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Berezin. Vessel Plus 2018;2:22 I http://dx.doi.org/10.20517/2574-1209.2018.23 Page 5 of 10
risk factors and diseases including diabetes mellitus themselves did not affect bone-marrow mobilization
of precursors, but they altered the EPC profile and decreased the circulating number of late outgrowth
[54]
EPCs with high proliferative capability that sufficiently worsend the reparative ability of vasculature .
On the other hand, local tissue ischemia is thought to be the strongest inductor of EPC mobilization,
angiogenesis and reparation, but data mentioned above did not confirm that several conditions, such as
DFS, obligatory accompany intensive angiogenesis are associated with increased circulating number of
angiogenic EPCs and high concentration of VEGF and fibroblast growth factor. Additionally, it has been
found that decreased soluble receptors for VEGF due to inactivation of VEGF, may correspond to decrease
in the number of EPCs in the circulation [56-58] . Although EPCs are crucial to vasculogenesis and angiogenesis
during ischemic neovascularization the controversial findings regarding both number and function of EPCs
in peripheral blood require to be explained in details. Probably, EPCs are under tight control of several
epigenetic mechanisms, i.e., DNA methylation, DNA phosphorylation, micro-RNA-related translation, etc.,
which mediate a modification of EPC function, decrease the number of EPCs and suppress their survival.
Moreover, it has been postulated that the worsening of EPCs function is attributed to the time period during
[59]
which EPCs have been in contact with CV risk factors and epigenetic stimuli . As a result, the ability of
the vasculature to repair itself is dramatically lowered. All these facts explain that even newly differentiated
mature endothelial cells from precursors did not completely restore vascular integrity and function. Finally,
endothelial dysfunction tends to persist and damage target organs leading to increased CV risk.

The next controversies affect the fact of unpredictable changes of number of EPCs in the peripheral blood
in acute situations, such as acute heart failure (AHF) or acute coronary syndrome (ACS), or cardiac/
vascular surgery procedures [60,61] . Some investigators reported that the number of circulating EPCs in
AHF or ACS/myocardial infarction was increased, but on the other hand there were reports of a lowered
or an unchanged number of EPCs in humans within hours or days after manifestation of the events [62-66] .
Also, the number of urgently recruited bone-marrow precursors can be limited due to previous expenditures for
tissue reparations, which occurred prior to CV events, i.e., traumas and infections. On the other hand, ischemia/
hypoxia, several spectra of pro-inflammatory cytokines [tumor necrosis factor-alpha, interleukin (IL)-2, IL-4,
IL-6, C-reactive protein], chemokines (E selectin), active molecules (intercellular adhesion molecule-1),
matrix metalloproteinases (MMPs) and ROS that accompany atherothrombotic states, AHF, and release
due progression of them are established factors for mobilization, proliferation and differentiation of EPC [66-69] .
These factors impair hypoxia inducible factor-1 alpha (HIF)/p-Akt/p-eNOS/MMP-9 signaling system
in stem cells and circulating precursors that lead to delayed and reduced EPC mobilization from bone-
marrow and probably from peripheral tissues [70,71] . The final result for changes of the number of circulating
of EPCs depends on a balance between the ability of stimuli to immediately mobilize precursors from bone-
marrow/tissues and the pool of putative precursor cells [72-74] . Interestingly, improved functions of EPCs in
hypertensive patients can be attained with the implementation of renin-angiotensin system blockers, such
as angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, direct renin inhibitors, and
probably mineralocorticoid antagonists acting via intracellular signaling mechanisms related to SDF-1/CXC
chemokine receptor four (CXCR4) and Janus kinase-2/CXCR4 axis [75-78] . Thus, EPC dysfunction is a novel
pathophysiological mechanism underlying defective neovascularization and vascular/tissues reparation in
CVD.

THE DIAGNOSTIC AND PROGNOSTIC VALUES OF EPCS IN HYPERTENSION
Endothelial dysfunction is expressed by an increase of the endothelin-1 level and decreased bioavailability
of nitric oxide associated with altered pro-coagulative, pro-inflammatory, and pro-vasoconstrictive pheno-
[79]
types, and it is an early event in CVD that frequently precedes CV complications . It has been reported
that EPC colony number was significantly and inversely correlated with systolic and diastolic BP in subjects
with hypertension . A lowered number of EPCs in circulation was found at an early stage and represents
[78]
a reliable predictor of endothelial dysfunction as well as a marker of target organ damages [80-82] . Indeed,