Cardiovascular morbidities of obstructive sleep apnea and the role of circulating extracellular vesicles

Abstract

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway collapse during sleep resulting in impaired blood gas exchange, namely intermittent hypoxia (IH) and hypercapnia, fragmented sleep (SF), increased oxidative stress and systemic inflammation. Among a myriad of potential associated morbidities, OSA has been particularly implicated as mechanistically contributing to the prevalence and severity of cardiovascular diseases (CVD). However, the benefits of continuous positive airway pressure (CPAP), which is generally employed in OSA treatment, to either prevent or improve CVD outcomes remain unconvincing, suggesting that the pathophysiological mechanisms underlying the incremental CVD risk associated with OSA are not clearly understood. One of the challenges in development of non-invasive diagnostic assays is the ability to identify clinically and mechanistically relevant biomarkers. Circulating extracellular vesicles (EVs) and their cargos reflect underlying changes in cellular homeostasis and can provide insights into how cells and systems cope with physiological perturbations by virtue of the identity and abundance of miRNAs, mRNAs, proteins, and lipids that are packaged in the EVs under normal as well as diseased states, such as OSA. EVs can not only provide unique insights into coordinated cellular responses at the organ or systemic level, but can also serve as reporters of the effects of OSA in CVD, either by their properties enabling regeneration and repair of injured vascular cells or by damaging them. Here, we highlight recent progress in the pathological CVD consequences of OSA, and explore the putative roles of EVs in OSA-associated CVD, along with emerging diagnostic and therapeutic opportunities.

The reviews of this paper are available via the supplemental material section.

Keywords

CVDs exosomes extracellular vesicles pathology of OSA OSA

Obstructive sleep apnea and cardiovascular morbidity and treatment

Obstructive sleep apnea (OSA) is a highly prevalent condition characterized by repetitive episodes of partial (hypopnea) or complete (apnea) obstruction of the upper airways, resulting in episodic reductions in oxyhemoglobin saturation followed by reoxygenation upon upper airway opening during sleep,¹ a phenomenon usually denoted as intermittent hypoxia (IH). OSA is also associated with recurrent intermittent hypercapnia, increased intrathoracic pressure swings, and with sleep fragmentation, as illustrated by the recurring arousals triggered by the respiratory perturbations. The actual prevalence of OSA varies tremendously between studies, with more conservative estimates of 3% in women and 10% in men between the ages of 30–49 years, and 9% in women and 17% in men between the age of 50–70 years.^2–8 Among myriad reported associations on OSA morbidity, untreated OSA has been particularly reported to exert adverse consequences, such as excessive daytime sleepiness, cardiometabolic complications, neurocognitive and mood disorders, and an increased incidence of motor vehicle accidents, along with poor overall quality of life and increased overall mortality.^9–13 In Figure 1, we show the impact of OSA on end-organ function as being mediated by interactions of four different categories (events, mechanisms, consequences, and diseases), ultimately leading to unique personal fingerprints of OSA in each individual.¹⁴ Intermittent hypoxia, sleep fragmentation, short sleep duration, and circadian misalignment, either individually or in combination, can lead to the activation of several pathogenetic pathways, ultimately resulting in oxidative stress and inflammation, along with recruitment of autonomic nervous system imbalance with increased sympathetic outflow and reactivity, as well as vagal withdrawal in the context of major activation of stress pathways as reflected by the recruitment of the hypothalamic-pituitary-adrenal (HPA) axis. As consequences, increased systemic blood pressure, endothelial dysfunction, hypercoagulability, dyslipidemia, and insulin resistance are representative elements of end-organ dysfunction that ultimately lead to systemic hypertension, atherosclerosis, and associated ischemic cardiovascular and cerebrovascular diseases, and metabolic disorders.^15–18 It has been proposed that stiffness of endothelial cells is closely linked to the function of the vasculature, as it regulates the release of vasoactive substances such as nitric oxide (NO) and reactive oxygen species.¹⁹ OSA has been linked with increased oxidative stress characterized by increasing superoxide anion release from circulating leukocytes, leading to reduced nitric oxide bioavailability and increased lipid peroxidation.^20,21 Associations between sleep disturbances, circadian dysfunction, and adverse outcomes affecting the cardiovascular and metabolic systems, in addition to multiple other deleterious consequences, have been reported, and the evidence continues to gain credibility toward causative biological plausibility. For example, sleep restriction or disruption impact molecular mechanisms in peripheral tissues, such as innate immune cells and metabolically active organs.^22–27 Recently, we have shown that alternating dark–light cycles mimicking shift work in mice altered their fecal microbiota and colonic epithelium permeability, ultimately leading to metabolic dysfunction.²⁸ Several studies have explored the diurnal and evening-to-morning differences in circulating microvesicles, including in OSA, and, conversely, the potential role of circulating microvesicles in regulating peripheral clocks has also been investigated.^29–33

Figure 1.

Schematic diagram illustrating the systems-based approach to the pathology of OSA, by enunciating the major physiologic alterations in OSA, including four different categories of events (intermittent hypoxia, sleep fragmentation, short sleep duration, and circadian misalignment), mechanisms (sympathetic activation, HPA axis alterations, oxidative stress, and inflammation), consequences (endothelial dysfunction, increased blood pressure, islet cell dysfunction, and insulin resistance), and diseases (hypertension, atherosclerosis, coronary artery disease, and metabolic disorders).

To better understand the implications of OSA and its associated morbidities, a substantial search for generation of adequate animal models that reliably mimic the human disease has been the focus of major research efforts for over several decades.^34–45 A wealth of accumulated evidence suggests that chronic intermittent hypoxia (CIH), generated during repetitive apneic episodes, is one of the major key causal factors linking OSA and CVD.⁴⁶ OSA is clearly an independent mechanistically associated factor in the development of systemic hypertension, with the risk increasing as the severity of OSA increases.⁴⁷ In light of the chronicity of OSA, it becomes apparent that CIH exposures mimic OSA more closely than acute IH exposures, and the physiological responses to acute IH or acute sleep fragmentation can differ markedly from the responses to chronic comparable exposures, thereby lending the temporal domain of complexity to an already quite complex array of responses to either IH or fragmented sleep.^48–50 Indeed, the IH profiles can markedly vary in severity, cycle frequency, and duration of hypoxemia.³⁵ The choice of frequency and pattern of the stimulus results in markedly different saturations of oxyhemoglobin, with usual reported ranges from 60% to 80% in mice exposed to cycles with an inspired fraction of oxygen (F_IO₂) of 5% every 30 s, and from 83% to 86% in mice exposed to cycles with F_IO₂ of 6–10%. In this regard, different experimental protocols can be generated to simulate different degrees of severity of the disease, corresponding to mild, moderate, or severe OSA.⁵¹

The deleterious metabolic effects of CIH and prolonged sleep fragmentation in lean animals are further exacerbated by the presence of obesity or high-fat diets or the presence or absence of concurrent physical activity or nutritional supplements, emphasizing the multidirectional relationships and interactions between OSA and obesity in metabolic health.³⁹ Several of our previous studies showed that mice exposed to a well characterized sleep-fragmentation model have demonstrated the emergence of hyperphagic behaviors in awake mice when exposed to chronic sleep fragmentation,^45,52,53 resulting in accelerated body weight and visceral fat mass accruals over time, and ultimately leading to frank obesity.^42,54,55 Epidemiologic evidence has also identified the presence of a strong association between untreated OSA and the morbidity and mortality of various prevalent cardiovascular diseases.^16,56 Cardiovascular disease (CVD) is the leading global cause of death, and accounts for approximately one of every four deaths annually, thereby posing a great economic burden to both society and healthcare systems (see: https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm).⁵⁷ Identifying and developing new diagnostic or therapeutic strategies may provide multiple opportunities for reductions in the mortality increases associated with OSA in the context of CVD. Furthermore, coronary artery disease (CAD) is one of the most prevalent chronic CVD, and represents a leading cause of mortality worldwide.⁵⁸ More recent implementation of coronary computed tomography angiography (CTA) has allowed for rapid, noninvasive and direct assessment of the burden of CAD, and is a valid and increasingly employed tool in the assessment of CAD in the OSA population.^59–61

Many human diseases, including OSA, are the end-result of many dynamic and lifelong gene–environment interactions that are modulated by multilevel biological networks.⁶² CPAP treatment of OSA, particularly if adhered to, can improve cognitive function, reduce insulin resistance, and is the most effective approach to lower blood pressure in OSA patients with refractory hypertension. However, and to the substantial surprise of the sleep research community, the use of CPAP was not associated with reduced risks of cardiovascular outcomes, diabetes mellitus, or death for patients with OSA in recent randomized controlled trials.^63–68 Therefore, it is essential to develop novel pharmacological agents to counteract the pathophysiological mechanisms responsible for OSA-related adverse consequences, namely oxidative stress, sympathetic activation, and low-grade inflammation.⁶³ Beneficial effects of CPAP therapy on the level of microparticles (MPs) were reported in a small trial that consisted of the withdrawal of CPAP therapy for 2 weeks. Discontinuation of CPAP and re-emergence of OSA were associated with a significant increase in endothelial MPs levels, providing evidence that MPs formation may be causally linked to OSA, and may be promoting endothelial activation and dysfunction in these patients.⁶⁹ The increased CVD risk of patients with OSA might be due to elevated platelet-derived MPs (PDMPs), as illustrated by decreases in plasma levels of PDMPs following treatment with CPAP.⁷⁰ Of note, PDMPs can be released via platelet activation by various agonists, including inflammatory cytokines, adenosine degradation products, or high shear stress.^70–75 Microvesicles (MVs) have been implicated in the pathogenic mechanisms of OSA; however, the data have been somewhat inconsistent, possibly due to circadian and temporal variation in the levels of circulating MVs.²⁹ Furthermore, it has been reported that, in OSA patients, circulating MPs can induce endothelial dysfunction by promoting reductions in endothelial-derived NO production.⁷¹ It has also been reported that OSA is associated with upregulation of circulating sCD40L levels and increased propensity for platelet-monocyte to aggregate that may account for the increased incidence of cardiovascular events in this population.⁷⁶

Noteworthy, circulating levels of extracellular vesicles (EVs) derived from blood vessel cells are increased in CVD, including acute myocardial infarction (AMI), leading to the assumption that such EVs may serve not only as prognostic or diagnostic biomarkers, but in addition due to their ability to carry and transfer biological information at the level of the organism they present the potential to serve as biological vectors.^77,78 As such, and as a corollary to the major objectives of the present review, a succinct description of EVs and their potential usefulness in OSA will be developed.

Circulating extracellular vesicles

EVs were initially described over 30 years ago when two independent groups observed that multivesicular bodies in reticulocytes released such vesicles into the extracellular space.^79,80 Since then, EVs have been purified from nearly all mammalian cell types. Importantly, the secretion of EVs is not restricted to mammalian cells, but has also been identified in lower eukaryotes and prokaryotes.^81–83 EVs have been classified based on their cellular origin and their biological function(s). There are three main classes of EVs as determined based on their biogenesis: exosomes (30–120 nm), microvesicles (100–1000 nm), and apoptotic bodies (1000–5000 nm). Exosomes are classified as a well specified subtype of EVs, and are distinct from other types of EVs as they contain a lipid bilayer on their envelope secreted by many cell types.^84,85 Exosomes carry a large diversity of cargos including messenger RNA (mRNA), micro-RNA (miRNAs), proteins, and lipids, and play key roles in intercellular communication.^86–88 Exosomes can be isolated from many types of body fluids and conditioned cell culture medium.^86,90 Due to the important role of exosomes in intercellular communication, exosomes have the potential to be used clinically in a variety of different ways, such as to be harnessed as pharmacological delivery agents, refined as noninvasive biomarkers for early diagnosis of disease states or disease-associated consequences, and as biologic reagents to treat diseases as well as to enhance tissue repair and regeneration.^90,91 Several methods that have been proposed as providing optimal approaches to EVs isolation, but each of them is fraught with limitations, particularly in the context of epidemiological studies, where thousands of samples need to be analyzed. Therefore, further improvements in EV purification, isolation, and content characterization are required to refine their applicability and minimize interassay variability.^92–95 In addition, current isolation technologies make it difficult to distinguish different EV subpopulations. Furthermore, contamination from protein aggregates, RNA–protein complexes, and other particles may affect the EV quantification and characterization results.⁹⁶ Therefore, further research is crucial to develop simple technologies that carry a reasonable cost to isolate highly purified EVs for downstream application analysis (transcriptomics, proteomics, and lipidomics).⁹⁶ We and others believe that further improvements of EVs isolation and characterization methods, and in Omics technologies including transcriptomics, proteomics, and lipidomic analyses of EVs biological contents, will enable clinicians to adopt and refine the use of EVs and their cargos to diagnose and monitor CVDs.⁹⁷ The composition and the quantity of EVs would provide additional information on the severity of the disease.^85,98,99 Recently, we showed exosome isolation and characterization procedures as a general application pipeline that incorporates several methods for isolation, validation, and characterization.¹⁰⁰

Physiological and pathological functions of extracellular vesicles

As mentioned, EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions to change cell phenotype. Most of the studies regarding the possible physiological roles of EVs have been based on indirect in vitro evidence, especially in the context of immune system and cell-to-cell communication.¹⁰¹ Furthermore, several physiological functions of exosomes have been identified in vitro when different types of mRNAs, miRNAs, or lncRNA change their abundance inside the vesicles.^102,103 Exosomes also exhibit proangiogenesis, procoagulant and pro- or anti-inflammatory effects as well as altering effects on vascular tone and vessel wall, most likely related to exosome capability of transporting and cell–cell transferring of proteins, mRNAs, and miRNA, among others.¹⁰⁴ All these features make EVs strong candidates as reporters and effectors of disease. In the context of CVD, EVs are involved in cell proliferation and differentiation, inflammation, stress response, angiogenesis, senescence, stem cell maintenance, tissue repair, and cardiovascular remodeling,^105–110 which are associated with many cardiovascular pathologies such as cardiac hypertrophy, heart failure, hypertension, atherogenesis, and diabetic cardiomyopathy.^111–116

Extracellular vesicle uptake and function

EVs from donor cells can be taken up by recipient cells. The unique structure and outer envelope of EVs protects their cargo from enzymatic degradation during transit through the extracellular environment.^85,117 The most common method for detecting EV uptake involves the use of fluorescent lipid membrane dyes (lipophilic dyes), including PKH67, PKH26, rhodamine B, DiI, and DiD, to stain EV membranes.^50,118,119 EVs have been suggested to be internalized into target cells by various uptake mechanisms, including membrane fusion and different endocytic pathways including phagocytosis, receptor-mediated endocytosis, lipid raft–mediated endocytosis, caveolin-mediated endocytosis, clathrin-mediated endocytosis, and micropinocytosis.^{85,100,120–122}

EVs derived from mononuclear blood cells (MBCs) have been involved in horizontal mRNA transfer and induce proangiogenic effects in vitro and in vivo.¹²³ In addition, EV-mediated crosstalk between endothelial cells (ECs) depends on miR-214, which was shown to activate angiogenic programming in target cells while EC senescence was suppressed.¹⁰⁷ Moreover, increased understanding of the role of EVs in vascularization has opened up the potential use of EVs in vascular therapeutics, with emerging concepts focused on the development of EVs for pro- or antiangiogenic therapies used for organ regeneration or cancer treatments, respectively.¹²⁴ In the context of OSA, we have shown that plasma exosomal miRNAs play an important role in endothelial dysfunction in both children and in adults.^119,125,126 The mechanism by which miRNAs are received and processed by target cells in a biologically active state is, as yet, undefined.

In physiological conditions, EVs may bind to the membrane proteins of the surface of target cells through receptor–ligand interactions, resulting in intracellular stimulation of signal transduction scaffolds and gene pathways. Upon EV binding and active mRNA and miRNA loading inside the recipient cell, gene expression through de novo translation and post-translational regulation of target mRNAs is effectively regulated.^127–130 The ability of EVs to alter the transcriptome and signaling activity within recipient cells allows them to induce highly specific and circumscribed phenotypic changes.¹³¹ Intravenously injected exosomes disappear rapidly from blood circulation and accumulate in the liver, spleen, and lung.¹³² Furthermore, following exosomes injection via different routes showed that intraperitoneal injection resulted in higher accumulation in the pancreas and gastrointestinal tract compared with intravenous injection, whereas subcutaneous injection resulted in much lower accumulation of exosomes in all measured organs.¹³³ Figure 2 presents a schematic diagram illustrating the release of EVs in the context of the perturbations elicited by sleep-disordered-breathing that target many tissues through either autocrine, paracrine, or endocrine mechanisms and affect heterogeneous cell populations in tissues from different organs. Recently, we showed that exosomes derived from children or adult subjects were internalized by endothelial cells.^119,125,134 We also showed that exosomes from the plasma of mice exposed to either intermittent hypoxia or sleep fragmentation were internalized in mouse adipocytes in vitro and delivered their miRNA, protein, or lipid cargo.⁵⁰

Figure 2.

Schematic diagram illustrating release in sleep-disordered breathing of EVs that target many tissues through either autocrine, paracrine or endocrine processes to selectively target cells from different organs. EVs carry active component cargos, which, in turn, modulate or mediate many OSA-associated morbidities.

Dual effects of extracellular vesicles on cardiovascular diseases

A very large degree of variability in the effect of CPAP treatment on blood pressure (BP) levels has been observed, likely because of the multifactorial nature of systemic hypertension.¹³⁵ Actually, 25%–30% of patients who use CPAP treatment for >4 h/night do not experience a positive effect on BP.^136,137 Such disappointing outcomes could also reflect the fact that the criteria for adherence to therapy may not necessarily translate to optimal outcomes, since evidence supporting more extensive regular use of CPAP throughout the duration of sleep is more likely to results in better symptomatic improvements.^138,139 Furthermore, it is possible that some degree of irreversibility is present in OSA patients, particularly among those who have sustained the sleep-associated perturbations for very long periods of time before seeking treatment. Indeed, in recent studies, we and others have focused specifically on this issue. Short-term intermittent hypoxia during sleep that mimics OSA leads to structural alterations in the vasculature that appear to be reversible.¹⁴⁰ In contrast, long-term exposures to similar models of OSA are associated with either partial or minimal function and structural recovery.^141–143

Over the last a few years, the role of EVs has changed from being only a marker of vascular integrity toward being a functionally relevant effector in the context of intercellular vascular signaling.¹⁴⁴ The potential of exosomes as diagnostic biomarkers or therapeutic agents for CVD has attracted significant attention since the first study in isolating exosomes from cultures of cardiomyocytes grown in vitro.^145,146 Furthermore, EVs are released from most cell types in the circulation including erythrocytes, leukocytes, platelets, and endothelial cells, and carry a multitude of biological information to alter the pathophysiological processes of CVD.^77,147 Various studies showed that EVs act in an autocrine or paracrine fashion and mediate cardioprotection, while another study showed that stimulation with hypoxia resulted in the release of EVs that were enriched in miR-30.^148,149 EVs that were taken up by endothelial cells induced their proliferation and angiogenesis in vitro.¹⁵⁰ Patients with vascular diseases with evidence of systemic endothelial damage, such as atherosclerosis, show significantly increased levels of circulating EVs.¹⁵¹ In addition, EVs from various cellular sources contribute to vascular inflammatory processes including endothelial activation, monocyte adhesion, and transmigration,^152,153 and certain subtypes of EVs can mediate vascular protection and endothelial regeneration.^77,154,155 On the one hand, EVs contribute to development and propagation of atherosclerosis by promoting endothelial dysfunction, while, on the other hand, evidence of the beneficial effects of certain EVs on vascular function and endothelial regeneration has also emerged.¹⁵⁴ Indeed, stem cell-derived EVs exert a protective effect against cardiac myocyte (CM) apoptosis during myocardial infarction and ischemia/reperfusion injury.^156,157 In addition, exosomes derived from heat shock protein 20 (HSP20)-overexpressing CM also protect against the hyperglycemia-induced CM death through increased levels of HSP20.¹⁵⁸ Furthermore, EVs secreted by stem cells play not only critical roles in repairing CM function and in restoring angiogenic potential of endothelial cells (ECs), but also mesenchymal stem cells (MSCs) exposed to hypoxia release EVs, which promote neo-angiogenesis and preserve cardiac performance after myocardial infarction.^159,160

Recently, we showed that circulating exosomes derived from untreated patients with OSA induce significant increases in endothelial cell senescence markers with reciprocal decreases in sirtuin expression, which are only partially reversed upon long-term adherent CPAP treatment (average of 6 h CPAP use per night every night for 12 months).¹⁶¹ Our findings suggest that circulating exosomes contribute to the senescence of endothelium in OSA, and are amenable to improvements, at least in part, after treatment of OSA with adherent CPAP.¹⁶¹ In regards to OSA patients, plasma exosomes obtained before OSA treatment induce endothelial dysfunction in naïve endothelial cells. In obese or OSA children with evidence of endothelial dysfunction, but not among those with preserved endothelial function, plasma exosomes induce marked in vitro and in vivo functional and structural alterations in naïve endothelium that are mediated by selective components of the exosomal miRNA cargo.¹²⁶ Plasma-derived exosomes in otherwise healthy subjects exposed to 4 days of intermittent hypoxia mimicking OSA are constitutively altered in their miRNA cargo, and exhibit the ability to induce endothelial dysfunction in vitro. We further demonstrated that such properties are reversed upon normoxic recovery.¹²⁵ In patients suffering from the obstructive hypoventilation syndrome (OHS) (the most severe form of sleep-disordered-breathing) as well as in mice exposed to intermittent hypoxia or sleep fragmentation as seen in moderate to severe OSA, plasma exosomes lead to reduced insulin sensitivity in naïve adipocytes in vitro, and such effects were attenuated by CPAP treatment, particularly after long-term adherent therapy. In contrast, the beneficial effects of CPAP on exosome-induced insulin resistance were undetectable among OSA patients who opted not to receive any treatment.^50,162 Figure 3 shows how during untreated OSA, EVs can be released from different cell types and effect endothelial dysfunction. At this point, we have not tested if EVs can induce endothelial protection either in vitro or in vivo studies if they are released from specific progenitor cells or are generated under specific circumstances afforded by age, gender, genetic variance, severity of hypoxia, etc.^163–166

Figure 3.

Schema illustrating the potential for dual effects of EVs whose cargoes have been modified in patients suffering from OSA. EVs can be released from several cell types, including endothelial cells, stem cells, immune cells and other cell types, which can then promote damage to cardiovascular systems, resulting in the induction or acceleration of cardiovascular diseases. Alternatively, the effects of EVs derived from OSA patients can confer protection of cardiovascular targets. Studies are needed to delineate more specifically the major operators of these two EVs-related effects.

Potential roles of extracellular vesicles as therapeutic applications and biomarkers

EVs convey biological cargos derived from parent cells to the destination cell targets and their functions are intrinsically dependent on the functional status of the original cells.⁸⁵ The bilayer lipid membrane of EVs acts as an efficient protection barrier for their inner molecules, thus contributing to their stable measurements in body fluids.^85,100,167 EVs can readily become novel minimally invasive (using blood samples) or noninvasive diagnostic markers (based on analysis of urine and saliva) to overcome the current setbacks of traditional needle or excision biopsies.¹⁶⁸ In addition, EVs provide several unique advantages over the use of cells for therapeutic applications, which include the absence of conservation of activity between species, lower immunogenic potential, and theoretically improved tissue- or cell-targeting potential.^169,170 The use of EVs for therapy of human disease is becoming a central focus of nanomedicine for their ability to deliver biologically active material to target cells.^90,171 Several investigators demonstrated that overexpression of miRNAs enhanced the therapeutic effects of exosomes, and also showed that overexpression of proteins that can change the expression profile of targeted miRNAs and proteins may improve the therapeutic profile of exosomes.^172,173 Furthermore, EVs from MSCs have been used to stimulate tissue repair following myocardial infarction, and EVs derived from tumor antigen-pulsed dendritic cells (DCs) have been exploited for cancer immunotherapy, suggesting that these vesicles serve as potential drug delivery vehicles.^174,175 EVs can be engineered to have certain tissue- or cell-type-specific targeting ligands present on their surface by expressing plasmid fusion constructs comprising targeting ligands fused to extracellular vesicle transmembrane proteins. Loading cargoes into EVs can be divided into two basic approaches: exogenous loading (with incorporation of small molecules/proteins/RNA into or onto isolated EVs) and endogenous loading (providing cells with the means to incorporate small molecules/proteins/RNAs into EVs during their biogenesis).⁸⁸ The ability of EVs to shuttle proteins and nucleic acids from one cell to another may be applied for therapeutic purposes, particularly as certain EVs preferentially bind to specific cells and could thus deliver a drug, a ligand mediating a receptor-induced signal, an altered protein, or an RNA, in order to affect the desired cellular processes.¹⁷⁶

Several studies have reported increased sensitivity for EVs-based biomarkers compared with whole serum or other body fluid biomarkers.^176,178 Furthermore, repeated evidence has emerged of EVs enrichment with specific molecular components (RNAs, proteins, and lipids) that reflect the status of the parental cell or tissue source,¹⁷⁷ and, as indicated, EVs might represent not only robust vehicles of disease-specific biomarkers, but may also be engineered as uniquely effective therapeutic targets. However, efforts in that direction have not yet been specifically addressed to date.

Conclusion

OSA is a major public health concern attributable mainly to its significant link with cardiovascular morbidity and mortality. The benefit of CPAP therapy on cardiovascular outcomes remains uncertain, and it is unclear whether such benefits can be potentiated via precision-based selection of the candidate patients most likely to benefit from such intervention rather than apply a one therapy fits all approach. EVs are important players of exchanges between cells, through the transmission of various proteins, bioactive lipids and genetic information to alter the phenotype and function of recipient cells. Thus, EVs have not only been implicated in numerous biological and pathological processes but are emerging as robust candidates for integration with sleep disorders such as OSA in the quest to develop improved predictive biomarkers and innovative targeted therapies, ultimately enabling attenuation or reversal of OSA effects on the cardiovascular system and other end-organ systems affected by this condition.

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Footnotes

Funding

The author(s) received no financial support for the research, authorship, and publication of this article.

Conflict of interest statement

The authors declare that there is no conflict of interest.

ORCID iD

David Gozal

Supplemental material

The reviews of this paper are available via the supplemental material section.

References

Malhotra

White

. Obstructive sleep apnoea. Lancet 2002; 360: 237–245.

Young

Palta

Dempsey

, et al. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin sleep cohort study. WMJ 2010; 108: 246–249.

Peppard

Young

Barnet

, et al. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 2013; 177: 1006–1014.

Veasey

Rosen

. Obstructive sleep apnea in adults. N Engl J Med 2019; 380: 1442–1449.

Heinzer

Vat

Marques-Vidal

, et al. Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med 2015; 3: 310–318.

Heinzer

Marti-Soler

Marques-Vidal

, et al. Impact of sex and menopausal status on the prevalence, clinical presentation, and comorbidities of sleep-disordered breathing. Sleep Med 2018; 51: 29–36.

Sarkar

Mukherjee

Chai-Coetzer

, et al. The epidemiology of obstructive sleep apnoea and cardiovascular disease. J Thorac Dis 2018; 10(Suppl. 34): S4189–S4200.

Peppard

Hagen

. The last 25 years of obstructive sleep apnea epidemiology-and the next 25? Am J Respir Crit Care Med 2018; 197: 310–312.

Evans

Yap

Turner

. Screening commercial vehicle drivers for obstructive sleep apnea: tools, barriers, and recommendations. Workplace Health Saf 2017; 65: 487–492.

10.

Garbarino

Durando

Guglielmi

, et al. Sleep apnea, sleep debt and daytime sleepiness are independently associated with road accidents. A cross-sectional study on truck drivers. PLoS One 2016; 11: e0166262.

11.

Lacasse

Godbout

Series

. Health-related quality of life in obstructive sleep apnoea. Eur Respir J 2002; 19: 499–503.

12.

Young

Finn

Peppard

, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008; 31: 1071–1078.

13.

Khalyfa

Qiao

Gileles-Hillel

, et al. Activation of the integrated stress response and metabolic dysfunction in a murine model of sleep apnea. Am J Respir Cell Mol Biol 2017; 57: 477–486.

14.

Martinez-Garcia

Campos-Rodriguez

Barbe

, et al. Precision medicine in obstructive sleep apnoea. Lancet Respir Med 2019; 7: 456–464.

15.

Dematteis

Julien

Guillermet

, et al. Intermittent hypoxia induces early functional cardiovascular remodeling in mice. Am J Respir Crit Care Med 2008; 177: 227–235.

16.

Sánchez-de-la-Torre

Campos-Rodriguez

Barbé

. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med 2013; 1: 61–72.

17.

Beaudin

Waltz

Hanly

, et al. Impact of obstructive sleep apnoea and intermittent hypoxia on cardiovascular and cerebrovascular regulation. Exp Physiol 2017; 102: 743–763.

18.

Javaheri

Barbe

Campos-Rodriguez

, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol 2017; 69: 841–858.

19.

Fels

Kusche-Vihrog

. Endothelial nanomechanics in the context of endothelial (Dys)function and inflammation. Antioxid Redox Signal 2019; 30: 945–959.

20.

Lira

de Sousa Rodrigues

. Evaluation of oxidative stress markers in obstructive sleep apnea syndrome and additional antioxidant therapy: a review article. Sleep Breath 2016; 20: 1155–1160.

21.

Zhou

Chen

Peng

, et al. Role of oxidative stress in the neurocognitive dysfunction of obstructive sleep apnea syndrome. Oxid Med Cell Longev 2016; 2016: 9626831.

22.

Broussard

Ehrmann

Van Cauter

, et al. Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study. Ann Intern Med 2012; 157: 549–557.

23.

Wisor

Clegern

Schmidt

. Toll-like receptor 4 is a regulator of monocyte and electroencephalographic responses to sleep loss. Sleep 2011; 34: 1335–1345.

24.

Irwin

. Why sleep is important for health: a psychoneuroimmunology perspective. Annu Rev Psychol 2015; 66: 143–172.

25.

Carroll

Timmons

Cervantes-Silva

, et al. Immunometabolism around the clock. Trends Mol Med 2019; 25: 612–625.

26.

Maury

. Off the clock: from circadian disruption to metabolic disease. Int J Mol Sci 2019; 20: E1597.

27.

Reinke

Asher

. Crosstalk between metabolism and circadian clocks. Nat Rev Mol Cell Biol 2019; 20: 227–241.

28.

Khalyfa

Poroyko

Qiao

, et al. Exosomes and metabolic function in mice exposed to alternating dark-light cycles mimicking night shift work schedules. Front Physiol 2017; 8: 882.

29.

Bikov

Kunos

Pallinger

, et al. Diurnal variation of circulating microvesicles is associated with the severity of obstructive sleep apnoea. Sleep Breath 2017; 21: 595–600.

30.

Trzepizur

Priou

Paris

, et al. Nocturnal release of leukocyte-derived microparticles in males with obstructive sleep apnoea. Eur Respir J 2011; 37: 1293–1295.

31.

Koritzinsky

Street

Chari

, et al. Circadian variation in the release of small extracellular vesicles can be normalized by vesicle number or TSG101. Am J Physiol Renal Physiol 2019; 317: F1098–F1110.

32.

Dooner

Stewart

Deng

, et al. Daily rhythms influence the ability of lung-derived extracellular vesicles to modulate bone marrow cell phenotype. PLoS One 2018; 13: e0207444.

33.

Tao

Guo

. Extracellular vesicles: potential participants in circadian rhythm synchronization. Int J Biol Sci 2018; 14: 1610–1620.

34.

Barros

García-Río

. Obstructive sleep apnea and dyslipidemia: from animal models to clinical evidence. Sleep 2019; 42.

35.

Farré

Montserrat

Gozal

, et al. Intermittent hypoxia severity in animal models of sleep apnea. Front Physiol 2018; 9: 1556.

36.

Hunyor

Cook

. Models of intermittent hypoxia and obstructive sleep apnea: molecular pathways and their contribution to cancer. Am J Physiol Regul Integr Comp Physiol 2018; 315: R669–R687.

37.

Trzepizur

Cortese

Gozal

. Murine models of sleep apnea: functional implications of altered macrophage polarity and epigenetic modifications in adipose and vascular tissues. Metabolism 2018; 84: 44–55.

38.

Campillo

Jorba

Schaedel

, et al. A novel chip for cyclic stretch and intermittent hypoxia cell exposures mimicking obstructive sleep apnea. Front Physiol 2016; 7: 319.

39.

Gileles-Hillel

Kheirandish-Gozal

Gozal

. Biological plausibility linking sleep apnoea and metabolic dysfunction. Nat Rev Endocrinol 2016; 12: 290–298.

40.

Chopra

Polotsky

Jun

. Sleep apnea research in animals. Past, present, and future. Am J Respir Cell Mol Biol 2016; 54: 299–305.

41.

Linz

Mahfoud

Linz

, et al. Effect of obstructive respiratory events on blood pressure and renal perfusion in a pig model for sleep apnea. Am J Hypertens 2014; 27: 1293–1300.

42.

Wang

Carreras

Lee

, et al. Chronic sleep fragmentation promotes obesity in young adult mice. Obesity (Silver Spring) 2014; 22: 758–762.

43.

Lee

Hong

, et al. Establishment of a rabbit model of obstructive sleep apnea by paralyzing the genioglossus. JAMA Otolaryngol Head Neck Surg 2013; 139: 834–840.

44.

Davis

O’Donnell

. Rodent models of sleep apnea. Respir Physiol Neurobiol 2013; 188: 355–361.

45.

Nair

Zhang

Ramesh

, et al. Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse. Am J Respir Crit Care Med 2011; 184: 1305–1312.

46.

Ando

. Influence of hypoxia induced by sleep disordered breathing in case of hypertension and atrial fibrillation. J Cardiol 2018; 72: 10–18.

47.

Parati

Lombardi

Hedner

, et al. Recommendations for the management of patients with obstructive sleep apnoea and hypertension. Eur Respir J 2013; 41: 523–538.

48.

Almendros

Wang

Gozal

. The polymorphic and contradictory aspects of intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol 2014; 307: L129–L140.

49.

Dempsey

Veasey

Morgan

, et al. Pathophysiology of sleep apnea. Physiol Rev 2010; 90: 47–112.

50.

Khalyfa

Gozal

Masa

, et al. Sleep-disordered breathing, circulating exosomes, and insulin sensitivity in adipocytes. Int J Obes (Lond) 2018; 42: 1127–1139.

51.

Sforza

Roche

. Chronic intermittent hypoxia and obstructive sleep apnea: an experimental and clinical approach. Hypoxia 2016; 4: 99.

52.

Kaushal

Ramesh

Gozal

. Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 2012; 303: R19–R29.

53.

Ramesh

Nair

Zhang

, et al. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-alpha pathway. J Neuroinflammation 2012; 9: 91.

54.

Khalyfa

Wang

Zhang

, et al. Sleep fragmentation in mice induces nicotinamide adenine dinucleotide phosphate oxidase 2-dependent mobilization, proliferation, and differentiation of adipocyte progenitors in visceral white adipose tissue. Sleep 2014; 37: 999–1009.

55.

Hakim

Wang

Carreras

, et al. Chronic sleep fragmentation during the sleep period induces hypothalamic endoplasmic reticulum stress and PTP1b-mediated leptin resistance in male mice. Sleep 2015; 38: 31–40.

56.

Gopalakrishnan

Tak

. Obstructive sleep apnea and cardiovascular disease. Cardiol Rev 2011; 19: 279–290.

57.

Mozaffarian

Roger

, et al. Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation 2014; 129: 399–410.

58.

Mozaffarian

Roger

, et al. Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation 2014; 129: e28–e292.

59.

Murphy

Crinion

Redmond

, et al. Diagnostic accuracy of carotid intima media thickness in predicting coronary plaque burden on coronary computed tomography angiography in patients with obstructive sleep apnoea. J Cardiovasc Comput Tomogr 2017; 11: 227–233.

60.

Bikov

Kolossvary

Jermendy

, et al. Comprehensive coronary plaque assessment in patients with obstructive sleep apnea. J Sleep Res 2019; 28: e12828.

61.

Seo

Lee

Hahn

, et al. Association of obstructive sleep apnea with subclinical cardiovascular disease predicted by coronary artery calcium score in asymptomatic subjects. Am J Cardiol 2017; 120: 577–581.

62.

Noell

Cosio

Faner

, et al. Multi-level differential network analysis of COPD exacerbations. Eur Respir J 2017; 50.

63.

Zhou

McEvoy

, et al. Association of positive airway pressure with cardiovascular events and death in adults with sleep apnea: a systematic review and meta-analysis. JAMA 2017; 318: 156–166.

64.

Liu

Cao

Guo

, et al. Continuous positive airway pressure in patients with obstructive sleep apnea and resistant hypertension: a meta-analysis of randomized controlled trials. J Clin Hypertens (Greenwich) 2016; 18: 153–158.

65.

Labarca

Cruz

Jorquera

. Continuous positive airway pressure in patients with obstructive sleep apnea and non-alcoholic steatohepatitis: a systematic review and meta-analysis. J Clin Sleep Med 2018; 14: 133–139.

66.

da Silva Paulitsch

Zhang

. Continuous positive airway pressure for adults with obstructive sleep apnea and cardiovascular disease: a meta-analysis of randomized trials. Sleep Med 2019; 54: 28–34.

67.

Drager

McEvoy

Barbe

Lorenzi-Filho

, et al.; INCOSACT Initiative (International Collaboration of Sleep Apnea Cardiovascular Trialists). Sleep apnea and cardiovascular disease: lessons from recent trials and need for team science. Circulation 2017; 136: 1840–1850.

68.

McEvoy

Neal

Anderson

. CPAP in obstructive sleep apnea. N Engl J Med 2016; 375: 2302–2303.

69.

Ayers

Stoewhas

Ferry

, et al. Elevated levels of endothelial cell-derived microparticles following short-term withdrawal of continuous positive airway pressure in patients with obstructive sleep apnea: data from a randomized controlled trial. Respiration 2013; 85: 478–485.

70.

Maruyama

Morishita

Sekiya

, et al. Plasma levels of platelet-derived microparticles in patients with obstructive sleep apnea syndrome. J Atheroscler Thromb 2012; 19: 98–104.

71.

Tual-Chalot

Gagnadoux

Trzepizur

, et al. Circulating microparticles from obstructive sleep apnea syndrome patients induce endothelin-mediated angiogenesis. Biochim Biophys Acta 2014; 1842: 202–207.

72.

Yun

Jung

Chu

, et al. Increased circulating endothelial microparticles and carotid atherosclerosis in obstructive sleep apnea. J Clin Neurol 2010; 6: 89–98.

73.

Ayers

Ferry

Craig

, et al. Circulating cell-derived microparticles in patients with minimally symptomatic obstructive sleep apnoea. Eur Respir J 2009; 33: 574–580.

74.

Geiser

Buck

Meyer

, et al. In vivo platelet activation is increased during sleep in patients with obstructive sleep apnea syndrome. Respiration 2002; 69: 229–234.

75.

Akinnusi

El Solh

. Circulating endothelial microparticle levels and hemodynamic severity of pulmonary hypertension: is there a role for sleep apnea? Am J Respir Crit Care Med 2009; 179: 328; author reply 328–329.

76.

Akinnusi

Paasch

Szarpa

, et al. Impact of nasal continuous positive airway pressure therapy on markers of platelet activation in patients with obstructive sleep apnea. Respiration 2009; 77: 25–31.

77.

Boulanger

Loyer

Rautou

, et al. Extracellular vesicles in coronary artery disease. Nat Rev Cardiol 2017; 14: 259–272.

78.

Martinez

Andriantsitohaina

. Extracellular vesicles in metabolic syndrome. Circ Res 2017; 120: 1674–1686.

79.

Pan

Johnstone

. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 1983; 33: 967–978.

80.

Harding

Heuser

Stahl

. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur J Cell Biol 1984; 35: 256–263.

81.

Chaput

Théry

. Exosomes: immune properties and potential clinical implementations. Semin Immunopathol 2011; 33: 419–440.

82.

Ellis

Kuehn

. Virulence and immunomodulatory roles of bacterial outer membrane vesicles. Microbiol Mol Biol Rev 2010; 74: 81–94.

83.

Beveridge

. Structures of gram-negative cell walls and their derived membrane vesicles. J Bacteriol 1999; 181: 4725–4733.

84.

Théry

Zitvogel

Amigorena

. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2002; 2: 569–579.

85.

Khalyfa

Gozal

. Exosomal miRNAs as potential biomarkers of cardiovascular risk in children. J Transl Med 2014; 12: 162.

86.

Vlassov

Magdaleno

Setterquist

, et al. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 2012; 1820: 940–948.

87.

van der Pol

Boing

Harrison

, et al. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev 2012; 64: 676–705.

88.

Wiklander

OPB

Brennan

Lötvall

, et al. Advances in therapeutic applications of extracellular vesicles. Sci Transl Med 2019; 11: pii: eaav8521.

89.

Borosch

Dahmen

Beckers

, et al. Characterization of extracellular vesicles derived from cardiac cells in an in vitro model of preconditioning. J Extracell Vesicles 2017; 6: 1390391.

90.

Yang

Nadithe

. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B 2016; 6: 287–296.

91.

Han

Sun

Liu

, et al. Exosomes and their therapeutic potentials of stem cells. Stem Cells Int 2016; 2016: 7653489.

92.

Mussack

Wittmann

Pfaffl

. Comparing small urinary extracellular vesicle purification methods with a view to RNA sequencing-Enabling robust and non-invasive biomarker research. Biomol Detect Quantif 2019; 17: 100089.

93.

Barrachina

Calderon-Cruz

Fernandez-Rocca

, et al. Application of extracellular vesicles proteomics to cardiovascular disease: guidelines, data analysis, and future perspectives. Proteomics 2019; 19: e1800247.

94.

Sodar

Kovacs

Visnovitz

, et al. Best practice of identification and proteomic analysis of extracellular vesicles in human health and disease. Expert Rev Proteomics 2017; 14: 1073–1090.

95.

Coumans

FAW

Brisson

Buzas

, et al. Methodological guidelines to study extracellular vesicles. Circ Res 2017; 120: 1632–1648.

96.

Verma

Lam

Hebert

, et al. Extracellular vesicles: potential applications in cancer diagnosis, prognosis, and epidemiology. BMC Clin Pathol 2015; 15: 6.

97.

Lynch

Barallobre-Barreiro

Jahangiri

, et al. Vascular proteomics in metabolic and cardiovascular diseases. J Intern Med 2016; 280: 325–338.

98.

Lawson

Vicencio

Yellon

, et al. Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol 2016; 228: R57–R71.

99.

Kishore

Garikipati

Gumpert

. Tiny shuttles for information transfer: exosomes in cardiac health and disease. J Cardiovasc Transl Res 2016; 9: 169–175.

100.

Khalyfa

Kheirandish-Gozal

Gozal

. Exosome and macrophage crosstalk in sleep-disordered breathing-induced metabolic dysfunction. Int J Mol Sci 2018; 19: 3383.

101.

Cossetti

Smith

Iraci

, et al. Extracellular membrane vesicles and immune regulation in the brain. Front Physiol 2012; 3: 117.

102.

De Toro

Herschlik

Waldner

, et al. Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol 2015; 6: 203.

103.

Zhang

Tian

. Physiological and pathological impact of exosomes of adipose tissue. Cell Prolif 2016; 49: 3–13.

104.

Amabile

Rautou

Tedgui

, et al. Microparticles: key protagonists in cardiovascular disorders. Semin Thromb Hemost 2010; 36: 907–916.

105.

Gabriel

Becher-Deichsel

Hlavaty

, et al. The physiological expression of scavenger receptor SR-B1 in canine endometrial and placental epithelial cells and its potential involvement in pathogenesis of pyometra. Theriogenology 2016; 85: 1599–1609.e1592.

106.

Singla

. Stem cells and exosomes in cardiac repair. Curr Opin Pharmacol 2016; 27: 19–23.

107.

van Balkom

de Jong

Smits

, et al. Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood 2013; 121: 3997–4006, S3991–S3915.

108.

Shu

Taddeo

Roizman

. Tristetraprolin recruits the herpes simplex virion host shutoff RNase to AU-rich elements in stress response mRNAs to enable their cleavage. J Virol 2015; 89: 5643–5650.

109.

Lyu

Wang

, et al. A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes. J Mol Cell Cardiol 2015; 89(Pt B): 268–279.

110.

Takasugi

. Emerging roles of extracellular vesicles in cellular senescence and aging. Aging Cell 2018; 17: e12734.

111.

Mirzapoiazova

Lennon

Mambetsariev

, et al. Extracellular vesicles from caveolin-enriched microdomains regulate hyaluronan-mediated sustained vascular integrity. Int J Cell Biol 2015; 2015: 481493.

112.

Bang

Batkai

Dangwal

, et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 2014; 124: 2136–2146.

113.

Campbell

Berman

Weintraub

, et al. Electrical stimulation to optimize cardioprotective exosomes from cardiac stem cells. Med Hypotheses 2016; 88: 6–9.

114.

van Balkom

Eisele

Pegtel

, et al. Quantitative and qualitative analysis of small RNAs in human endothelial cells and exosomes provides insights into localized RNA processing, degradation and sorting. J Extracell Vesicles 2015; 4: 26760.

115.

Ailawadi

Wang

, et al. Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochim Biophys Acta 2015; 1852: 1–11.

116.

Davidson

Takov

Yellon

. Exosomes and cardiovascular protection. Cardiovasc Drugs Ther 2017; 31: 77–86.

117.

Keller

Ridinger

Rupp

, et al. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med 2011; 9: 86.

118.

Tian

Wang

, et al. Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J Cell Biochem 2010; 111: 488–496.

119.

Khalyfa

Youssefnia

Foster

, et al. Plasma exosomes and improvements in endothelial Function by angiotensin 2 type 1 receptor or cyclooxygenase 2 blockade following intermittent hypoxia. Front Neurol 2017; 8: 709.

120.

Parolini

Federici

Raggi

, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 2009; 284: 34211–34222.

121.

Feng

Zhao

, et al. Cellular internalization of exosomes occurs through phagocytosis. Traffic 2010; 11: 675–687.

122.

Costa Verdera

Gitz-Francois

Schiffelers

, et al. Cellular uptake of extracellular vesicles is mediated by clathrin-independent endocytosis and macropinocytosis. J Control Release 2017; 266: 100–108.

123.

Deregibus

Cantaluppi

Calogero

, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 2007; 110: 2440–2448.

124.

Yanez-Mo

Siljander

Andreu

, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015; 4: 27066.

125.

Khalyfa

Zhang

Khalyfa

, et al. Effect on intermittent hypoxia on plasma exosomal micro RNA signature and endothelial function in healthy adults. Sleep 2016; 39: 2077–2090.

126.

Khalyfa

Kheirandish-Gozal

Bhattacharjee

, et al. Circulating microRNAs as potential biomarkers of endothelial dysfunction in obese children. Chest 2016; 149: 786–800.

127.

Valadi

Ekstrom

Bossios

, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9: 654–659.

128.

Tang

Kaneda

O’Carroll

, et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev 2007; 21: 644–648.

129.

Jacobs

Bewicke-Copley

Poolman

, et al. Meta-analysis using a novel database, miRStress, reveals miRNAs that are frequently associated with the radiation and hypoxia stress-responses. PLoS One 2013; 8: e80844.

130.

Al-Mayah

Irons

Pink

, et al. Possible role of exosomes containing RNA in mediating nontargeted effect of ionizing radiation. Radiat Res 2012; 177: 539–545.

131.

Camussi

Deregibus

Bruno

, et al. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int 2010; 78: 838–848.

132.

Takahashi

Nishikawa

Shinotsuka

, et al. Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J Biotechnol 2013; 165: 77–84.

133.

Wiklander

Nordin

O’Loughlin

, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 2015; 4: 26316.

134.

Khalyfa

Kheirandish-Gozal

Khalyfa

, et al. Circulating plasma extracellular microvesicle microRNA cargo and endothelial dysfunction in children with obstructive sleep apnea. Am J Respir Crit Care Med 2016; 194: 1116–1126.

135.

Sánchez-de-la-Torre

Khalyfa

Sánchez-de-la-Torre

, et al. Precision medicine in patients with resistant hypertension and obstructive sleep apnea: blood pressure response to continuous positive airway pressure treatment. J Am Coll Cardiol 2015; 66: 1023–1032.

136.

Barbé

Duran-Cantolla

Sanchez-de-la-Torre

, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012; 307: 2161–2168.

137.

Martinez-Garcia

Capote

Campos-Rodriguez

, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013; 310: 2407–2415.

138.

Weaver

Maislin

Dinges

, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 2007; 30: 711–719.

139.

Bakker

Weaver

Parthasarathy

, et al. Adherence to CPAP: what should we be aiming for, and how can we get there? Chest 2019; 155: 1272–1287.

140.

Castro-Grattoni

Suarez-Giron

Benitez

, et al. Effect of age on the cardiovascular remodelling induced by chronic intermittent hypoxia as a murine model of sleep apnoea. Respirology. Epub ahead of print 18 June 2019. DOI: 10.1111/resp.13610.

141.

Cortese

Gileles-Hillel

Khalyfa

, et al. Aorta macrophage inflammatory and epigenetic changes in a murine model of obstructive sleep apnea: potential role of CD36. Sci Rep 2017; 7: 43648.

142.

Gileles-Hillel

Almendros

Khalyfa

, et al. Prolonged exposures to intermittent hypoxia promote visceral white adipose tissue inflammation in a murine model of severe sleep apnea: effect of normoxic recovery. Sleep 2017; 40: zsw074.

143.

Gozal

Khalyfa

Qiao

, et al. Temporal trajectories of novel object recognition performance in mice exposed to intermittent hypoxia. Eur Respir J 2017; 50: pii: 1701456.

144.

Boon

Vickers

. Intercellular transport of microRNAs. Arterioscler Thromb Vasc Biol 2013; 33: 186–192.

145.

Gupta

Knowlton

. HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am J Physiol Heart Circ Physiol 2007; 292: H3052–H3056.

146.

Xitong

Xiaorong

. Targeted therapeutic delivery using engineered exosomes and its applications in cardiovascular diseases. Gene 2016; 575(2 Pt. 2): 377–384.

147.

Lo Cicero

Stahl

Raposo

. Extracellular vesicles shuffling intercellular messages: for good or for bad. Curr Opin Cell Biol 2015; 35: 6–77.

148.

Chen

Wang

Pan

, et al. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Commun 2013; 431: 566–571.

149.

Kang

Jones

Naddell

, et al. Adipose-derived stem cells induce angiogenesis via microvesicle transport of miRNA-31. Stem Cells Transl Med 2016; 5: 440–450.

150.

Garcia

Ontoria-Oviedo

Gonzalez-King

, et al. Glucose starvation in cardiomyocytes enhances exosome secretion and promotes angiogenesis in endothelial cells. PLoS One 2015; 10: e0138849.

151.

Jansen

Xiang

Werner

. Role and function of extracellular vesicles in calcific aortic valve disease. Eur Heart J 2017; 38: 2714–2716.

152.

Yamamoto

Niida

Azuma

, et al. Inflammation-induced endothelial cell-derived extracellular vesicles modulate the cellular status of pericytes. Sci Rep 2015; 5: 8505.

153.

Robbins

Dorronsoro

Booker

. Regulation of chronic inflammatory and immune processes by extracellular vesicles. J Clin Invest 2016; 126: 1173–1180.

154.

Jansen

Pfeifer

, et al. Endothelial- and immune cell-derived extracellular vesicles in the regulation of cardiovascular health and disease. JACC Basic Transl Sci 2017; 2: 790–807.

155.

Rautou

Vion

Amabile

, et al. Microparticles, vascular function, and atherothrombosis. Circ Res 2011; 109: 593–606.

156.

Khan

Nickoloff

Abramova

, et al. Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res 2015; 117: 52–64.

157.

Wang

Zhang

, et al. Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 2015; 192: 61–69.

158.

Wang

Huang

, et al. Hsp20-mediated activation of exosome biogenesis in cardiomyocytes improves cardiac function and angiogenesis in diabetic mice. Diabetes 2016; 65: 3111–3128.

159.

Safari

Malekvandfard

Babashah

, et al. Mesenchymal stem cell-derived exosomes: a novel potential therapeutic avenue for cardiac regeneration. Cell Mol Biol (Noisy-le-grand) 2016; 62: 66–73.

160.

Bian

Zhang

Duan

, et al. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 2014; 92: 387–397.

161.

Khalyfa

Marin

Qiao

, et al. Plasma exosomes in OSA patients promote endothelial senescence: effect of long-term adherent continuous positive airway pressure. Sleep. Epub ahead of print 25 September 2019. DOI: 10.1093/sleep/zsz217.

162.

Bhattacharjee

Khalyfa

, et al. Exosomal cargo properties, endothelial function and treatment of obesity hypoventilation syndrome: a proof of concept study. J Clin Sleep Med 2018; 14: 797–807.

163.

Almendros

Carreras

Montserrat

, et al. Potential role of adult stem cells in obstructive sleep apnea. Front Neurol 2012; 3: 112.

164.

Gharib

Khalyfa

Kucia

, et al. Transcriptional landscape of bone marrow-derived very small embryonic-like stem cells during hypoxia. Respir Res 2011; 12: 63.

165.

Gharib

Dayyat

Khalyfa

, et al. Intermittent hypoxia mobilizes bone marrow-derived very small embryonic-like stem cells and activates developmental transcriptional programs in mice. Sleep 2010; 33: 1439–1446.

166.

Kheirandish-Gozal

Bhattacharjee

Kim

, et al. Endothelial progenitor cells and vascular dysfunction in children with obstructive sleep apnea. Am J Respir Crit Care Med 2010; 182: 92–97.

167.

Tual-Chalot

Leonetti

Andriantsitohaina

, et al. Microvesicles: intercellular vectors of biological messages. Mol Interv 2011; 11: 88–94.

168.

Zhang

Zheng

, et al. Characteristics and roles of exosomes in cardiovascular disease. DNA Cell Biol 2017; 36: 202–211.

169.

Bei

Yang

Wang

, et al. Circular RNAs as potential theranostics in the cardiovascular system. Mol Ther Nucleic Acids 2018; 13: 407–418.

170.

Sluijter

JPG

Davidson

Boulanger

, et al. Extracellular vesicles in diagnostics and therapy of the ischaemic heart: position paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 2018; 114: 19–34.

171.

Rezaie

Ajezi

Avci

, et al. Exosomes and their application in biomedical field: difficulties and advantages. Mol Neurobiol 2018; 55: 3372–3393.

172.

Zhang

Long

, et al. Overexpression of exosomal cardioprotective miRNAs mitigates hypoxia-induced H9c2 cells apoptosis. Int J Mol Sci 2017; 18.

173.

Yang

Varley

, et al. Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response. Br J Cancer 2018; 118: 62–71.

174.

Zou

Zhang

, et al. NK cell regulatory property is involved in the protective role of MSC-derived extracellular vesicles in renal ischemic reperfusion injury. Hum Gene Ther 2016; 27: 926–935.

175.

Haga

Yan

Takahashi

, et al. Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice. Stem Cells Transl Med 2017; 6: 1262–1272.

176.

van Balkom

Pisitkun

Verhaar

, et al. Exosomes and the kidney: prospects for diagnosis and therapy of renal diseases. Kidney Int 2011; 80: 1138–1145.

177.

Madhavan

Yue

Galli

, et al. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer 2015; 136: 2616–2627.

178.

Ogata-Kawata

Izumiya

Kurioka

, et al. Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS One 2014; 9: e92921.

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