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Page 4 of 10 Berezin. Vessel Plus 2018;2:22 I http://dx.doi.org/10.20517/2574-1209.2018.23

Additionally, there are data that confirmed that circulating EPCs originated from bone-marrow stem cells
and peripheral mononuclear cells may directly contact to the injury sites of endothelium and influence
them to induce local proliferation of residence cells, as well as promote auto- and paracrine effects. Indeed,
acting as circulating EPCs enables to exhibit auto- and paracrine influences of hematopoietic cells including
mononuclear cells, as well as local residence cells with high proliferative capacity [37-39] . In this way, EPCs
release micro vesicles with regulatory proteins, peptides, micro-RNAs, growth factors (VEGF), and
hormones (aldosterone) and secrete a wide spectrum of active molecules (E-selectin, P-selectin) directly
into the circulation [40,41] . Both secretome and proteome of EPCs were recognized as central players in the
[42]
reparation of the endothelial layer and restoring of vascular function . Indeed, EPCs turn over mature
endothelial cells and immediately become a target for inflammatory cytokines, factors of coagulation,
hormones (catecholamines, aldosterone, angiotensin-II, endothelin-1), active molecules that have the
ability to induce apoptosis. Apoptotic endothelial cells switch over to the secretion of micro vesicles
to nanoparticles, which contain chromatin. Apoptotic-related nanoparticles are produced by mature
endothelial cells and directly lead to injury of the endothelium and mediate inflammation and coagulation,
but activated mature endothelial cells realize micro vesicles with angiopoetic properties that enhance
vascular reparation and attenuate endothelial function [42,43] . Thus, EPCs with angiopoetic phenotypes may
interact with vasculature in direct and indirect ways depending on the pre-existing ability of EPCs to
proliferation, differentiation and survival as well as the spectrum of co-regulatory factors, which mainly alter
maturation and commitment of stem cells/progenitor precursors and impair EPC mobilization.

THE EPCS DYSFUNCTION: RELATION TO CARDIOVASCULAR RISK FACTORS
EPC dysfunction was described as a phenomenon strongly associated with decreased number and/or
[42]
weak function of circulating precursors . Deficiency of circulating number of EPCs and weak function
of them are found in senescence, atherosclerosis, stable coronary artery disease, myocardial infarction/
acute coronary syndrome, heart failure, atrial fibrillation/flutter, chronic kidney disease, morbid obesity,
diabetes mellitus, hyperthyroidism, insulin resistance [15,19] . Recent clinical studies have shown that EPCs
strongly related to metabolic comorbidities (hyperuricemia, dyslipidemia, hyperglycemia) and appeared to
resultin epigenetic modification of these cells [43-46] . Although simple count of circulating number of EPCs is
not superior to the assay of colony-shaping ability of EPCs in the context of association with CV mortality
rate, the number of circulating EPC has shown to be negatively correlated with CV risk factors and vascular
function and to predict CV disease/events independently of both conventional and non-traditional CV
risk factors [47-49] . Moreover, the loss of the ability to release micro vesicles from EPCs can be a mechanism
of worsening of glomerular function due to microvascular inflammation and endothelial dysfunction in
[50]
chronic kidney disease .
There is a suggestion that EPC dysfunction may appear prior to CVD without close association with CV
risk factors, although conflicting data were obtained by numerous investigators. It has been found that the
[44]
metabolic memory phenomenon in diabetics and pre-diabetics could be a result of EPC dysfunction .
Variability of glycated hemoglobin levels at early stages of diabetes mellitus development and insulin
resistance are well established factors contributing to lowered numbers and poor function of circulating
EPCs [19,40,51] . In contrast, there are studies that reported unchanged or increased numbers of circulating EPCs
in diabetics, in patients with increased serum uric acid and in individuals with hypertriglyceridemia in
comparison with healthy age-matched volunteers [52-54] . Previous studies reported that in healthy individuals
the gender had no essential effect on the number of EPCs and that there was no effect on the number of
[55]
[56]
EPCs factors such as: smoking, physical activity and alcohol consumption . Kulwas et al. reported that
an increased number of circulating EPCs was found in patients with diabetic foot syndrome (DFS), but in
diabetics without foot complications and healthy volunteers, the circulating number of EPCs was similar. In
contrast, subjects with DFS, even with healed ulceration, had fewer EPCs and more CD45-CD29(+)CD90(+)
[57]
mesenchymal stem cells when compared with the T2DM without DFS . However, numerous metabolic