心血管疾病中的内皮祖细胞和缺氧对阻塞性睡眠呼吸暂停的潜在影响--爱思唯尔期刊精选全文--爱唯医学网

Obstructive sleep apnea (OSA) syndrome is a highly prevalent condition. It affects at least 4% of adult men and 2% of adult women with characteristic symptoms, whereas in older populations, it is approximately 3-fold higher.^[1]^and ^[2] OSA is characterized by intermittent and recurrent pauses in respiration during sleep, initiated by a collapse of upper respiratory airways in the oropharynx, resulting in loud and intermittent snoring. The pauses in respiration, termed apneas/hypopneas, result in intermittent blood oxygen desaturation and sleep fragmentation. Apneas are complete respiration pauses of at least 10 s, whereas hypopneas are defined as a 50% decrease in air flow that lasts at least 10 s, leading to oxygen desaturation of at least 3% or a brief arousal.³ OSA is diagnosed by overnight polysomnography and a finding of at least 5 or 10 apneas or hypopneas during sleep. The severity of OSA is determined by 2 main measures. First, the apnea/hypopnea index (AHI) is calculated by the total number of apneas/hypopneas divided by the hours of sleep. The second parameter is the level of blood oxygen saturation during sleep or the number of decreases in oxygen desaturation of at least 3% normalized by the hours of sleep (oxygen desaturation index).^[3]^and ^[4] Obstruction of the upper airways during sleep occurs because of a disruption in the balance between the oropharynx muscles and negative pressure. As a result of this disruption in balance, the upper airway collapses. OSA patients can compensate for this imbalance by increasing muscle activity during waking but not during sleep.⁵

OSA is mainly associated with the male gender, middle age, central obesity, smoking, sedentary lifestyle, and a postmenopausal status in women. Loud snoring, chronic fatigue, and daytime sleepiness are the main symptoms. The ultimate and primary treatment for OSA is with nasal continuous positive airway pressure (nCPAP), which helps to keep the airway open, thus alleviating the repeated obstructions. However, advancing the lower jaw by a dental device, losing weight particularly by a bariatric surgery, exercise, improving sleep hygiene, treating nasal obstruction by surgery, avoiding alcohol, and quitting smoking also may help to improve OSA.^[3]^,^[6]^and ^[7]

In the past few years, a large body of evidence has shown that endothelial dysfunction, which is a subclinical sign of atherosclerosis, is a prominent feature of OSA. This finding may accelerate the development of cardiovascular morbidity and stroke in the setting of OSA.^[8]^,^[9]^and ^[10] Additionally, it was suggested that sleep apnea associated intermittent hypoxia (IH), similar to ischemia/reperfusion, can invoke complex metabolic molecular and cellular changes including increased production of reactive oxygen species (ROS) and vascular inflammation. These latter items are 2 fundamental mechanisms that promote atherosclerosis by initiating endothelial dysfunction.^[11]^and ^[12]

Recently, endothelial progenitor cells (EPCs) were implicated as one of the possible mechanisms that protect the vasculature from damage caused by atherosclerosis-associated oxidative stress and vascular inflammation. These bone–marrow-derived pluripotent cells were suggested to restore endothelial function of injured blood vessels by providing angiogenic repair capacity.¹³

The present review highlights the current findings suggesting that oxidative stress and inflammation are fundamental to the development of endothelial dysfunction, atherosclerosis, and cardiovascular morbidity in OSA as well as emphasizes the potential role of EPCs in the pathogenesis of vascular diseases pertinent to OSA.

Cardiovascular Morbidity and Mortality in OSA

Coronary artery disease (CAD) or atherosclerotic heart disease is a chronic life-threatening disease, which is characterized by reduced blood supply to the heart as a result of the accumulation of atheromatous plaques within the walls of the arteries that supply the myocardium. Progressive atherosclerosis in the coronary arteries may lead to intimal thickening and eventual artery occlusion. Coronary artery occlusion can cause acute myocardial ischemia as a result of reduced oxygen supply or increased oxygen demand.^[14]^,^[15]^and ^[16]

Intensive research in recent years points to negative consequences of OSA on the cardiovascular system. Higher rates of cardiovascular disease, particularly hypertension but also ischemic heart disease, myocardial infarction (MI), and stroke, have been shown to be prevalent among patients with OSA. Conversely, patients with cardiovascular diseases showed higher rates of clinically significant disordered breathing events than in the general population. Furthermore, a dose–response relationship between the severity of breathing disorders during sleep and cardiovascular morbidities suggests a specific link between cardiovascular diseases and OSA.¹¹ Numerous epidemiologic, cross-sectional, and prospective studies have shown that OSA syndrome is an independent risk factor for cardiovascular morbidity; therefore, patients with OSA are at an increased risk of dying from cardiovascular events.^[17]^and ^[18] Reviews summarizing these findings were published recently.^[19]^and ^[20]

Several mechanisms were proposed to explain the association between OSA and cardiovascular morbidity including sympathetic activation, intrathoracic pressure, and more recently, oxidative stress and inflammation. All these mechanisms promote endothelial dysfunction as well as atherosclerosis and therefore may contribute cardiovascular morbidity and stroke in the setting of OSA.^[11]^and ^[12] However, additional factors that may contribute and exacerbate endothelial dysfunction are platelet aggregability and hypercoagulability, obesity, various metabolic dysregulations such as hyperlipidemia, insulin resistance, and diabetes, which all cluster with OSA.¹² Moreover, in a recent study investigating the contribution of OSA and obesity to endothelial dysfunction, it was shown that OSA rather than obesity was a major cause of endothelial dysfunction and vascular inflammation in obese patients.²¹

Oxidative Stress and Vascular Inflammation in OSA

As mentioned previously, the frequent occurrence of IH in patients with OSA that results in multiple cycles of hypoxia/reoxygenation could be considered analogous to ischemia/reperfusion injury. Ischemia is defined as an insufficient blood supply to a local area usually because of blocked or damaged blood vessels as a result of local inflammation, MI, implantation, or trauma.²² A large body of evidence demonstrates that tissue damage mainly takes place during the postischemic reperfusion. Restoration of the blood supply and the rapid elevation of oxygen levels may alter redox balance toward oxidant-producing systems and may lead to oxidative stress. Oxidative stress in OSA mainly was shown by various circulating markers as lipid peroxidation.^[23]^and ^[24] In several studies, increased ROS production was demonstrated by inflammatory leukocytes from OSA patients, likely through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.^[25]^and ^[26] In animal models using long-term IH, increased NADPH oxidase gene and protein were identified in brain regions as one source of ROS.²⁷ Also, chronic IH in mice that caused pulmonary hypertension and vascular remodeling was associated with increased production of NADPH oxidase-derived ROS.²⁸ Additional potential sources of ROS in OSA such as dysfunctional mitochondria and xanthine oxidase were described elsewhere.^[11]^and ^[12]

Although, in homeostatic conditions, cells and tissues are constantly exposed to ROS, which normally serve as signaling molecules, excessive ROS formation resulting from ischemia/reperfusion or hypoxia/reoxygenation insult can damage macromolecules and cell membranes leading to tissue injury. Moreover, inflammatory responses in OSA as well as in animal models of IH are also exaggerated because of the activation of the inflammatory transcription factor nuclear factor kappa B (NF-κB) pathway and downstream inflammatory gene products such as adhesion molecules and inflammatory cytokines.¹²

Meticulous investigation of circulating inflammatory cells in patients with OSA revealed increased activation that was evident by increases in the production of ROS molecules ^[11]^,^[26]^and ^[29] as well as an increased expression of adhesion molecules and proinflammatory cytokines.¹² Specifically, in polymorphonuclear leukocytes (PMNs), which represent the first line of defense, activation was noted by an increased expression of adhesion molecules and by a decrease in apoptosis leading to a prolonged lifespan. Such activations facilitate increased damage toward endothelial cells.^[26]^and ^[30] In monocytes, an increased expression of adhesion molecules augmented the avidity to endothelial cells, possibly facilitating increased damage toward endothelial cells.^[26]^and ^[31] Similarly, lymphocytes expressed elevated levels of adhesion molecules as well as increased avidity and cytotoxicity toward endothelial cells.³² Additionally, monocytes and neutrophils of OSA patients expressed a higher activity of the proinflammatory transcription factor NF-κB, which was significantly decreased in response to nCPAP therapy.^[33]^and ^[34] Moreover, the activation of NF-κB was increased in human PMNs from healthy individuals exposed to IH ³⁵ as well as in animal models and cell culture models of IH.^[34]^and ^[36] This transcription factor mediates the expression of several important inflammatory cytokines such as tumor necrosis factor α (TNF-α).

The levels of TNF-α in OSA were determined in several studies. Although the findings in regard to circulating TNF-α levels are somewhat inconsistent, most studies have shown increases in the circulating levels of TNF-α in patients with OSA.³⁷ Moreover, these increases were independent from central obesity.³⁸ Also, in monocytes of patients with moderate-to-severe OSA, spontaneous TNF-α production was increased.³⁹ Similarly, spontaneous TNF-α production also was increased in cytotoxic T lymphocytes of patients with OSA.⁴⁰ Interestingly, the levels of soluble TNF receptor-1 (sTNFR-1) also were shown to increase significantly in OSA patients as compared with control subjects.⁴¹

The interaction of TNF-α with TNF receptor-1 triggers a series of intracellular events that ultimately activate 2 major transcription factors—NF-κB and c-Jun.⁴² Moreover, increased sTNFR-1 levels were shown to predict the incidence of cardiovascular events in several conditions, such as heart failure and acute coronary syndrome.^[43]^and ^[44] Jointly, increased ROS production and vascular inflammation evident in OSA can impair endothelial function, as determined in numerous studies.^[8]^,^[45]^and ^[46]

Endothelial Dysfunction in OSA

The endothelium is a dynamic cell layer that represents a physiological barrier between circulating blood and the surrounding tissues. Impaired endothelial function is a critical event in the initiation of atherosclerotic plaque development and thus may lead to vasoconstriction, vascular smooth muscle proliferation, hypercoagulability, thrombosis, and eventually, adverse cardiovascular events.⁸ Impaired endothelial function in OSA patients was reported in several studies by using various methods.^[9]^and ^[47] Of note, impaired vascular endothelial function was associated with the severity of apnea-induced hypoxemia during sleep ⁴⁸ and was improved by nCPAP therapy.^[45]^and ^[49] Moreover, the improved vascular function in these patients could be reversed by omitting the nCPAP therapy and thus was dependent on ongoing therapy.⁵⁰ Furthermore, in a recent study, flow-mediated dilation in OSA patients was inversely correlated with endothelial microparticles, whereas nCPAP treatment significantly improved endothelial function and decreased markers of endothelial apoptosis.⁴⁶ Hence, endothelial dysfunction associated with OSA may lead to adverse cardiovascular consequences that can be improved by nCPAP therapy.

Progenitor Cells

EPCs

In recent years EPCs, were implicated as one possible mechanism that protects the endothelium by promoting endothelial repair capacity through angiogenesis and restoring endothelial function of injured vessels. EPCs are recruited to the peripheral blood by several angiogenic factors and are capable of promoting neovascularization, improving blood perfusion, and facilitating the recovery of ischemic tissues.¹³

The first study describing EPCs was published by Asahara et al in 1997. In this seminal article, the authors have shown that the peripheral blood of adults contains a unique subtype of circulating, bone–marrow-derived cells with properties similar to those of embryonic angioblasts.⁵¹ These bone–marrow-derived cells were identified in the peripheral blood and were shown to proliferate and differentiate in vitro into endothelial cells. Therefore, they were termed EPCs. In the circulation, these cells are most commonly identified by certain membrane markers including the hematopoietic progenitor cell marker cluster of differentiation 34 (CD34) and human kinase insert domain receptor (KDR) which is the receptor for vascular endothelial growth factor (VEGF). The actual population of circulating EPCs represents between 0.0001% and 0.05% of total white blood cells in the peripheral blood. Such diversity can result from differences in antibody affinity or the health status of an individual. A typical flow cytometric analysis of human EPCs by double staining of CD34 and KDR is shown in Fig 1, A.

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Fig 1.

(A) A representative quantification of EPCs by flow cytometry. One hundred microliters of whole peripheral blood were incubated with specific antibodies (CD34-PE and KDR-APC). EPCs were determined in the lymphocyte region (G1). Double positive CD34/KDR cells (circled) were analyzed according to isotype control. (B) A representative image of EC-CFUs on the 7th day. (C) Endothelial tube formation in vitro by late-outgrowth EPCs. (D) Late-outgrowth EPCs are characterized be uptake of Dil-Ac-LDL (Red, arrowheads) and binding of UEA-1 (Green, arrows). (Color version of figure available online.)

However, using the method described can provide only a limited cell population that usually does not grow in culture. Hence, growing all mononuclear cells (MNCs) in endothelial specific culture conditions is widely used to augment differentiation and proliferation of EPCs.⁵² MNCs cultured in vitro on fibronectin-coated plates usually form endothelial cell colony-forming units (EC-CFUs) after 7 days. The EC-CFUs consist of a central cluster of round cells and multiple spindle-shaped cells in the periphery (Fig 1, B). The EC-CFU numbers most likely reflect functional and proliferative abilities of circulating EPCs.⁵³ Recently, it was shown that T lymphocytes assemble the colony core, whereas the out-growing spindle-shaped cells in the outside edge are monocytes, which are termed early-outgrowth EPCs.^[54]^and ^[55]

These monocyte-derived EPCs do not spontaneously form new vessels in vivo and keep their monocytic properties as they are positive for the specific monocytic marker CD14 and readily ingest bacteria.⁵⁴ However, early-outgrowth EPCs express some endothelial-specific markers and secrete angiogenic factors such as VEGF and thereby seem to exert paracrine effects and promote vascular growth. Yet, extended growing of MNCs in endothelial growth medium can provide cells with a cobblestone appearance, termed late-outgrowth EPCs. These cells possess high proliferative capacity and spontaneously participate in endothelial tube formation in vitro (Fig 1, C). These late-outgrowth EPCs appear as an endothelial-like monolayer and can incorporate acetylated low-density lipoprotein and bind Ulex europaeus agglutinin 1 (UEA-1), consistent with endothelial lineage cells (Fig 1, D). Furthermore, these cells display some characteristics of an endothelial phenotype, such as surface protein expression of CD34, KDR, von Willebrand Factor, and vascular endothelial cadherin. In addition, they express endothelial nitric oxide synthase (eNOS) and secrete angiogenic molecules such as VEGF.⁵⁶

Interestingly, the T lymphocytes in the central cluster of the EC-CFUs were identified as angiogenic T cells. These T cells are characterized by coexpression of platelet endothelial cell adhesion molecule-1 and Cys-X-Cys chemokine receptor 4 (CXCR4) for stromal-derived factor-1α (SDF-1α). Circulating levels of these cells are positively correlated with EC-CFU numbers and are inversely correlated with Framingham risk scores in humans (the Framingham risk score includes the following parameters: age, cholesterol, systolic blood pressure, treatment for hypertension, and cigarette smoking and represents a 10-year risk for developing severe coronary heart disease).⁵⁷ Angiogenic T cells enhance the differentiation of EPCs in vitro and play an important role in new vessel formation in vivo.⁵⁷ Furthermore, the presence of T cells is essential for the formation of the EC-CFUs by CD14-positive monocytes.⁵⁸ Therefore, circulating levels of angiogenic T cells may serve as a new biological marker for ischemic cardiovascular diseases.⁵⁷ Jointly, these findings suggest that angiogenic T cells and monocyte-derived EPCs play a crucial role in the process of neovascularization.

Mesenchyal stem cells (MSCs)

Similar to EPCs, mesenchymal stem cells (MSCs) are postnatal bone–marrow-derived pluripotent cells that recently were implicated in promoting neovascularization and tissue repair. Unlike EPCs, these cells are of nonhematopoietic lineage and can be found in other organs including placenta, adipose, cord-blood, and liver. MSCs are negative for CD45, CD34, and CD14 and are positive for CD44, CD73, CD90, CD105, CD166, and stromal precursor antigen-1.⁵⁹ Furthermore, these cells can promote angiogenesis, as they produce numerous growth factors and cytokines, including VEGF.⁶⁰ In addition, MSCs were shown to have the potential to differentiate into cardiovascular lineages, and they are involved in the treatment of ischemic vascular diseases and repair of infarcted tissues.⁶¹

EPCs in Patients with Acute MI

In several studies a high prevalence of previously undiagnosed OSA (22% to 65%) was reported in patients admitted with acute myocardial infarction (AMI).^[62]^,^[63]^,^[64]^and ^[65]

Similarly, preliminary data from our laboratory show that, out of 180 AMI patients admitted for hospitalization, 44% were diagnosed with sleep-disordered breathing and had an AHI ≥20 (Aronson et al, unpublished observations). However, in studies on patients with acute coronary syndromes, the presence of OSA did not confer an increased risk of mortality.^[17]^,^[64]^and ^[65] Similarly, our unpublished data did not show changes with regard to hard clinical endpoints such as mortality, heart failure, or recurrent infarctions in OSA patients with AMI despite a worse risk profile. Therefore, it may be hypothesized that these observations could result from activation of adaptive pathways elicited by chronic IH that confer cardioprotection.^[66]^and ^[67]

Several epidemiological studies reported higher numbers of EPCs in patients with AMI.^[68]^and ^[69] However, the exact mechanisms inducing increased recruitment of EPCs after an AMI remain unclear. Of note, increased mobilization of circulating progenitor cells (CPCs) was observed in patients with cardiovascular diseases after treatment with ischemic stimuli. Furthermore, these CPCs expressed higher levels of CXCR4, the receptor for SDF-1α, which may lead to an improved integration of EPCs into endothelial networks.⁷⁰ Therefore, IH associated with OSA also may act in mobilizing EPCs after a severe ischemic event such as an AMI.

Although low-EPC levels may predict the development of cardiovascular morbidity,^[71]^,^[72]^,^[73]^,^[74]^and ^[75] increased recruitment of EPCs may confer cardioprotection and repair of the damaged blood vessels after an ischemic injury. Thus, diagnosing OSA in patients with acute ischemic injury, such as AMI, could have some possible prognostic value. Additional information describing the impact of AMI on stem cell function, mobilization, and clinical trials using stem cells for possible therapy was reviewed recently.⁷⁶

EPCs in Hypoxia and Ischemia/Reperfusion

Oxygen deprivation resulting in tissue hypoxia/ischemia mobilizes EPCs from the bone marrow, stimulates the differentiation of peripheral blood MNCs into EPCs in vitro, and induces angiogenic properties in these cells.⁷⁷ Hypoxia, which is a major driving force for angiogenesis, activates the expression of several global transcription factors, including hypoxia-inducible factor-1α (HIF-1α).⁷⁸ HIF-1α is a master regulator, controlling the transcription of hundreds of genes that participate in oxygen sensing and angiogenesis. One major gene product encoded by HIF-1α is VEGF, which plays a major compensating role in ischemia.⁷⁹ Furthermore, VEGF plays a crucial role in the mobilization of EPCs and participates in the development of coronary collaterals. Thereby, VEGF can protect the myocardium during severe ischemic events. It should be noted that, in OSA, the levels of circulating VEGF are up-regulated in a severity-dependent manner and are attenuated by nCPAP treatment.⁸⁰

Another important mediator of cell recruitment and homing is SDF-1α, which is elevated in areas of tissue damage and hypoxia. This elevation in SDF-1α expression in ischemic tissues, is regulated by HIF-1α.⁵⁷ EPCs also express the SDF-1α receptor CXCR4, which mediates their recruitment to the sites of neovascularization.⁸¹ Hypoxia can induce a high expression of CXCR4 in different cell types (monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells), which was dependent on HIF-1α activation and stabilization.⁸² Therefore, the SDF-1α/CXCR4 pathway may regulate recruitment and homing of circulating EPCs to hypoxic tissues or organs to be repaired or maintained.

Interestingly, mice with induced MI expressed higher SDF-1α mRNA and protein levels in the infarcted area. Also, high SDF-1α levels were strongly associated with an increased recruitment ability of CXCR4 positive bone–marrow-derived cells to the infarcted heart, whereas using a SDF-1α specific inhibitor (AMD3100) significantly diminished its recruitment abilities.⁸³ Importantly, in a subgroup of OSA children with endothelial dysfunction, plasma SDF-1α levels were significantly lower, whereas no significant differences were noted between OSA children with normal endothelial function and healthy controls.⁸⁴ Also, using a rat model of MI has shown that hypoxic preconditioning up-regulated cardiac expression of SDF-1α and reduced the heart susceptibility to ischemia/reperfusion injury by increasing mobilization and homing of CD34+CXCR4+ progenitor cells.⁸⁵ These findings support the importance of the SDF-1α/CXCR4 axis in the recruitment and homing of EPCs to damaged tissues under various hypoxic conditions.

Postischemic blood reperfusion to the tissues generally is accompanied by a rapid elevation of blood oxygen levels, which can lead to a high production of ROS and oxidative stress. During ischemia/reperfusion, ROS can be produced by both endothelial cells and circulating leukocytes. Chronic oxidative stress can accelerate the onset of senescence in human endothelial cells.⁸⁶ In addition, several studies demonstrated a link between chronic oxidative stress and apoptosis of endothelial cells, which may lead to endothelial dysfunction.^[86]^,^[87]^and ^[88] Importantly, EPCs express significantly higher levels of intracellular antioxidant enzymes such as catalase, glutathione peroxidase, and the mitochondrial manganese superoxide dismutase. Moreover, EPCs were shown to be resistant to oxidants such as H₂O₂ and ROS as compared with human umbilical cord vein endothelial cells (HUVECs) or human microvascular endothelial cells. Also, EPCs were shown to resist apoptosis induced by the redox cycler LY-83583 as compared with HUVECs.^[89]^and ^[90] Thus, unlike endothelial cells, which are sensitive to oxidants and oxidative stress, EPCs were shown to resist oxidant environment and function under oxidative stress conditions. Employing such mechanisms can help EPCs to execute a regenerative program during exposure to oxidative stress to promote angiogenesis and to restore endothelial function of injured vessels under hypoxia/reoxygenation or ischemia/reperfusion conditions.

Ischemic Preconditioning—Effects on EPCs and Relevance to OSA

Numerous studies over the last 20 years identified ischemic preconditioning (IPC) as a protective mechanism for the cardiovascular system.⁹¹ However, IPC is a general phenomenon and was shown to occur in various tissues including skeletal muscles, gut, brain, and liver.^[92]^,^[93]^,^[94]^and ^[95] IPC refers to repeated brief periods of ischemia, which can provide a profound protection from MI, arrhythmias, and additional ischemic insults.¹⁵ This phenomenon was first described by Murry et al in 1986.⁹⁶ By occluding one of the left circumflex arteries for 40 min, the size of an infarct could be reduced by 75% if the heart was subjected to 4 brief episodes of 5 min ischemia and 5 min reperfusion prior to the prolonged ischemia.

Recurrent events of IH associated with OSA may resemble the brief periods of ischemia/reperfusion and elicit IPC in some instances. Indeed, patients admitted for acute MI and diagnosed with OSA did not show an impaired microvascular perfusion after primary percutaneous coronary intervention as compared with MI patients without OSA.⁶⁴ Furthermore, the presence of preinfarction angina may reduce myocardial damage and favor myocardial viability after an acute MI by activating IPC mechanisms.⁹⁷ In fact, pretreating skeletal myoblasts by multiple short duration cycles of ischemia/reperfusion was more effective to precondition the cells and improved their resistance to subsequent episodes of lethal ischemia as compared with 1-time, longer-term continuous exposure to hypoxia of the same duration and intensity.⁹⁸ In addition, pharmacological preconditioning of skeletal myoblasts significantly improved their survival and resistance to oxidant stress in vitro and in vivo after transplantation to the infarcted myocardium.⁹⁹

In a recent study, IPC was shown to protect the heart against ischemia/reperfusion injury by enhancing the mobilization of CD34+ progenitor cells from the bone marrow.¹⁰⁰ Preconditioning with 2 cycles of 30-min ischemia and 10-min reperfusion showed significant activation and nuclear translocation of HIF-1α in bone–marrow-derived, multipotent postnatal MSCs.⁹⁸ Additionally, in a mouse model of hindlimb ischemia, hypoxia preconditioned MSCs were shown to enhance ischemic tissue recovery as well as to facilitate vascular cell mobilization and skeletal muscle fiber regeneration.¹⁰¹ Also, hypoxic/normoxic preconditioning significantly increased endothelial differentiation of human bone–marrow-derived CD133+ cells, as measured by EC-CFU analysis.¹⁰² In addition, IPC directly stimulated differentiation of EPCs from peripheral blood or circulating MNCs and augmented the efficacy of these cells for therapeutic neovascularization in a rat model of hindlimb ischemia.⁷⁷ In a rat model of MI, hypoxic preconditioning protected rat hearts by stimulating recruitment of CD34+CXCR4+ progenitor cells to the peripheral blood and myocardium.⁸⁵ Furthermore, an IPC stimulus induced by upper limb ischemia 6 times a day significantly increased VEGF plasma concentrations and circulating EPCs levels in humans.¹⁰³ Thus, alternating hypoxic/normoxic conditions can grant a better environment for the mobilization, differentiation, and function of EPCs.

EPCs in OSA: Evidence in Human Patients and Animal Models

Thus far, the studies describing EPCs levels and their functions in OSA are limited and inconsistent (summarized in Table I). Yet of the few recent studies reported on the subject, 2 studies have shown that, in OSA patients without comorbidities, circulating levels of EPCs were lower than in controls and were increased after effective nCPAP treatment.^[46]^and ^[104] Similarly, circulating EPC numbers were shown to be lower in comorbidity-free patients with OSA but endothelial function was comparable with controls, and plasma VEGF levels were higher.¹⁰⁵ In yet another study, no differences were observed in circulating endothelial cells or EPCs between OSA patients and healthy controls.¹⁰⁶ In a more recent study, circulating EPCs were increased in OSA patients and decreased after nCPAP treatment. Similar findings also were reported for angiotensin II, VEGF, and oxidized low-density lipoprotein (LDL).¹⁰⁷ In a study conducted on children with OSA that investigated EPCs and endothelial dysfunction, 2 patient subgroups were identified—a group with normal endothelial function and a group with endothelial dysfunction. EPC levels were significantly lower in the OSA group with endothelial dysfunction as compared with control subjects. However, in children with OSA exhibiting normal endothelial function, EPCs were significantly higher than in the control group.⁸⁴ Such findings may explain the inconsistencies observed thus far in OSA. But more importantly, these findings suggest that EPCs may serve as a biological marker for endothelial dysfunction in these patients.

Table I. EPCs levels in human patients with OSA ^*

Study	EPCs Phenotype	Groups	EPCs Counts	Endothelial Function in OSA	nCPAP Follow-up	EPCs Levels After nCPAP
Jelic et al ⁴⁶	CD133⁺/CD34⁺/VEGF-R2⁺	OSA - 16 Cont.- 16	3-fold decrease in OSA	Impaired	4 wks	2-fold increase
Jelic et al ¹⁰⁴	CD133⁺/CD34⁺/VEGF-R2⁺	OSA - 22 Cont.- 15	OSA - 0.013 ± 0.006% Cont. - 0.049 ± 0.022%	Impaired	4 wks	Increased to 0.037 ± 0.020%
de la Pena et al ¹⁰⁵	CD34⁺/VEGF-R2⁺	OSA - 13 Cont.- 13	OSA - 5.9E⁻⁴ ± 7.5E⁻⁵% Cont. - 1.2E⁻³ ± 2.6E⁻⁴%	Normal	NA	NA
Martin et al ¹⁰⁶	CD45⁺/CD133⁺/CD34⁺	OSA - 10 Cont. - 17	OSA - 853 ± 176 cells/mL Cont. - 1077 ± 318 cells/mL	NA	NA	NA
Kizawa et al ¹⁰⁷	CD133⁺/CD34⁺/CD202b⁺/CD45^-	OSA - 38 Cont.- 37	OSA - 1.40 ± 0.33% Cont. - 0.48 ± 0.09%	NA	12 wks	Decreased to 0.75 ± 0.18%
Kheirandish-Gozal et al ⁸⁴	CD133⁺/CD34⁺/VEGF-R2⁺	OSA - 20 Cont.- 20	2-fold decrease in OSA	Impaired	NA	NA
Kheirandish-Gozal et al ⁸⁴	CD133⁺/CD34⁺/VEGF-R2⁺	OSA - 20 Cont.- 20	1.5-fold increase in OSA	Normal	NA	NA

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wks, weeks; NA, not available.

^* In Jelic et al,¹⁰⁴ the EPCs values represent the % out of gated lymphocytes; in de la Pena et al,¹⁰⁵ the EPCs values represent the % of total MNCs; in Kizawa et al,¹⁰⁷ the EPCs values represent the % out of total white blood cells.

Evidence arising from animal models of OSA demonstrates that experimental IH results in elevated recruitment of MSCs and very small embryonic-like stem cells to the circulation compared with controls.^[108]^and ^[109] Moreover, early activation of MSCs and enhanced endothelial wound healing were reported in rats subjected to recurrent obstructive apneas.¹¹⁰ Furthermore, intravenous injection of MSCs reduced inflammation, suggesting that these cells can moderate the inflammatory response in OSA.¹¹¹ Thus, from the limited number of studies conducted to date in patients with OSA and in animal models mimicking OSA, the role of EPCs/MSCs in the pathogenesis of OSA remains unclear.

Nitric Oxide and Endothelial Dysfunction in OSA: A Possible Role for EPCs

The integrity of the endothelial monolayer is crucial for intact vascular activity and is regulated by multiple growth factors and vasoactive mediators. One of the most important mediators of vascular function is nitric oxide (NO). Endothelial cells expressing eNOS are the main source of NO in the vasculature. Decreased NO bioavailability may lead to altered blood vessel vasodilatation and eventually to endothelial dysfunction.¹¹²

In recent years, NO has been identified as a powerful and specific mobilizing factor for EPCs.¹¹³ Moreover, eNOS was shown to be essential for neovascularization.¹¹⁴ Accordingly, in a mouse model of hind-limb ischemia lacking eNOS, mobilization of EPCs was significantly lower and neovascularization was impaired. Conversely, intravenous infusion of EPCs from wild-type mice to the eNOS-deficient mice improved limb reperfusion and improved neovascularization. These findings demonstrate the importance of functional eNOS for EPCs recruitment from the bone marrow under ischemic conditions.¹¹³ Furthermore, EPCs recruited to the myocardium by IPC express high levels of NO synthase isoforms, thus providing increased NO availability at the site of ischemia/reperfusion-induced endothelial injury. This provides cardioprotection that normally occurs after IPC.¹¹⁵ In addition, the NO pathway can modulate EPC activities and functions and plays a critical role in blood vessel formation in response to injury as well as in normal endothelial cell maintenance.^[116]^and ^[117]

In several studies, circulating NO levels of OSA patients were shown to be lower than in controls, whereas treatment with nCPAP was shown to increase circulating NO levels.^[118]^,^[119]^and ^[120] Also, flow-mediated dilation, eNOS expression, and NO production by endothelial cells, as well as the numbers of EPCs, were shown to be lower in patients with OSA than in controls. Treatment with nCPAP significantly reversed these measures.¹⁰⁴ Therefore, decreased NO availability may impair EPCs mobilization resulting in endothelial dysfunction, whereas effective nCPAP treatment increased NO levels and improved endothelial function. These findings implicate the presence of EPCs in restoring endothelial function in OSA.

Activation of Adaptive Mechanisms in OSA: A Possible Role for EPCs

Although OSA is a recognized risk factor for cardiovascular diseases, not all patients with OSA develop cardiovascular morbidity. Paradoxical data exist that are consistent with the survival advantage of elderly patients with moderate OSA.¹²¹ For instance, elderly patients with total coronary occlusion diagnosed with OSA had increased coronary collateral vessel (CCV) development as compared with their matched controls without OSA.⁶⁶ CCV formation is one major protective mechanism in occlusive ischemic heart disease and can preserve the ischemic myocardium during coronary obstruction. Thus, increased collateralization in patients with OSA as compared with non-OSA patients may provide a possible activation of cardio-protective mechanisms in elderly OSA patients.⁶⁷ In addition, improved CCV development was shown in patients with chronic obstructive pulmonary disease (COPD) as compared with a control group. This finding could be related to the presence of the chronic hypoxemia characteristic of COPD patients.¹²² Indeed emerging evidence in the past few years suggests that IH may contribute to modifications in the cardiovascular system and protect the heart against ischemia/reperfusion injury.^[123]^and ^[124] Furthermore, IH may lead to neovascularization by inducing the stabilization and activity of HIF-1α as well as by increasing the angiogenic properties of endothelial cells.⁷⁸ In a recent study, an increased risk of incidents of heart failure in middle-aged and older men was associated with severe OSA (AHI ≥30). Yet, no significant differences were found between mild-to-moderate OSA (5 ≤ AHI < 30) and the control group (AHI <5).¹²⁵ Collectively, these findings support a possible association between mild OSA in elderly patients and the activation of adaptive mechanisms, such as ischemic preconditioning and postischemic angiogenesis, which can provide a profound cardio protection from infarction, arrhythmias, and additional ischemic insults.^[67]^and ^[126]

Although several studies demonstrated an inverse correlation between the levels of circulating EPCs and severity of CAD,^[75]^and ^[77] the number of EC-CFUs in culture that developed from circulating MNCs was significantly increased in patients with CAD.¹²⁷ In fact, CAD patients with good collaterals exhibited an increased number of EC-CFUs, suggesting that angiogenesis mediated by monocyte-derived EPCs could be associated with collateral formation in humans.¹²⁸ In addition, increased circulating EPCs numbers were associated with increased collateral development in patients with MI.¹²⁹ Apparently, circulating EPCs participate in collateral formation in a paracrine mechanism by secretion of angiogenic factors.¹³⁰

The mononuclear origin of the EC-CFUs can explain the well-established involvement of the inflammatory cells in the process of collateral growth. Inflammatory cells have been implicated in the growth of preexisting collateral arteries after occluding the arterial blood supply to the myocardium and peripheral limbs. It was reported that increased numbers of T-cells (CD3+) accumulate in the developing collateral vessels.¹³¹ In addition, CD4 knockout mice demonstrated reduced collateral flow as well as a significant impairment in the arteriogenic response to acute hindlimb ischemia. Moreover, CD4+ lymphocytes can induce monocyte-macrophage accumulation in the ischemic muscle.¹³² The accumulating monocytes and macrophages then secrete a broad array of cytokines and growth factors, including VEGF and metalloproteinases, which promote collateral development.^[132]^and ^[133] It is likely that monocyte-derived EPCs directly adhere to the sites of damaged endothelium, providing a quick response to vascular injury.¹³⁴

Conclusions

Hypoxia/reoxygenation associated with OSA can lead to endothelial dysfunction by promoting oxidative stress and vascular inflammation. Although OSA has multiple negative effects on the cardiovascular system, not all OSA patients develop comorbidities or cardiovascular complications. EPCs may play a crucial role in protecting the cardiovascular system as they contribute and maintain endothelial function. Furthermore, EPCs can promote collateral development in human coronary circulation. The inconsistent findings in regard to the EPC levels in OSA suggest that not all patients are susceptible to the adverse effects related to hypoxia/reoxygenation to the same extent, and it is likely that the durations and the intensity of the intermittency have a crucial role in this respect. Thus, it remains to be seen whether IH associated with OSA increases or decreases EPC mobilization and function and what the intermittent hypoxic conditions are that favor increased EPCs mobilization and function. Hence, a possible activation of adaptive mechanisms in some patients with OSA may confer protection to the cardiovascular system by the recruitment of progenitor cells and by the development of coronary collateral arteries.

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Supported in part by Grant 2005265 from the Binational US–Israel Foundation.