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Berezin et al. Vessel Plus 2020;4:15 I http://dx.doi.org/10.20517/2574-1209.2020.03 Page 9 of 13

which promotes endothelial dysfunction and accelerates atherosclerosis through the high-affinity receptor
[92]
BLTR1 . In fact, the presence of dysregulated inflammatory molecules on the surface of the endothelial
cell layer was associated with increased coagulation due to over-expression of the glycoprotein (GP) IIb/
IIIa (integrin αIIbβ3) receptor, anomalous clot formation or shaping amyloid fibrin [93,94] . Importantly,
the GPIIb/IIIa receptors were additionally shed into EVs and transferred as cargo to the target cells for
translation of activation signals remotely. Another finding has demonstrated that heat shock protein
27 (HSP27) packaged into EVs via activating TLR-4/NF-κB in the target cells can attenuate endothelial
function, reduce vascular and plaque inflammation, lower cholesterol levels and suppress atherogenesis
[95]
in animal models . However, the angiopoetic role of activated endothelial cell-derived EVs is not always
considered as having a positive impact on the endothelium. For instance, neovascularization of the
shoulder region of the plaque’s cap was associated with instability of the atheroma due to the increased
risk of rupture [94,96] . There are several excellent reviews that are dedicated the role of EVs in vascular
homeostasis and its relation to CV disease development [97,98] . Thus, EVs promote the function of target cells
through the transfer of surface integrins and receptors, cellular fusion and the delivery of various active
molecules.

EVs as diagnostic and predictive biomarkers of atherosclerosis
The diagnostic and predictive roles of endothelial cell-derived EVs in atherosclerosis and MACEs are
[99]
uncertain . However, there has been progress in the diagnosis, prognostication and treatment of CV
diseases with EVs [100] . For instance, HSP27 packaged in endothelial cell-derived EVs was found to be a
[95]
predictor of a lower CV risk among patients having a heart attack, stroke, or death from CV disease . The
imbalance between activated and apoptotic endothelial cell-derived EVs has provided additional prognostic
information for patients with established CV disease, including acute myocardial infarction, acute coronary
syndrome, ischemic heart failure, MACEs, and arrhythmias, as well as individuals with metabolic diseases
having a higher risk of CV events and disease [101-104] .

Future directions toward the role of EVs in atherosclerosis
EVs have demonstrated a pivotal role in transferring numerous bioactive molecules, supporting cell-to-cell
cooperation, and regulate gene expression in target cells. EVs-based therapeutic regenerative strategies may
thus be used to attenuate tissue injury and promote vascular regeneration and repair [105,106] . Accumulating
evidence implicates EVs in the development and progression of atherosclerosis, and creates the possibility
of using EVs for personalized therapeutic strategies. Therefore, single-EV analysis may identify signatures
of exosome-derived DNA/non-coding RNAs including microRNA, regulator proteins, and other
components both as diagnostic and predictive biomarkers in atherosclerosis [107] . Large clinical studies are
required for further elucidation of whether EVs can be excellent options for point-of-care diagnosis and
individual treatment.

CONCLUSION
EVs could be promising biomarkers with both diagnostic and predictive values, while their number,
content, immune phenotype and origin may provide more useful information about the pathophysiology of
atherosclerosis and help stratify patients at risk of MACEs. The emergence of endothelial cell-derived EVs
provide favorable and promising strategies, not only for CV risk stratification in vulnerable populations but
for individualized treatment of atherosclerosis and other CV diseases.

DECLARATIONS
Authors’ contributions
Participated in drafting the article, revised it critically for important intellectual content: Berezin AE
Gave final approval of the version to be submitted: Berezin AA
Both authors make eqaual contributions to conception and design, searchig data, analysis, interpretation of
data and writting of the manuscript.