The Cardiovascular and Metabolic Effects of Chronic Hypoxia in Animal Models: A Mini-Review

Animal models are useful to understand the myriad physiological effects of hypoxia. Such models attempt to recapitulate the hypoxemia of human disease in various ways. In this mini-review, we consider the various animal models which have been deployed to understand the effects of chronic hypoxia on pulmonary and systemic blood pressure, glucose and lipid metabolism, atherosclerosis, and stroke. Chronic sustained hypoxia (CSH)—a model of chronic lung or heart diseases in which hypoxemia may be longstanding and persistent, or of high altitude, in which effective atmospheric oxygen concentration is low—reliably induces pulmonary hypertension in rodents, and appears to have protective effects on glucose metabolism. Chronic intermittent hypoxia (CIH) has long been used as a model of obstructive sleep apnea (OSA), in which recurrent airway occlusion results in intermittent reductions in oxyhemoglobin saturations throughout the night. CIH was first shown to increase systemic blood pressure, but has also been associated with other maladaptive physiological changes, including glucose dysregulation, atherosclerosis, progression of nonalcoholic fatty liver disease, and endothelial dysfunction. However, models of CIH have generally been implemented so as to mimic severe human OSA, with comparatively less focus on milder hypoxic regimens. Here we discuss CSH and CIH conceptually, the effects of these stimuli, and limitations of the available data.

Introduction

Animal models have been useful for demonstrating various physiological effects of hypoxia, thus providing deeper understanding of the impact of hypoxemia in human disease. Chronic sustained hypoxia (CSH) and chronic intermittent hypoxia (CIH) are each associated with cardiovascular and metabolic changes, which can be adaptive or maladaptive. In this mini-review we consider the outcomes associated with both CSH and CIH as they pertain to cardio-metabolic disease. Specifically, we will address cardiovascular and metabolic outcomes of CSH and CIH models in animals which aim to mimic human disease states. We will not focus on models of acute sustained or intermittent hypoxia (lasting minutes to hours), which may have variable consequences. Moreover, in this mini-review, we consider only CSH and CIH models which might resemble chronic hypoxic conditions in humans. Intriguing reports of the effects of intermittent hypoxia on neuroplasticity with low-frequency hypoxic episodes lasting several minutes (Gonzalez-Rothi et al., 2015; Navarrete-Opazo et al., 2015) are subjects of other expert reviews (Randelman et al., 2021). Finally, we note that our intention is to cover significant breadth of understanding of the topic of cardio-metabolic consequences of chronic hypoxia in animal models, sacrificing some depth of specific models and outcomes. We invite the reader to explore specific citations for important study details.

Hypoxia as a Model of Human Disease

Both CSH and CIH in animal models have been used to simulate various disease states. CSH has been applied to rodents at varying fraction of inspired oxygen (FiO₂), generally ranging from 0.10 to 0.15 (Hislop and Reid, 1976; Cowburn et al., 2017; Ioja et al., 2018; Prieto-Lloret et al., 2021), either been normobaric or hypobaric relative to sea level. Though resulting peripheral saturations are not always considered, the severity of CSH is a critical variable: For instance, CSH of FiO₂ 0.10 as a model of high altitude exposure might recapitulate the effective oxygen content at an altitude of 5800 m (Mt. Kilimanjaro), whereas an FiO₂ of 0.15 might be representative of a lower altitude (2400 m, Aspen, CO). In considering analogues of human disease, an FiO₂ of 0.10 would be expected to model only very hypoxemic diseases like cyanotic heart disease, whereas an FiO₂ of 0.15 might model chronic obstructive pulmonary disease (COPD), or other chronic lung diseases which are far more common.

Similarly, CIH has been applied to animal models in a variety of ways, although most studies roughly reproduce conditions used by Fletcher et al., who first studied CIH in rodents as a model of OSA (Fletcher et al., 1992b). In CIH, multiple variables of desaturation and resaturation are important to define. In Fletcher’s experiments, rats were exposed to rapid reductions of FiO₂ from 0.21 to 0.05 over 12 s, then quickly returned to 0.21. This process was repeated every 90 s (corresponding to an oxyhemoglobin desaturation index [ODI] of 40 events/h), for 7 h per day, for up to 5 weeks. Each of these variables—rate of deoxygenation, depth of deoxygenation, rate of reoxygenation, ODI, duration of daily exposure, and overall experiment duration—may be manipulated in different animal experiments (Farré et al., 2018). At least one study has demonstrated tissue-specific effects of various hypoxic profiles of CIH in rodents (Reinke et al., 2011). Thus, there are several considerations when designing animal experiments seeking to elucidate the physiological effects of either CSH or CIH.

Cardio-Metabolic Effects of Chronic Sustained Hypoxia

CSH and Pulmonary Hypertension

In humans and in animal models, acute alveolar hypoxia has been shown to cause pulmonary vasoconstriction, leading to acute pulmonary hypertension (PH) (Fishman, 1976; Wagenvoort, 1977; Rabinovitch et al., 1979; Perkin and Anas, 1984; Voelkel, 1986). Both hypoxic pulmonary vasoconstriction and PH may revert after cessation of hypoxic exposure. By contrast, exposure to CSH results in chronic PH which may be irreversible (Meyrick and Reid, 1978; Stenmark et al., 2009). Vascular remodeling due to CSH consists of muscularization of the small arteries of the alveolar wall and proliferation of cells expressing α-smooth muscle actin, followed by thickening of the precapillary pulmonary arteries, inflammation, and fibrosis of the large proximal pulmonary arteries (Stenmark et al., 2009). CSH causes PH so reliably in rodents that it has been widely adopted as a model for studying mechanisms and downstream effects of PH. However, the response to CSH is variable between species (Stenmark et al., 2009). Although CSH leads to PH both in mice and rats, the degree of vascular remodeling is typically less in mice (Hislop and Reid, 1976; Frank et al., 2008; Cahill et al., 2012).

Sustained Hypoxia and Systemic Blood Pressure

While CSH causes PH in rodent models, the effect of CSH on systemic blood pressure is less clear. Acute ascent to high altitude, an inherently hypoxic environment, can reversibly increase systemic blood pressure (Bender et al., 1988; Wolfel et al., 1991, Wolfel et al., 1994). Epidemiological studies have shown that humans living at high altitude have lower systemic blood pressure than those living at sea level (Rotta, 1947; Ruiz and Peñaloza, 1977), highlighting the difference between acute exposure and those acclimatized to such an environment. In rodents exposed to normobaric or hypobaric CSH, results have been mixed. Vilar et al. demonstrated a reduction in blood pressure in spontaneously hypertensive rats after exposure to normobaric CSH (FiO₂ of 0.10 for 8 weeks) (Vilar et al., 2008), induction of pro-angiogenic pathways; and they showed that neutralizing antibodies targeting vascular endothelial growth factor-A (VEGF-A) both abrogated the effects of hypoxia on angiogenesis, and increased blood pressure. Other studies also showed that CSH decreased systemic blood pressure in young spontaneously hypertensive rats (Henley and Tucker, 1987), and that hypoxia mitigated blood pressure elevation in the renal hypertensive rat (Fregly, 1963, Fregly, 1970). However, one study demonstrated that CSH (FiO₂ of 0.10) did change blood pressure in male rats at durations of anywhere from 1 to 30 days, despite an increase in carotid body catecholaminergic signaling (Hui et al., 2003). Our group has also not observed changes in systemic blood pressure in young mice exposed to 40 days of CSH of similar severity (Zhen et al., 2021). Vaziri et al. demonstrated increased blood pressure in rats exposed to hypobaric CSH (effective FiO₂ of 0.10–0.11) that persisted even after the restoration of normoxia (Vaziri and Wang, 1996). Thus, the effects of CSH on systemic blood pressure are complex, and perhaps dependent on the specific conditions and animals.

Effects of CSH on Atherosclerosis and Stroke

Atherosclerosis is the major underlying etiology of cardiovascular disease, which is the leading cause of death worldwide (Mendis et al., 2011). Evidence for the contribution of hypoxia to the progression of atherosclerosis is largely circumstantial. Hypoxia inducible factor-1α (HIF-1α), a subunit of HIF-1, the major regulator of the cellular response to hypoxia, is normally quickly hydroxylated and degraded in normoxia. In hypoxia, however, HIF-1α is stabilized and can dimerize with HIF-1β, allowing binding to hypoxia responsive elements in the promoter regions of target genes of interest (Iyer et al., 1998). HIF-1α is stabilized in macrophages and smooth muscle cells near the necrotic core of atherosclerotic vascular lesions in humans and in animal models (Sluimer et al., 2008; Lim et al., 2013; Ferns and Heikal, 2017), and HIF-1 has been implicated in atherosclerosis progression (Kasivisvanathan et al., 2011). Moreover, hyperbaric oxygen (FiO₂ 1.0, 2.4–2.5 atm) improves atherosclerosis in both rabbits and mice (Kudchodkar et al., 2000, Kudchodkar et al., 2007, Kudchodkar et al., 2008). It is therefore conceivable that hypoxia could contribute to the development of atherosclerosis, but to our knowledge, CSH has never been shown to directly impact atherosclerosis in animal models.

Atherosclerosis, among other factors, may lead to acute ischemic stroke, which causes over 130,000 deaths in the United States yearly. Patients with pre-existing atherosclerotic lesions who then become hypoxemic (e.g., respiratory failure in the ICU setting) may develop sufficient brain ischemia to manifest as a stroke. However, recent data suggest that acute hypoxic exposure in animal models of ischemic stroke may be protective. Mice with stroke induced by middle cerebral artery occlusion and then exposed to variably severe hypoxia (FiO₂ of 0.07–0.12) for two to 8 weeks (Zhang et al., 2020) showed improved collateral blood flow in a “dose-dependent” manner, with more severe and longer duration of hypoxia generating more robust collateral circulation. These effects were durable even after cessation of hypoxia. These data suggest that while some effects of CSH may be maladaptive, some might be beneficial, and that adaptive responses to hypoxia may present in unique ways.

Metabolic Effects of CSH

Despite our ability to implement CSH as a stimulus with relative ease in animal studies, the metabolic effects of CSH are less well explored than the cardiovascular effects. Gamboa et al. were the first to recognize the potentially beneficial effects of CSH on glucose metabolism (Gamboa et al., 2011), finding that CSH with an FiO₂ of 0.10 reduced plasma fasting glucose and insulin, increased insulin sensitivity, and improved insulin-dependent glucose uptake by skeletal muscle. Since that time, similar findings have been replicated by us (Zhen et al., 2021) and others (Lee et al., 2013; Ioja et al., 2018), with additional data demonstrating hypoxia-dependent effects on the liver transcriptome (Zhen et al., 2021) and changes in liver and skeletal muscle mitochondrial function (Ioja et al., 2018). Lipid metabolism also appears to be altered in CSH, with elevated serum triglyceride and low-density lipoprotein levels resulting from CSH with an FiO₂ of 0.10 (Zhen et al., 2021). We and others have noted that CSH causes weight loss in rodents. In our studies, however, we found a complex interaction between hypoxia and weight, and that beneficial metabolic effects of CSH cannot solely be explained by weight reduction (Zhen et al., 2021).

Cardio-Metabolic Effects of Chronic Intermittent Hypoxia

CIH has been used to model OSA, the most common respiratory disease in the world (Benjafield et al., 2019). Epidemiologic associations have been made between OSA and a wide variety of adverse health outcomes, including cardiovascular disease, diabetes, cognitive and mood disorders, and others. However, OSA has several significant manifestations aside from intermittent hypoxemia, including hypercapnia, intrathoracic pressure swings, and fragmented sleep. CIH models attempt to understand the mechanisms by which the hypoxemia of OSA may uniquely contribute to these outcomes of interest.

CIH and Pulmonary Hypertension

OSA in humans is associated with PH, although the effect is typically mild (Sajkov and McEvoy, 2009) and the impact of OSA on PH independent of other comorbidities has been debated (Chaouat et al., 1996; Sajkov et al., 1999). In OSA, the duration of hypoxemia resulting from respiratory events (apneas or hypopneas), rather than the frequency of respiratory events as gauged by the apnea-hypopnea index per se, is linked with more severe pulmonary hypertension (Samhouri et al., 2020). In early animal models involving dogs, repetitive airway occlusion was induced by tracheal obstruction of variable duration. These studies showed that pulmonary arterial (PA) pressure increased as a function of the severity of desaturation (Iwase et al., 1992). Further, the authors showed that airway occlusion in animals allowed to breathe 100% oxygen (which prevented significant desaturations), did not increase PA pressure. Likewise, when another set of dogs were allowed to breathe hypoxic gas without airway occlusion, PA pressures increased. These observations suggested that hypoxemia is likely the most critical of the several physiological manifestations of OSA to cause PH. There are several studies examining the impact of CIH on pulmonary hypertension in rodent models (Fagan, 2001; McGuire and Bradford, 2001; Campen et al., 2005; Nisbet et al., 2009; Nara et al., 2015; Snow et al., 2020; Zhen et al., 2021). Some of these studies appear to show increases in right ventricular systolic pressure, right ventricular mass, and/or pulmonary vascular remodeling in response to CIH, although we did not observe these effects in young C57BL/6J mice (Zhen et al., 2021). CIH also does not increase right ventricular pressures to the same degree as CSH (Fagan, 2001; Zhen et al., 2021). Any putative effect of CIH to worsen pulmonary hypertension may be due to changes in nitric oxide bioavailability (Nisbet et al., 2009) and/or increases in endothelin-1 expression and endothelial damage (Wang et al., 2013), leading to pulmonary vasoconstriction.

CIH and Systemic Blood Pressure

As mentioned above, the first demonstrated physiological effects of CIH were to increase systemic blood pressure in rats (Fletcher et al., 1992b). Since that time, this finding has been demonstrated by others (Fletcher, 2001; Prabhakar and Kumar, 2010). The major mechanism by which CIH is thought to induce hypertension is by activation of the sympathetic nervous system. Fletcher et al. showed that surgical denervation of peripheral chemoreceptors in the carotid body prevented CIH-induced elevations in arterial blood pressure in rats (Fletcher et al., 1992a). CIH also impairs endothelium-dependent vasodilation of skeletal muscle resistance arteries (Tahawi et al., 2001; Phillips et al., 2004) and causes vascular remodeling (Fletcher et al., 1992b). CIH increases the responsiveness of the carotid body to hypoxia, causing upregulation of pro-inflammatory cytokines, and activation of the sympathetic nervous system (Lesske et al., 1997; Braga et al., 2006; Dick et al., 2007; Lam et al., 2012, Lam et al., 2014; Zoccal et al., 2019). HIF-1 has also been implicated in the development of hypertension in animal models, via downstream effects on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Yuan et al., 2011; Schulz et al., 2014; Semenza and Prabhakar, 2015). The CIH-mediated increase in blood pressure persists even after cessation of CIH, and CIH may increase blood pressure in male rats in as little as 2 days of exposure (Hinojosa-Laborde and Mifflin, 2005). Our group has noted that there may be acclimatization to CIH causing normalization of blood pressure over prolonged periods (4–5 weeks) (Zhen et al., 2021), but more work is needed to define this effect further.

Effects of CIH on Atherosclerosis and Stroke

While exposing wild-type mice to CIH may induce vascular inflammation and remodeling (Gileles-Hillel et al., 2014), it does not appear to result in overt atherosclerosis (Savransky et al., 2007b; Drager et al., 2013), even after prolonged exposure (e.g., 20 weeks) (Song et al., 2012). However, atherosclerosis is observed in wild-type mice fed a high cholesterol diet in conjunction with exposure to CIH (Savransky et al., 2007b). Additionally, in studies using ApoE-deficient mice, which are more susceptible to atherogenesis, CIH exposure induces atherosclerosis (Jun et al., 2010; Arnaud et al., 2011; Fang et al., 2012; Gautier-Veyret et al., 2013). The major mechanism for the development of atherosclerosis in CIH appears to be the excess expression of pro-inflammatory pathways. Nuclear factor kappa B (NF-κB) is important for the development of atherosclerosis in rodents exposed to CIH (Fang et al., 2012; Song et al., 2018), and HIF-1 also may play a role in the development of CIH-induced atherosclerosis (Drager et al., 2013; Zhou et al., 2014).

Compared to the outcomes mentioned above, few animal studies have examined the relationship between CIH and stroke, even though human epidemiological studies have strongly linked OSA to stroke risk (Dyken et al., 1996; Yaggi et al., 2005; Das and Khan, 2012). CIH increases the brain’s susceptibility to hypoxia by altering cerebral blood flow (Phillips et al., 2004; Capone et al., 2012). Mechanisms for this include increased endotheliln-1 and increased oxidative stress via NADPH oxidase (Capone et al., 2012). Canzani et al. demonstrated that intermittent airway obstruction increased reperfusion injury in a mouse model of ischemia-reperfusion injury (Cananzi et al., 2020). Another intriguing study showed that CIH with a nadir FiO₂ of 0.10 may be neuroprotective, whereas a nadir FiO₂ of 0.06 may exacerbate neurological damage (Jackman et al., 2014), suggesting that the specific model of CIH, mimicking a specific severity of OSA, is fundamentally important.

Metabolic Effects of CIH

CIH also reliably impacts glucose and lipid metabolism. CIH induces insulin resistance and glucose intolerance in obese mice, whether due to diet or genetic modification (leptin-deficient Ob⁻/Ob⁻ mice) (Polotsky et al., 2003; Drager et al., 2011). We and others have noted similar effects of CIH in lean mice (Iiyori et al., 2007; Zhen et al., 2021). Although some groups have noted either sex-specific effects of CIH on glucose metabolism (Marcouiller et al., 2021), or improvement in glucose tolerance with CIH (Polotsky et al., 2003; Carreras et al., 2012; Thomas et al., 2017), this is usually accompanied by an increase in whole-body insulin resistance, suggesting the complexity of the response to CIH on glycemia, which may at best be mixed, and in some scenarios deleterious. Additionally, CIH worsens nonalcoholic fatty liver disease and other types of liver injury in mice with diet-induced obesity (Savransky et al., 2007a, Savransky et al., 2007c; Mesarwi et al., 2021), and alters lipid metabolism (Drager et al., 2012; Jun et al., 2012; Yao et al., 2013; Zhen et al., 2021). It is important to note that the CIH model used in these studies is frequently designed to simulate severe OSA—that is, with severe reductions in nadir FiO₂ (0.04–0.07), and a high ODI. The effects of less severe CIH on glucose and lipid metabolism are not well described.

Future Directions

Though much has been accomplished regarding our understanding of the diverse cardio-metabolic consequences of CSH and CIH, there are clearly areas which merit further investigation. First, there are gaps in our understanding of the physiological effects of milder CIH and CSH. CSH has been investigated mostly with an FiO₂ of 0.10, which likely represents a level of hypoxemia more severe than commonly observed in chronic heart/lung diseases in humans. It has been suggested that one might expect adaptive, rather than maladaptive, physiological responses to milder CIH (Navarrete-Opazo and Mitchell, 2014). Second, some of the outcomes presented in this mini-review have only a minimal amount of accompanying mechanistic data; there is undoubtedly room to devote more complete exploration of these concepts. Third, in particular when considering effects of CSH, one must consider whether normobaric hypoxia differs from hypobaric hypoxia, which has relevance for studies involving physiological outcomes of CSH models intended to mimic exposure to high altitude. Although there has been debate about this topic for years (Millet et al., 2012; Mounier and Brugniaux, 2012), animal studies examining the effects of CSH are typically not performed in both conditions, creating uncertainty about the impact of atmospheric pressure on the outcome being measured. Indeed, the uncertainty on this point extends to human-based research as well (Coppel et al., 2015). Finally, in our group, we have noted unique cardio-metabolic consequences of combined sustained and intermittent hypoxia, or “overlap hypoxia”, which may be used to model the COPD/OSA overlap syndrome, or periodic breathing at high altitude (Zhen et al., 2021). A systematic approach to understanding the hypoxemia of this unique condition is needed.

Conclusion

Both CSH and CIH are associated with unique, and sometimes maladaptive, physiological responses, though there are considerable differences between these types of hypoxic exposures. CSH and CIH are intended to mimic hypoxemia in human disease states, but the heterogeneity of hypoxemia severity in cardiovascular and pulmonary disease mandates that attention be given to novel and more nuanced models. Future work can be directed toward these goals, as well as toward better understanding of the mechanisms by which hypoxia alters cardio-metabolic physiology in animals.

Author Contributions

All authors agree to be accountable for the content of the work in this manuscript. OM, AS, and LB all contributed equally to the writing of the manuscript. LB and OM made final edits.

Funding

LB is funded by NIH T32HL134632. OM is funded by NIH K08HL143140. AS is funded by an Alfonso Martin Escudero grant.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Arnaud C., Poulain L., Lévy P., Dematteis M. (2011). Inflammation Contributes to the Atherogenic Role of Intermittent Hypoxia in Apolipoprotein-E Knock out Mice. Atherosclerosis 219, 425–431. doi:10.1016/j.atherosclerosis.2011.07.122

Bender P. R., Groves B. M., McCullough R. E., McCullough R. G., Huang S. Y., Hamilton A. J., et al. (1988). Oxygen Transport to Exercising Leg in Chronic Hypoxia. J. Appl. Physiol. 65, 2592–2597. doi:10.1152/jappl.1988.65.6.2592

Benjafield A. V., Ayas N. T., Eastwood P. R., Heinzer R., Ip M. S. M., Morrell M. J., et al. (2019). Estimation of the Global Prevalence and burden of Obstructive Sleep Apnoea: a Literature-Based Analysis. Lancet Respir. Med. 7, 687–698. doi:10.1016/S2213-2600(19)30198-5

Braga V. A., Soriano R. N., Machado B. H. (2006). Sympathoexcitatory Response to Peripheral Chemoreflex Activation Is Enhanced in Juvenile Rats Exposed to Chronic Intermittent Hypoxia. Exp. Physiol. 91, 1025–1031. doi:10.1113/expphysiol.2006.034868

Cahill E., Rowan S. C., Sands M., Banahan M., Ryan D., Howell K., et al. (2012). The Pathophysiological Basis of Chronic Hypoxic Pulmonary Hypertension in the Mouse: Vasoconstrictor and Structural Mechanisms Contribute Equally. Exp. Physiol. 97, 796–806. doi:10.1113/expphysiol.2012.065474

Campen M. J., Shimoda L. A., O’Donnell C. P. (2005). Acute and Chronic Cardiovascular Effects of Intermittent Hypoxia in C57BL/6J Mice. J. Appl. Physiology(1985) 99, 2028–2035. doi:10.1152/japplphysiol.00411.2005

Cananzi S. G., White L. A., Barzegar M., Boyer C. J., Chernyshev O. Y., Yun J. W., et al. (2020). Obstructive Sleep Apnea Intensifies Stroke Severity Following Middle Cerebral Artery Occlusion. Sleep Med. 67, 278–285. doi:10.1016/j.sleep.2020.01.014

Capone C., Faraco G., Coleman C., Young C. N., Pickel V. M., Anrather J., et al. (2012). Endothelin 1-dependent Neurovascular Dysfunction in Chronic Intermittent Hypoxia. Hypertension 60, 106–113. doi:10.1161/HYPERTENSIONAHA.112.193672

Carreras A., Kayali F., Zhang J., Hirotsu C., Wang Y., Gozal D. (2012). Metabolic Effects of Intermittent Hypoxia in Mice: Steady versus High-Frequency Applied Hypoxia Daily during the Rest Period. Am. J. Physiology-Regulatory, Integr. Comp. Physiol. 303, R700–R709. doi:10.1152/ajpregu.00258.2012

Chaouat A., Weitzenblum E., Krieger J., Oswald M., Kessler R. (1996). Pulmonary Hemodynamics in the Obstructive Sleep Apnea Syndrome. Chest 109, 380–386. doi:10.1378/chest.109.2.380

Coppel J., Hennis P., Gilbert-Kawai E., Grocott M. P. (2015). The Physiological Effects of Hypobaric Hypoxia versus Normobaric Hypoxia: a Systematic Review of Crossover Trials. Extrem Physiol. Med. 4, 2. doi:10.1186/s13728-014-0021-6

Cowburn A. S., Macias D., Summers C., Chilvers E. R., Johnson R. S. (2017). Cardiovascular Adaptation to Hypoxia and the Role of Peripheral Resistance. Elife 6, e28755. doi:10.7554/eLife.28755

Das A. M., Khan M. (2012). Obstructive Sleep Apnea and Stroke. Expert Rev. Cardiovasc. Ther. 10, 525–535. doi:10.1586/erc.12.25

Dick T. E., Hsieh Y.-H., Wang N., Prabhakar N. (2007). Acute Intermittent Hypoxia Increases Both Phrenic and Sympathetic Nerve Activities in the Rat. Exp. Physiol. 92, 87–97. doi:10.1113/expphysiol.2006.035758

Drager L. F., Li J., Reinke C., Bevans-Fonti S., Jun J. C., Polotsky V. Y. (2011). Intermittent Hypoxia Exacerbates Metabolic Effects of Diet-Induced Obesity. Obesity (Silver Spring) 19, 2167–2174. doi:10.1038/oby.2011.240

Drager L. F., Li J., Shin M.-K., Reinke C., Aggarwal N. R., Jun J. C., et al. (2012). Intermittent Hypoxia Inhibits Clearance of Triglyceride-Rich Lipoproteins and Inactivates Adipose Lipoprotein Lipase in a Mouse Model of Sleep Apnoea. Eur. Heart J. 33, 783–790. doi:10.1093/eurheartj/ehr097

Drager L. F., Yao Q., Hernandez K. L., Shin M.-K., Bevans-Fonti S., Gay J., et al. (2013). Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4. Am. J. Respir. Crit. Care Med. 188, 240–248. doi:10.1164/rccm.201209-1688OC

Dyken M. E., Somers V. K., Yamada T., Ren Z.-Y., Zimmerman M. B. (1996). Investigating the Relationship between Stroke and Obstructive Sleep Apnea. Stroke 27, 401–407. doi:10.1161/01.str.27.3.401

Fagan K. A. (2001). Selected Contribution: Pulmonary Hypertension in Mice Following Intermittent Hypoxia. J. Appl. Physiology(1985) 90, 2502–2507. doi:10.1152/jappl.2001.90.6.2502

Fang G., Song D., Ye X., Mao S.-z., Liu G., Liu S. F. (2012). Chronic Intermittent Hypoxia Exposure Induces Atherosclerosis in ApoE Knockout Mice. Am. J. Pathol. 181, 1530–1539. doi:10.1016/j.ajpath.2012.07.024

Farré R., Montserrat J. M., Gozal D., Almendros I., Navajas D. (2018). Intermittent Hypoxia Severity in Animal Models of Sleep Apnea. Front. Physiol. 9, 1556. doi:10.3389/fphys.2018.01556

Ferns G. A. A., Heikal L. (2017). Hypoxia in Atherogenesis. Angiology 68, 472–493. doi:10.1177/0003319716662423

Fishman A. P. (1976). Hypoxia on the Pulmonary Circulation. How and where it Acts. Circ. Res. 38, 221–231. doi:10.1161/01.res.38.4.221

Fletcher E. C. (2001). Invited Review: Physiological Consequences of Intermittent Hypoxia: Systemic Blood Pressure. J. Appl. Physiology(1985) 90, 1600–1605. doi:10.1152/jappl.2001.90.4.1600

Fletcher E. C., Lesske J., Behm R., Miller C. C., Stauss H., Unger T. (1992). Carotid Chemoreceptors, Systemic Blood Pressure, and Chronic Episodic Hypoxia Mimicking Sleep Apnea. J. Appl. Phys. 72, 1978–1984. doi:10.1152/jappl.1992.72.5.1978

Fletcher E. C., Lesske J., Qian W., Miller C. C., Unger T. (1992). Repetitive, Episodic Hypoxia Causes Diurnal Elevation of Blood Pressure in Rats. Hypertension 19, 555–561. doi:10.1161/01.hyp.19.6.555

Frank D. B., Lowery J., Anderson L., Brink M., Reese J., de Caestecker M. (2008). Increased Susceptibility to Hypoxic Pulmonary Hypertension in Bmpr2 Mutant Mice Is Associated with Endothelial Dysfunction in the Pulmonary Vasculature. Am. J. Physiology-Lung Cell Mol. Physiol. 294, L98–L109. doi:10.1152/ajplung.00034.2007

Fregly M. J. (1963). Effect of Chronic Exposure to Hypoxia on Blood Pressure and Thyroid function of Hypertensive Rats. Florida: Florida Univ Gainesville J Hillis Miller Health Center. Available at: https://apps.dtic.mil/sti/citations/AD0402013 (Accessed February 8, 2022).

Fregly M. J. (1970). Effect of Chronic Exposure to Hypoxia on Development and Maintenance of Renal Hypertension in Rats. Exp. Biol. Med. 134, 78–82. doi:10.3181/00379727-134-34732

Gamboa J. L., Garcia-Cazarin M. L., Andrade F. H. (2011). Chronic Hypoxia Increases Insulin-Stimulated Glucose Uptake in Mouse Soleus Muscle. Am. J. Physiology-Regulatory, Integr. Comp. Physiol. 300, R85–R91. doi:10.1152/ajpregu.00078.2010

Gautier-Veyret E., Arnaud C., Bäck M., Pépin J.-L., Petri M. H., Baguet J.-P., et al. (2013). Intermittent Hypoxia-Activated Cyclooxygenase Pathway: Role in Atherosclerosis. Eur. Respir. J. 42, 404–413. doi:10.1183/09031936.00096512

Gileles-Hillel A., Almendros I., Khalyfa A., Zhang S. X., Wang Y., Gozal D. (2014). Early Intermittent Hypoxia Induces Proatherogenic Changes in Aortic wall Macrophages in a Murine Model of Obstructive Sleep Apnea. Am. J. Respir. Crit. Care Med. 190, 958–961. doi:10.1164/rccm.201406-1149LE

Gonzalez-Rothi E. J., Lee K.-Z., Dale E. A., Reier P. J., Mitchell G. S., Fuller D. D. (2015). Intermittent Hypoxia and Neurorehabilitation. J. Appl. Physiology(1985) 119, 1455–1465. doi:10.1152/japplphysiol.00235.2015

Henley W. N., Tucker A. (1987). Hypoxic Moderation of Systemic Hypertension in the Spontaneously Hypertensive Rat. Am. J. Physiology-Regulatory, Integr. Comp. Physiol. 252, R554–R561. doi:10.1152/ajpregu.1987.252.3.R554

Hinojosa-Laborde C., Mifflin S. W. (2005). Sex Differences in Blood Pressure Response to Intermittent Hypoxia in Rats. Hypertension 46, 1016–1021. doi:10.1161/01.HYP.0000175477.33816.f3

Hislop A., Reid L. (1976). New Findings in Pulmonary Arteries of Rats with Hypoxia-Induced Pulmonary Hypertension. Br. J. Exp. Pathol. 57, 542–554.

Hui A. S., Striet J. B., Gudelsky G., Soukhova G. K., Gozal E., Beitner-Johnson D., et al. (2003). Regulation of Catecholamines by Sustained and Intermittent Hypoxia in Neuroendocrine Cells and Sympathetic Neurons. Hypertension 42, 1130–1136. doi:10.1161/01.HYP.0000101691.12358.26

Iiyori N., Alonso L. C., Li J., Sanders M. H., Garcia-Ocana A., O'Doherty R. M., et al. (2007). Intermittent Hypoxia Causes Insulin Resistance in Lean Mice Independent of Autonomic Activity. Am. J. Respir. Crit. Care Med. 175, 851–857. doi:10.1164/rccm.200610-1527OC

Ioja S., Singamsetty S., Corey C., Guo L., Shah F., Jurczak M. J., et al. (2018). Nocturnal Hypoxia Improves Glucose Disposal, Decreases Mitochondrial Efficiency, and Increases Reactive Oxygen Species in the Muscle and Liver of C57BL/6J Mice Independent of Weight Change. Oxidative Med. Cell Longevity 2018, 1–12. doi:10.1155/2018/9649608

Iwase N., Kikuchi Y., Hida W., Miki H., Taguchi O., Satoh M., et al. (1992). Effects of Repetitive Airway Obstruction on O2Saturation and Systemic and Pulmonary Arterial Pressure in Anesthetized Dogs. Am. Rev. Respir. Dis. 146, 1402–1410. doi:10.1164/ajrccm/146.6.1402

Iyer N. V., Kotch L. E., Agani F., Leung S. W., Laughner E., Wenger R. H., et al. (1998). Cellular and Developmental Control of O2 Homeostasis by Hypoxia-Inducible Factor 1α. Genes Dev. 12, 149–162. doi:10.1101/gad.12.2.149

Jackman K. A., Zhou P., Faraco G., Peixoto P. M., Coleman C., Voss H. U., et al. (2014). Dichotomous Effects of Chronic Intermittent Hypoxia on Focal Cerebral Ischemic Injury. Stroke 45, 1460–1467. doi:10.1161/STROKEAHA.114.004816

Jun J. C., Shin M.-K., Yao Q., Bevans-Fonti S., Poole J., Drager L. F., et al. (2012). Acute Hypoxia Induces Hypertriglyceridemia by Decreasing Plasma Triglyceride Clearance in Mice. Am. J. Physiology-Endocrinology Metab. 303, E377–E388. doi:10.1152/ajpendo.00641.2011

Jun J., Reinke C., Bedja D., Berkowitz D., Bevans-Fonti S., Li J., et al. (2010). Effect of Intermittent Hypoxia on Atherosclerosis in Apolipoprotein E-Deficient Mice. Atherosclerosis 209, 381–386. doi:10.1016/j.atherosclerosis.2009.10.017

Kasivisvanathan V., Shalhoub J., S. Lim C., C. Shepherd A., Thapar A., H. Davies A. (2011). Hypoxia-inducible Factor-1 in Arterial Disease: a Putative Therapeutic Target. Cvp 9, 333–349. doi:10.2174/157016111795495602

Kudchodkar B., Jones H., Simecka J., Dory L. (2008). Hyperbaric Oxygen Treatment Attenuates the Pro-inflammatory and Immune Responses in Apolipoprotein E Knockout Mice. Clin. Immunol. 128, 435–441. doi:10.1016/j.clim.2008.05.004

Kudchodkar B. J., Pierce A., Dory L. (2007). Chronic Hyperbaric Oxygen Treatment Elicits an Anti-oxidant Response and Attenuates Atherosclerosis in apoE Knockout Mice. Atherosclerosis 193, 28–35. doi:10.1016/j.atherosclerosis.2006.08.018

Kudchodkar B. J., Wilson J., Lacko A., Dory L. (2000). Hyperbaric Oxygen Reduces the Progression and Accelerates the Regression of Atherosclerosis in Rabbits. Atvb 20, 1637–1643. doi:10.1161/01.atv.20.6.1637

Lam S.-Y., Liu Y., Ng K.-M., Lau C.-F., Liong E. C., Tipoe G. L., et al. (2012). Chronic Intermittent Hypoxia Induces Local Inflammation of the Rat Carotid Body via Functional Upregulation of Proinflammatory Cytokine Pathways. Histochem. Cel Biol 137, 303–317. doi:10.1007/s00418-011-0900-5

Lam S.-Y., Liu Y., Ng K.-M., Liong E. C., Tipoe G. L., Leung P. S., et al. (2014). Upregulation of a Local Renin-Angiotensin System in the Rat Carotid Body during Chronic Intermittent Hypoxia. Exp. Physiol. 99, 220–231. doi:10.1113/expphysiol.2013.074591

Lee E. J., Alonso L. C., Stefanovski D., Strollo H. C., Romano L. C., Zou B., et al. (2013). Time-dependent Changes in Glucose and Insulin Regulation during Intermittent Hypoxia and Continuous Hypoxia. Eur. J. Appl. Physiol. 113, 467–478. doi:10.1007/s00421-012-2452-3

Lesske J., Fletcher E. C., Bao G., Unger T. (1997). Hypertension Caused by Chronic Intermittent Hypoxia - Influence of Chemoreceptors and Sympathetic Nervous System. J. Hypertens. 15, 1593–1603. doi:10.1097/00004872-199715120-00060

Lim C. S., Kiriakidis S., Sandison A., Paleolog E. M., Davies A. H. (2013). Hypoxia-inducible Factor Pathway and Diseases of the Vascular wall. J. Vasc. Surg. 58, 219–230. doi:10.1016/j.jvs.2013.02.240

Marcouiller F., Jochmans-Lemoine A., Ganouna-Cohen G., Mouchiroud M., Laplante M., Marette A., et al. (2021). Metabolic Responses to Intermittent Hypoxia Are Regulated by Sex and Estradiol in Mice. Am. J. Physiology-Endocrinology Metab. 320, E316–E325. doi:10.1152/ajpendo.00272.2020

McGuire M., Bradford A. (2001). Chronic Intermittent Hypercapnic Hypoxia Increases Pulmonary Arterial Pressure and Haematocrit in Rats. Eur. Respir. J. 18, 279–285. doi:10.1183/09031936.01.00078801

Mendis S., Puska P., Norrving B., Organization W. H., Federation W. H., Organization W. S. (2011). Global Atlas on Cardiovascular Disease Prevention and Control. World Health Organization Available at: https://apps.who.int/iris/handle/10665/44701 (Accessed February 8, 2022).

Mesarwi O. A., Moya E. A., Zhen X., Gautane M., Zhao H., Wegbrans Giró P., et al. (2021). Hepatocyte HIF-1 and Intermittent Hypoxia Independently Impact Liver Fibrosis in Murine Nonalcoholic Fatty Liver Disease. Am. J. Respir. Cel Mol Biol 65, 390–402. doi:10.1165/rcmb.2020-0492OC

Meyrick B., Reid L. (1978). The Effect of Continued Hypoxia on Rat Pulmonary Arterial Circulation. An Ultrastructural Study. Lab. Invest. 38, 188–200.

Millet G. P., Faiss R., Pialoux V. (2012). Point: Counterpoint: Hypobaric Hypoxia Induces/does Not Induce Different Responses from Normobaric Hypoxia. J. Appl. Physiology(1985) 112, 1783–1784. doi:10.1152/japplphysiol.00067.2012

Mounier R., Brugniaux J. V. (2012). Counterpoint: Hypobaric Hypoxia Does Not Induce Different Responses from Normobaric Hypoxia. J. Appl. Physiology(1985) 112, 1784–1786. doi:10.1152/japplphysiol.00067.2012a

Nara A., Nagai H., Shintani-Ishida K., Ogura S., Shimosawa T., Kuwahira I., et al. (2015). Pulmonary Arterial Hypertension in Rats Due to Age-Related Arginase Activation in Intermittent Hypoxia. Am. J. Respir. Cel Mol Biol 53, 184–192. doi:10.1165/rcmb.2014-0163OC

Navarrete-Opazo A., Mitchell G. S. (2014). Therapeutic Potential of Intermittent Hypoxia: a Matter of Dose. Am. J. Physiology-Regulatory, Integr. Comp. Physiol. 307, R1181–R1197. doi:10.1152/ajpregu.00208.2014

Navarrete-Opazo A., Vinit S., Dougherty B. J., Mitchell G. S. (2015). Daily Acute Intermittent Hypoxia Elicits Functional Recovery of Diaphragm and Inspiratory Intercostal Muscle Activity after Acute Cervical Spinal Injury. Exp. Neurol. 266, 1–10. doi:10.1016/j.expneurol.2015.02.007

Nisbet R. E., Graves A. S., Kleinhenz D. J., Rupnow H. L., Reed A. L., Fan T.-H. M., et al. (2009). The Role of NADPH Oxidase in Chronic Intermittent Hypoxia-Induced Pulmonary Hypertension in Mice. Am. J. Respir. Cel Mol Biol 40, 601–609. doi:10.1165/2008-0145OC

Perkin R. M., Anas N. G. (1984). Pulmonary Hypertension in Pediatric Patients. J. Pediatr. 105, 511–522. doi:10.1016/s0022-3476(84)80413-8

Phillips S. A., Olson E. B., Morgan B. J., Lombard J. H. (2004). Chronic Intermittent Hypoxia Impairs Endothelium-dependent Dilation in Rat Cerebral and Skeletal Muscle Resistance Arteries. Am. J. Physiology-Heart Circulatory Physiol. 286, H388–H393. doi:10.1152/ajpheart.00683.2003

Polotsky V. Y., Li J., Punjabi N. M., Rubin A. E., Smith P. L., Schwartz A. R., et al. (2003). Intermittent Hypoxia Increases Insulin Resistance in Genetically Obese Mice. J. Physiol. 552, 253–264. doi:10.1113/jphysiol.2003.048173

Prabhakar N. R., Kumar G. K. (2010). Mechanisms of Sympathetic Activation and Blood Pressure Elevation by Intermittent Hypoxia. Respir. Physiol. Neurobiol. 174, 156–161. doi:10.1016/j.resp.2010.08.021

Prieto-Lloret J., Olea E., Gordillo-Cano A., Docio I., Obeso A., Gomez-Niño A., et al. (2021). Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat. Antioxidants 11, 54. doi:10.3390/antiox11010054

Rabinovitch M., Gamble W., Nadas A. S., Miettinen O. S., Reid L. (1979). Rat Pulmonary Circulation after Chronic Hypoxia: Hemodynamic and Structural Features. Am. J. Physiology-Heart Circulatory Physiol. 236, H818–H827. doi:10.1152/ajpheart.1979.236.6.H818

Randelman M., Zholudeva L. V., Vinit S., Lane M. A. (2021). Respiratory Training and Plasticity after Cervical Spinal Cord Injury. Front. Cel. Neurosci. 15, 700821. doi:10.3389/fncel.2021.700821

Reinke C., Bevans-Fonti S., Drager L. F., Shin M.-K., Polotsky V. Y. (2011). Effects of Different Acute Hypoxic Regimens on Tissue Oxygen Profiles and Metabolic Outcomes. J. Appl. Physiology(1985) 111, 881–890. doi:10.1152/japplphysiol.00492.2011

Rotta A. (1947). Physiologic Condition of the Heart in the Natives of High Altitudes. Am. Heart J. 33, 669–676. doi:10.1016/0002-8703(47)90083-5

Ruiz L., Peñaloza D. (1977). Altitude and Hypertension. Mayo Clin. Proc. 52, 442–445.

Sajkov D., McEvoy R. D. (2009). Obstructive Sleep Apnea and Pulmonary Hypertension. Prog. Cardiovasc. Dis. 51, 363–370. doi:10.1016/j.pcad.2008.06.001

Sajkov D., Wang T., Saunders N. A., Bune A. J., Neill A. M., McEvoy R. D. (1999). Daytime Pulmonary Hemodynamics in Patients with Obstructive Sleep Apnea without Lung Disease. Am. J. Respir. Crit. Care Med. 159, 1518–1526. doi:10.1164/ajrccm.159.5.9805086

Samhouri B., Venkatasaburamini M., Paz Y Mar H., Li M., Mehra R., Chaisson N. F. (2020). Pulmonary Artery Hemodynamics Are Associated with Duration of Nocturnal Desaturation but Not Apnea-Hypopnea index. J. Clin. Sleep Med. 16, 1231–1239. doi:10.5664/jcsm.8468

Savransky V., Bevans S., Nanayakkara A., Li J., Smith P. L., Torbenson M. S., et al. (2007a). Chronic Intermittent Hypoxia Causes Hepatitis in a Mouse Model of Diet-Induced Fatty Liver. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G871–G877. doi:10.1152/ajpgi.00145.2007

Savransky V., Nanayakkara A., Li J., Bevans S., Smith P. L., Rodriguez A., et al. (2007b). Chronic Intermittent Hypoxia Induces Atherosclerosis. Am. J. Respir. Crit. Care Med. 175, 1290–1297. doi:10.1164/rccm.200612-1771OC

Savransky V., Nanayakkara A., Vivero A., Li J., Bevans S., Smith P. L., et al. (2007c). Chronic Intermittent Hypoxia Predisposes to Liver Injury. Hepatology 45, 1007–1013. doi:10.1002/hep.21593

Schulz R., Murzabekova G., Egemnazarov B., Kraut S., Eisele H.-J., Dumitrascu R., et al. (2014). Arterial Hypertension in a Murine Model of Sleep Apnea. J. Hypertens. 32, 300–305. doi:10.1097/HJH.0000000000000016

Semenza G. L., Prabhakar N. R. (2015). Neural Regulation of Hypoxia-Inducible Factors and Redox State Drives the Pathogenesis of Hypertension in a Rodent Model of Sleep Apnea. J. Appl. Physiology(1985) 119, 1152–1156. doi:10.1152/japplphysiol.00162.2015

Sluimer J. C., Gasc J.-M., van Wanroij J. L., Kisters N., Groeneweg M., Sollewijn Gelpke M. D., et al. (2008). Hypoxia, Hypoxia-Inducible Transcription Factor, and Macrophages in Human Atherosclerotic Plaques Are Correlated with Intraplaque Angiogenesis. J. Am. Coll. Cardiol. 51, 1258–1265. doi:10.1016/j.jacc.2007.12.025

Snow J. B., Norton C. E., Sands M. A., Weise-Cross L., Yan S., Herbert L. M., et al. (2020). Intermittent Hypoxia Augments Pulmonary Vasoconstrictor Reactivity through PKCβ/Mitochondrial Oxidant Signaling. Am. J. Respir. Cel Mol Biol 62, 732–746. doi:10.1165/rcmb.2019-0351OC

Song D., Fang G., Mao S.-Z., Ye X., Liu G., Gong Y., et al. (2012). Chronic Intermittent Hypoxia Induces Atherosclerosis by NF-κb-dependent Mechanisms. Biochim. Biophys. Acta (Bba) - Mol. Basis Dis. 1822, 1650–1659. doi:10.1016/j.bbadis.2012.07.010

Song D., Fang G., Mao S.-Z., Ye X., Liu G., Miller E. J., et al. (2018). Selective Inhibition of Endothelial NF-Κb Signaling Attenuates Chronic Intermittent Hypoxia-Induced Atherosclerosis in Mice. Atherosclerosis 270, 68–75. doi:10.1016/j.atherosclerosis.2018.01.027

Stenmark K. R., Meyrick B., Galie N., Mooi W. J., McMurtry I. F. (2009). Animal Models of Pulmonary Arterial Hypertension: the hope for Etiological Discovery and Pharmacological Cure. Am. J. Physiology-Lung Cell Mol. Physiol. 297, L1013–L1032. doi:10.1152/ajplung.00217.2009

Tahawi Z., Orolinova N., Joshua I. G., Bader M., Fletcher E. C. (2001). Selected Contribution: Altered Vascular Reactivity in Arterioles of Chronic Intermittent Hypoxic Rats. J. Appl. Physiology(1985) 90, 2007–2013. discussion 2000. doi:10.1152/jappl.2001.90.5.2007

Thomas A., Belaidi E., Moulin S., Horman S., van der Zon G. C., Viollet B., et al. (2017). Chronic Intermittent Hypoxia Impairs Insulin Sensitivity but Improves Whole-Body Glucose Tolerance by Activating Skeletal Muscle AMPK. Diabetes 66, 2942–2951. doi:10.2337/db17-0186

Vaziri N. D., Wang Z. Q. (1996). Sustained Systemic Arterial Hypertension Induced by Extended Hypobaric Hypoxia. Kidney Int. 49, 1457–1463. doi:10.1038/ki.1996.205

Vilar J., Waeckel L., Bonnin P., Cochain C., Loinard C., Duriez M., et al. (2008). Chronic Hypoxia-Induced Angiogenesis Normalizes Blood Pressure in Spontaneously Hypertensive Rats. Circ. Res. 103, 761–769. doi:10.1161/CIRCRESAHA.108.182758

Voelkel N. F. (1986). Mechanisms of Hypoxic Pulmonary Vasoconstriction. Am. Rev. Respir. Dis. 133, 1186–1195. doi:10.1164/arrd.1986.133.6.1186

Wagenvoort C. A. (1977). Pathology of Pulmonary Hypertension. New York: Wiley.

Wang Z., Li A.-Y., Guo Q.-H., Zhang J.-P., An Q., Guo Y.-j., et al. (2013). Effects of Cyclic Intermittent Hypoxia on ET-1 Responsiveness and Endothelial Dysfunction of Pulmonary Arteries in Rats. PLoS One 8, e58078. doi:10.1371/journal.pone.0058078

Wolfel E. E., Groves B. M., Brooks G. A., Butterfield G. E., Mazzeo R. S., Moore L. G., et al. (1991). Oxygen Transport during Steady-State Submaximal Exercise in Chronic Hypoxia. J. Appl. Physiology(1985) 70, 1129–1136. doi:10.1152/jappl.1991.70.3.1129

Wolfel E. E., Selland M. A., Mazzeo R. S., Reeves J. T. (1994). Systemic Hypertension at 4,300 M Is Related to Sympathoadrenal Activity. J. Appl. Physiology(1985) 76, 1643–1650. doi:10.1152/jappl.1994.76.4.1643

Yaggi H. K., Concato J., Kernan W. N., Lichtman J. H., Brass L. M., Mohsenin V. (2005). Obstructive Sleep Apnea as a Risk Factor for Stroke and Death. N. Engl. J. Med. 353, 2034–2041. doi:10.1056/NEJMoa043104

Yao Q., Shin M.-K., Jun J. C., Hernandez K. L., Aggarwal N. R., Mock J. R., et al. (2013). Effect of Chronic Intermittent Hypoxia on Triglyceride Uptake in Different Tissues. J. Lipid Res. 54, 1058–1065. doi:10.1194/jlr.M034272

Yuan G., Khan S. A., Luo W., Nanduri J., Semenza G. L., Prabhakar N. R. (2011). Hypoxia-inducible Factor 1 Mediates Increased Expression of NADPH Oxidase-2 in Response to Intermittent Hypoxia. J. Cel. Physiol. 226, 2925–2933. doi:10.1002/jcp.22640

Zhang H., Rzechorzek W., Aghajanian A., Faber J. E. (2020). Hypoxia Induces De Novo Formation of Cerebral Collaterals and Lessens the Severity of Ischemic Stroke. J. Cereb. Blood Flow Metab. 40, 1806–1822. doi:10.1177/0271678X20924107

Zhen X., Moya E. A., Gautane M., Zhao H., Lawrence E. S., Gu W., et al. (2021). Combined Intermittent and Sustained Hypoxia Is a Novel and Deleterious Cardio-Metabolic Phenotype. Sleep, zsab290. doi:10.1093/sleep/zsab290

Zhou S., Wang Y., Tan Y., Cai X., Cai L., Cai J., et al. (2014). Deletion of Metallothionein Exacerbates Intermittent Hypoxia-Induced Oxidative and Inflammatory Injury in Aorta. Oxidative Med. Cell Longevity 2014, 1–11. doi:10.1155/2014/141053

Zoccal D. B., Colombari D. S. A., Colombari E., Flor K. C., da Silva M. P., Costa‐Silva J. H., et al. (2019). Centrally Acting Adrenomedullin in the Long‐term Potentiation of Sympathetic Vasoconstrictor Activity Induced by Intermittent Hypoxia in Rats. Exp. Physiol. 104, 1371–1383. doi:10.1113/EP087613