIF-1α in metabolic reprogramming in skeletal muscle. Skeletal muscle from mice with the PHd1 gene deleted, which prevents normal degradation of HIF-1α in normoxia, shows decreased O2 consumption and shift towards anaerobic glycolysis (Aragones et al., 2008). HIF expression patterns indicated that HIF-2α is more important than HIF-1α in these metabolic changes to reduce O2 demand under hypoxic conditions. Such decreased O2 consumption complements the physiological effects of ventilatory acclimatization to increase O2 supply in chronic hypoxia.

The physiological role of HIF-3α is not clear yet (Heidelbreder et al., 2003). However, descriptive studies show similar patterns for expression of HIF-2α and HIF-3α in chronic, sustained versus intermittent hypoxia (Lam et al., 2008b), which suggests the functions similar to those discussed above for HIF-2α.

Hypoxia activates several other transcription factors besides HIF but in general their role in VAH is not known (Cummins and Taylor, 2005). Nuclear factor-kappaB (NF-κB) is a master transcriptional regulator of inflammatory and antiapoptotic gene expression that is also increased by hypoxia (Cummins et al., 2007). Chronic hypoxia increases inflammatory cytokines in the carotid body that are known to activate NF-κB and increase calcium influx to glomus cells during acute hypoxia (Lam et al., 2008a). Activator protein-1 (AP-1) is another hypoxia sensitive transcription factor that appears to be involved in carotid body mechanisms of acclimatization to chronic intermittent hypoxia (Prabhakar and Kumar, 2004).

2. HIF-1α and the Hypoxic Ventilatory Response (HVR)

HIF-1α is not necessary for a normal HVR in mice but it does contribute to O2-sensing in the carotid body. Kline and co-workers (2002) studied transgenic mice with a heterozygous loss of function in the HIF-1α gene and found no difference in carotid body morphology, the ventilatory response to CO2, or the acute HVR compared to control, wild type mice. However, carotid bodies in these heterozygous HIF-1α knock out mice had a depressed neural response to hypoxia. The investigators hypothesize that non-carotid body arterial chemoreceptors compensate for a loss of carotid body function to preserve a normal HVR, similar to what has been observed in carotid body denervation experiments. Their theory was supported by results showing a depressed HVR in heterozygous HIF-1α knockout mice following vagotomy, which removed sensory input from non-carotid body arterial chemoreceptors. The authors speculate that non-carotid body chemoreceptors do not depend on HIF-1α for normal O2-sensitivity but plasticity in CNS integration of arterial chemoreceptor afferent input could also explain the results.

The mechanism for depressed O2-sensitivity in the carotid bodies of heterozygous HIF-1α knockout mice is unknown. The carotid body response to cyanide is not depressed in the heterozygous HIF-1α knockout mice, which indicates that histotoxic versus hypoxic chemosensory mechanisms are under differential genetic control. Lahiri and co-workers (Roy et al., 2007) have suggested that HIF-1α and neural activity in the carotid body depend on a common O2-sensor that is mitochondrial cytochrome a3. However, it is not obvious how this could be involved in the depressed O2-sensitivity in the carotid bodies of heterozygous HIF-1α knock out mice.

3. HIF-1α and Ventilatory Acclimatization to Hypoxia (VAH)

3.1. Arterial chemoreceptor plasticity

HIF1-α increases in the carotid body after as little as 1 h of hypoxia (Kline et al., 2002; Pascual et al., 2001). The heterozygous HIF1-α knockout mice discussed above also show abnormal VAH (Kline et al., 2002). Chronic hypoxia increased the HVR in wild type mice, primarily by an effect on respiratory frequency (fR), but fR actually decreased in hypoxia after acclimatization in the heterozygous HIF1-α knockout mice. Acute hypoxia increased carotid body activity less in heterozygous HIF1-α knockout mice compared to normal mice so this depression of carotid body O2-sensitivity likely contributed to the depressed VAH. However, carotid body O2-sensitivity has not been recorded after chronic hypoxia in the heterozygous HIF1-α knockout mice yet and CNS mechanisms of VAH may be compromised in these transgenic mice also (see below).

3.2. Central Nervous System (CNS) plasticity

In addition to increased carotid body O2-sensitivity with chronic hypoxia, VAH involves an increase in the CNS gain of the HVR, which is defined as an increased ventilatory motor response to a given afferent input from carotid bodies. This has been demonstrated in anesthetized rats as an increased phrenic nerve response to electrical stimulation of the carotid sinus nerve after chronic hypoxia (Dwinell and Powell, 1999). HIF-1α increases in the CNS respiratory centers after as little as 1 hour and peak changes in neurons are observed after 6 hours (Pascual et al., 2001). To investigate the role of HIF-1α in the increased CNS gain of the HVR with chronic hypoxia, we have begun to study transgenic mice with a CNS-specific deletion of the HIF-1α gene (Helton et al., 2005).

Preliminary results show the acute HVR is normal in CNS HIF-1α knockout mice. However in contrast to wild type mice, the knockout mice do not show an increased HVR after chronic hypoxia (Bavis et al., 2007). The HIF-1α gene was not deleted in the carotid bodies of these CNS-specific knockout mice (Kim, Fu and Powell, unpublished observations) indicating that HIF-1α in the CNS also plays a role in VAH. Determining the exact sites of plasticity that are induced by HIF-1α in the CNS and contribute to VAH will require spatial and temporal resolution not possible with the transgenic breeding strategies used for these studies.

4. HIF-1α and Chronic Intermittent Hypoxia (CIH)

CIH has been studied as a model for sleep disordered breathing and obstructive sleep apnea and consists of repeated bouts of hypoxia lasting seconds to minutes for several hours per day. Peng and colleagues (2006) studied the role of HIF-1α in ventilatory control plasticity during CIH using transgenic mice with one HIF-1α gene deleted (heterozygous HIF-1α knockouts). In control, wild type mice, CIH (nine 15 second bouts of hypoxia per hour, 8 hrs per day, 10 days) caused changes in ventilation and the poikilocapnic HVR similar to what is observed with chronic sustained hypoxia, i.e. ventilation increased in hypoxia and normoxia. However, CIH also causes changes that are not observed with chronic sustained hypoxia. For example, CIH pretreatment enabled long term facilitation of the carotid body response (sensory LTF; Peng and Prabhakar, 2004), and enhanced long term facilitation of phrenic nerve activity following acute intermittent hypoxia (phrenic LTF; LING et al., 2001). In heterozygous HIF-1α knockout mice, all of these responses to CIH were either absent or attenuated indicating a necessary role for HIF-1α in intermittent as well as continuous chronic hypoxia.

Results of reactive oxygen species (ROS) measurements and experiments with ROS scavengers suggested the effects of CIH involve positive feedback interactions between HIF-1α and ROS. Experiments using PC12 cells as a model for carotid body glomus cells suggest that intermittent hypoxia induces HIF-1α transcriptional activity via a novel signaling pathway involving calcium/calmodulin-dependent (CaM) kinase II (Yuan et al., 2005). Determining the relationships between control of HIF-1α expression and its effects in intermittent versus sustained hypoxia should prove useful in unraveling the mechanisms of ventilatory acclimatization that are unique to these two patterns of chronic hypoxia.

5. Potential mechanisms for plasticity induced by HIF-1α

This section considers the targets of HIF-1α that could contribute to VAH. Metabolic responses to HIF could also contribute to VAH by altering local O2 levels that are the stimuli for hypoxic responses, or by modulating metabolic control of neurotransmission. However, such potential effects are not considered further in this review.

5.1. Erythropoietin (EPO)

HIF-1α was originally discovered as an important transcription factor for EPO, which is released from the kidneys in response to hypoxia and increases the oxygen carrying capacity of blood by stimulating erythropoiesis in bone marrow (Semenza, 1999). However, EPO and its receptor (EPO-R) have also been localized to the CNS in glia and neurons where it must have different functions. EPO in the brain is reported to have a protective role during hypoxemic or ischemic injury (Gassmann et al., 2003). Recent studies with transgenic mice that overexpress human EPO in the brain support a role for EPO in VAH also (Soliz et al., 2005). The Tg21 line of transgenic mice have over 3-fold higher EPO levels in the brainstem than wild type mice but plasma EPO and hematocrits are not elevated. With chronic hypoxia, Tg21 mice increase ventilation more than control, wild type mice, although the persistent hyperventilation when normoxia is restored is similar in both strains. EPO-R is localized in respiratory centers such as pre-Bötzinger complex, the nucleus tractus solitarius (NTS) and catecholaminergic cell groups in the medulla (A1C1, A2C2) and pons (A5, A6). The soluble EPO receptor (sEPO-R) may play the primary role in EPO effects on VAH in the brain (Soliz et al., 2007). sEPO-R in the brain is downregulated by chronic hypoxia and intracerebroventricular infusion of sEPO-R to chronically hypoxic mice decreases EPO and reverses VAH. Hence, HIF-1α affects both hematological and ventilatory acclimatization to chronic hypoxia.

Studies on a different transgenic mouse (Tg6), which over-expresses EPO in the brain and systemically so hematocrit increases, suggest that EPO exerts effects on the HVR both centrally and peripherally (Soliz et al., 2007). In Tg6 mice, norepinepherine is increased in the A5 cell group of the pons and this is known to increase respiratory frequency (Dick and Coles, 2000). Systemic EPO also increases frequency by actions on the carotid body (Soliz et al., 2005).

5.2. Vascular Endothelial Growth Factor (VEGF)

VEGF is one of the most studied HIF-1α targets because of its role in increasing tumor vascularity, which suggests a promising avenue for anticancer therapeutics. However, VEGF has been localized also to motor neurons (Murakami et al., 2003) and may play a role in neural plasticity during chronic hypoxia. VEGF activates similar cellular signaling pathways as brain derived neurotrophic growth factor (BDNF), which has been shown to play a critical role in long term facilitation of ventilation (LTF) following intermittent hypoxia by binding TrkB receptors (Baker-Herman et al., 2004). VEGF effects are exerted by binding another tyrosine kinase receptor, VEGFR2 (Roitbak et al., 2008). Also, VEGF and BDNF are both involved in neural plasticity after cerebral ischemia (Chen et al., 2005; Roitbak et al., 2008). A similar role for VEGF inducing neural plasticity in respiratory control circuits during chronic hypoxia could support the other effects of HIF-1α on acclimatization but it remains to be demonstrated experimentally.

5.3. Endothelin-1 (ET-1)

ET-1 is a vasoactive peptide that increases with chronic hypoxia in the carotid body (J. Chen et al., 2002; Lam et al., 2008b) as well as other O2-sensitive tissues such as the pulmonary artery (Li et al., 1994). ET-1 is also widely distributed in the brain where it plays an important role in the response to stress (Kurihara et al., 2000). Hypoxia regulates ET-1 expression through HIF-1α (Hu et al., 1998) and a specific role for ET-1 in mediating VAH is supported by experiments showing that antagonists for ETA receptors reverse the increased O2-sensitivity observed in carotid bodies from chronically hypoxic rats (Y. Chen et al., 2002). While ET-1 alone does not excite carotid bodies, it does enhance the response to hypoxia and this effect is mediated by ETA receptors on glomus cells (J. Chen et al., 2002), which are increased with chronic hypoxia (Y. Chen et al., 2002). ET-1 may increase O2-sensitivity of glomus cells by effects on the G-coupled ETA receptor to increase calcium currents (Y. Chen et al., 2002). However, ET-1 may also have effects on CNS mechanisms of hypoxia responses considering that the HVR is blunted in anesthetized mice with a heterozygous knock-out of the ET-1 gene (Kuwaki et al., 1996). Experiments manipulating ET-1 and ETA expression specifically in the CNS and during acclimatization to chronic hypoxia (versus life-long deletion) will be necessary to test this hypothesis.

5.4. Heme oxygenase (HO)

Two isoforms of HO may be involved in ventilatory O2-sensitivity via O2-dependent catalysis of heme into CO, biliverdin and iron (Maines and Gibbs, 2005) and both forms affect neuronal ion channels (Boehning and Snyder, 2003; Lopez-Barneo et al., 2004). HO-1 is known to be induced by HIF-1α (Semenza, 1999) and HO-1 is also induced by chronic hypoxia in the rostral ventrolateral medulla, where it has been hypothesized to increase central O2-sensitivity (Mazza et al., 2001). However, it should be noted that HO-1 may be activated by more stimuli than any other gene (Maines and Gibbs, 2005) so the changes observed in chronic hypoxia may not depend on HIF-1α. Also, a specific role for HO-1 in central O2-sensitivity remains to be demonstrated.

HO-2 is a constitutive isoform that is also expressed in the rostral ventrolateral medulla, the C1 region and pre-Bötzinger complex, all of which demonstrate O2-sensitivity and affect breathing (Mazza et al., 2001). HO-2 is hypothesized to be involved in acute ventilatory responses to CNS hypoxia but levels do not change with chronic hypoxia as expected if it was important for plasticity (Mazza et al., 2001; Adachi et al., 2004).

5.5. Tyrosine hydroxylase (TH)

Dopaminergic modulation of the HVR in both the CNS and arterial chemoreceptor changes with ventilatory acclimatization to hypoxia (Huey et al., 2003). TH is the rate limiting enzyme for biosynthesis of dopamine and its expression is increased by hypoxia. However, the role of HIF-1α in causing changes in TH and dopamine during chronic hypoxia is not certain. The HRE in the TH gene can bind HIF-1α but AP1 appears to be the main factor responsible for increased TH gene expression with hypoxia in PC 12 cells (Millhorn et al., 1997). Both TH transcription and mRNA stability are increased by hypoxia in PC12 cells (Czyzyk-Krzeska et al., 1994). Hence, HIF-1α may be involved in VAH through effects on TH but this has not been proven conclusively.

In the medulla, HIF-1α is increased by hypoxia selectively in cardiorespiratory centers and is co-localized with TH in many-- but not all -- catecholaminergic neurons, e.g. A1C1 and A2C2 cell groups (Pascual et al., 2001). In carotid body cells, HIF-2α correlates more closely than HIF-1α with increased TH in chronic hypoxia. Both chronic intermittent and sustained hypoxia increase TH and HIF-2α but HIF-1α is only increased by chronic sustained hypoxia (Lam et al., 2008b). HIF-1α in the carotid body may be more important for hypertrophy and increased vascularization than changes in O2-sensitivity with chronic sustained hypoxia. On the other hand, HIF-1α correlates more closely than HIF-2α with developmental changes in carotid body TH and O2-sensitivity. HIF-1α decreases in the carotid body as O2-sensitivity increases during the perinatal period, while HIF-2α does not change during the same period (Roux et al., 2005). Experimental interventions instead of correlative studies will be necessary to determine the role of various HIFs in controlling TH and mechanisms of ventilatory acclimatization to hypoxia.

5.6. Nitric Oxide Synthase (NOS)

Generally, HIF-1α is thought to affect nitric oxide (NO) through induction of inducible NOS (iNOS, Semenza, 1999) but recent experiments show that hypoxia leads to activation of a novel neuronal NOS (nNOS) promoter. Ward and co-workers (2005) showed that HIF-1α binds specifically under hypoxic conditions to a HRE found in the human nNOS sequence and produces mRNA with high translational efficiency. Nitric oxide (NO) itself has important effects on ventilation and the HVR. Increasing NO in the nucleus tractus solitarius stimulates ventilation (Ogawa et al., 1995) while increasing NO in the carotid body depresses O2-sensitivity and thereby the HVR (Bisgard, 2000). Hence, changes in NO from induction of nNOS during chronic hypoxia could be involved in ventilatory acclimatization.

Hypoxemia from anemia increases HIF-1α and mRNA for nNOS in the cerebral cortex (McLaren et al., 2007) and chronic hypoxia increases mRNA and protein for nNOS in both peripheral and central neurons (Prabhakar et al., 1996). Selective inhibition nNOS in the brainstem has no effect on ventilation or the HVR in control mice but it decreases ventilation in chronically hypoxic mice (Hasnaoui-Saadani et al., 2007). Hence, effects of HIF-1α on NO appear to enhance O2 delivery from effects on ventilation in chronic hypoxia, as well as from the effects of NO-induced vasodilation on vascular O2 delivery. NO also decreases O2 demand by its inhibitory effects mitochondrial respiration. Ward and colleagues (2005) point out that this latter effect could establish negative feedback control of nNOS expression at the transcriptional level by NO-dependent prolyl hydroxylase disinhibition that prevents HIF-1α stabilization.

A further complexity in nNOS regulation by HIF-1α may involve ET-1, another HIF-1α target involved in VAH (see above). In the kidney, ET-1 upregulates nNOS through an effect on ETA receptors (Cummins et al., 2007). If ET-1 has the same effect on nNOS in the brain or carotid bodies, then it could provide another level of interaction between HIF-1α and nNOS in VAH.

5.7. Neuroglobin (Ngb) and Cytoglobin (Cygb)

Genomic studies lead to the discovery of Ngb and Cygb, which bind oxygen reversibly via iron atoms in a porphyrin ring in a fashion similar to hemoglobin and myoglobin. Ngb is a candidate for mediating neural plasticity in hypoxic neurons because it is up-regulated in the brain by hypoxic-ischemic injury, it protects neurons from further damage by hypoxia, it may scavenge reactive oxygen species and NO, and it may function as an oxygen sensor (Sun et al., 2001; Fordel et al., 2004). However, Ngb expression does not depend on HIF-1α (Fordel et al., 2004).

In contrast, increased Cygb expression in hypoxia does depend on HIF-1α and comparative studies plus the O2 binding properties of Cygb suggest it may facilitate O2 delivery in the hypoxic tissue. Hence, HIF-1α could enhance O2 delivery in the CNS serially: firstly, by its effect to increase hemoglobin and arterial O2 content (via EPO), and secondly, by increased Cygb to facilitate tissue O2 delivery (similar to the role of myoglobin in skeletal muscle) (Williams et al., 2008). This could modulate ventilatory acclimatization to hypoxia by causing time-dependent changes in the PO2 at O2-chemosensitive sites in the brain.

6. Conclusions and Future Directions

HIF-1α produces a suite of coordinated responses to chronic hypoxia. These contribute to ventilatory acclimatization to hypoxia but they cannot explain every aspect of the plasticity observed in ventilatory control with chronic hypoxia. Also, the effects of HIF-1α differ between chronic intermittent versus sustained hypoxia. Together, these observations suggest that experimental manipulations of HIF-1α in specific pathways of ventilatory acclimatization may help us dissect the integrated response to various patterns of hypoxia. Understanding how the individual mechanisms interact could help us develop therapeutics for treating specific patterns of hypoxemia, for example intermittent hypoxia with obstructive sleep apnea versus sustained hypoxia with chronic obstructive pulmonary disease.

Acknowledgments

This work was supported by NIH 1R01HL081823 and the University of California White Mountain Research Station.

Footnotes

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