Cardiovascular (CV) diseases including atherosclerosis, arrhythmia, myocardial infarction, heart failure remains to be a main cause of death worldwide. Recent animal and clinical studies have shown that an endothelium, which is involved in the pathogenesis of CV diseases across all stages of CV continuum, could coordinate both mutual counteracting processes, i.e. vascular injury and reparation [2, 3]. The endothelial progenitor cells (EPCs), which enhance angiogenesis, neovascularization and vascular function, act, as endogenous repair system and play a pivotal role in the endothelium homeostasis [4, 5].

Pioneer investigations of Asahara et al [6, 7] have been shown that EPCs located in a bone marrow and probably in peripheral tissues are able to migrate into injury sites and directly turning into mature endothelial cells and even into smooth muscle cells shaping new vessels. Authors reported that EPCs dramatically enhance the angiopoetic capacity including cell proliferation, migration, and tubule-like formation as well as promote tissue reparation with a reduction in fibrotic tissue and improved neovascularization via significant suppression of inflammatory cell recruitment. Although mechanism of EPC-mediated reparation is not fully understood, it has been found that the EPCs may synthase and secrete a broad spectrum of angiopoetic factors, i.e. vascular endothelial growth factor (VEGF), stromal-cell-derived factor-1 (SDF-1), and fibroblast growth factor (FGF). These factors involve into an attenuation of angiogenesis and vascularization through epigenetic mechanisms affecting as endothelial precursors, as more mature endothelial cells [8]. Acting through several intracellular pro-survival regulators (hypoxia induced factor-1α, Akt / eNOS signaling) EPC-depending cytokines mediate cytoprotective effects on the target cells in injured tissues [9].

Recent studies have revealed the CV risk factors, i.e. diabetes, obesity, impaired fasting glucose, hypothyroidism, hyperuricemia, may directly induce lowering EPC number and weak their functionality that has determined as EPC dysfunction [10-13]. In a result, EPC dysfunction precedes manifestation of endothelial dysfunction and CV diseases through worsening vascular repair capability [9, 14]. On the other hand, EPC dysfunction could appear prior CV diseases and even CV risk factors, although there is no a clear explanation of the phenomenon [14-16]. Probably epigenetic dysregulation is a main cause leading to both lowered number and weak function of EPCs beyond influencing conventional CV risk factors [17]. Taken together all these facts suggest that various CV risk factor may impact on structure, function, an ability to colony forming and differentiation of different immune phenotypes of EPCs in a distinguished manner.

Recent studies performed ex-vivo with cultured EPCs allow recognizing two different phenotypes of EPCs labelled as early outgrowth EPCs and late outgrowth EPCs and isolated from similar source having similar markers expressing on their surfaces, i.e. CD144, CD309 (VEGF receptor - VEGFR), and CD45 [18, 19]. Late outgrowths EPCs may easily shape colony of endothelial cells than early outgrow EPC. Moreover, late outgrowths EPCs were able to produce more nitric oxide and got better attenuation of capillary structure when compared to early EPC [18]. Consequently, early outgrow EPCs may produce slightly broad spectrum of pro-angiogenic and angiopoetic cytokines including VEGF and interleukin (IL)-6 [19, 20]. Additionally, there was a considerable difference between early outgrow EPCs and late outgrow EPCs in gene expression profiles that affect their ability to express some intracellular signal systems, i.e. stem cell factor (SCF)/c-Kit, angiopoietin-1/Tie2, and SDF-1/CXCR4 [21]. It has been postulated that the difference in gene expression in EPC populations could enhance their ability to realize variable effects toward secretion and differentiation. However, nowadays we do not exactly know whether both immune phenotypes of EPCs distinguishing their ability to shaping endothelial cell colony in culture. In this context, cytokine-triggered low intense inflammation as a common pathogenetic factor of CV diseases may up-regulate an expression of various genes leading to worsening survival ability of EPCs and number depletion of ones [22].

Indeed, an exhaustion of circulating number of EPCs labeled as CD34+ and / or CD133+, AC133+, endothelial cell markers (CD309, CD31, CD 144) was found in patient with atherosclerosis, cardiac dysfunction, myocardial infarction / acute coronary syndrome, hypertension, diabetes mellitus, thyroid dysfunction [14, 15, 23-25].

However, there are several controversies regarding the role of different immune phenotypes of EPCs in tissue reparation. Koller et al (2016) [23] reported that EPCs, defined as triple-positive cells with phenotype CD34+CD45-CD309+, was a significant and independent inverse predictor of mortality of heart failure as ischemic as well as non-ischemic etiology. There is evidence that the number of circulating non-hemopoetic EPCs with immune phenotypes CD14+CD309+ and CD14+CD309+Tie2+ could demonstrate more pretty discriminative value in ischemia-induced cardiac failure than CD45+ CD309+ EPCs [24]. Therefore, lowered number of CD14+CD309+Tie2+ EPCs may suggest shaping systolic cardiac dysfunction, whereas hemopoetically originated EPCs did not exhibit predictive value in left ventricular hypertrophy and isolated diastolic function [14, 25].

In population of the asymptomatic coronary artery disease patients increased circulating number of CD45-CD34+ EPCs and a reduced non-classical EPC’ population defined as CD14+CD309+ and CD14+CD309+Tie2+ were found [26]. Interestingly, there was an association between number of non-classical phenotype EPCs and diabetes mellitus, highly sensitive C-reactive protein, and Agatston score index , whereas CD45-CD34+ EPCs’ number did not exhibit similar relations [26]. Moreover, incorporation of number of CD14+CD309+Tie2+ EPCs as a predictive biomarker into biomarker risk score for cumulative CV events in heart failure patients may sufficiently improve sensitivity, specificity, reliability and final discriminative value of the scale [27]. Yang et al [28] reported that count of circulating EPCs with immune phenotype CD34-/CD133+/KDR+ (VEGFR+) may exhibit osteogenic potential and strong correlates with coronary atherosclerosis at the early stage. Similar results were received by Berezin A et al (2016) [29] in diabetic cohort. Authors reported that lowered number of non-classical EPCs with immune phenotypes CD14+CD309+ and CD14+CD309+Tie2+, but CD34+ subsets of EPCs did not associated well with biomarker of atherosclerosis in individuals with type 2 diabetes mellitus. Finally, EPCs with classical CD34+CD133+CD309+ phenotype and non-classical CD34+Tie2+ phenotypes may sufficiently distinguish each other in their ability to predict CV diseases and exhibit discriminative value for clinical CV outcomes [30, 31].

Whether increased number of EPCs with various non-classical phenotypes in individuals suspected to atherosclerosis could reflect the risk of all-cause mortality is not fully understood. Further large clinical trials are required to explain the role of various immune phenotypes of circulating EPCs as a biomarker of CV disease with promising predictive value.

Conclusion

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CV disease development associates with exhausting number of circulating EPCs and / or lowered functional ability of ones. CV risk factors are able to modulate innate features of circulating EPCs with different immune phenotypes, which correspond to a risk of CV events and CV mortality. However, there is no clear evidence regarding pretty predominance in useful of measurement of immune phenotypes of EPCs to predict CV disease that requires more clinical investigations.

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