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Page 2 of 13 Berezin et al. Vessel Plus 2020;4:15 I http://dx.doi.org/10.20517/2574-1209.2020.03

developed countries over the last decade, mortality trends from coronary artery disease (CAD) have been
[2,3]
more varied . The decline in risk of potentially fatal complications from atherosclerosis in high-income
countries has been reported to be closely connected with improved control of conventional CV risk factors
[4,5]
such as hypertension, obesity and smoking, after implementation of current clinical guidelines . Overall,
the impact of atherosclerosis on MACEs, CV disease manifestation and disability in both developed and
developing countries continues to be under investigation because full control of traditional CV risk factors
(i.e., dyslipidemia, and diabetes mellitus) did not achieve disease reversal.

Non-adaptive remodeling in atherosclerosis leads to plaque formation, which is a consequence of events
including endothelial dysfunction, impaired vascular repair, systemic and microvascular inflammation,
[6]
and the migration, proliferation and phenotypic switch of smooth muscle cells . There are numerous
cellular and molecular mechanisms that contribute to the initiation and progression of vascular lesions
in atherosclerosis including the infiltration of oxidized lipids into the sub-intima, transformation of
macrophages from an anti-inflammatory into a pro-inflammatory phenotype, modification of the
extracellular matrix due to imbalance between activities of matrix metalloproteinases and their inhibitors,
the development of foam cells, over-production of inflammatory cytokines in the atherosclerotic plaque and
[7-9]
within the sub-intima layer, expansion of the lipid core in the plaque and vascular tone dysregulation . In
turn, endothelial and vascular integrity are ensured by interaction of genetic and epigenetic programs that
play a pivotal role in the maintenance of vascular homeostasis [10,11] .

Previous pre-clinical and clinical studies have shown that extracellular vesicles (EVs) originate from
progenitor and mature endothelial cells. EVs may act both locally and remotely as powerful regulators
of vascular function and integrity through the transfer of biological information [12-14] . EVs are also
involved in several pathological processes underlying progression of atherosclerosis such as systemic and
microvascular inflammation, immunity, signal transduction, cell proliferation, differentiation, survival and
apoptosis, as well as neovascularization, angiogenesis, thrombosis, and autophagy [14-16] . The purpose of this
review is to summarize current knowledge on the role of endothelial cell-derived EVs in the manifestation
and progression of atherosclerosis, and to discuss the clinical use and benefits of using altered immune
phenotypes of these endothelial-cell derived EVs as predictive biomarkers in both asymptomatic and
subclinical atherosclerosis.

DEFINITION AND NOMENCLATURE OF EVS
EVs are a heterogenic population of secreted, membrane-enclosed particles. This includes exosomes,
ectosomes, microvesicles, smal size microvesicles, micro particles, nano particles, apoptotic bodies
and other subsets. Some (ectosomes and micro particles) are not distinct from each other, and several
classification approaches (sedimentation speed-derived criteria, immune phenotype, origin, mechanism of
release, and size) were applied to EV subsets to qualify them in some categories.

According to the last update of the Executive Committee of the International Society for EVs, EVs are
defined as a mixture of particles ranging from 30-2000 nm in diameter, released by various types of viable
cells through several mechanisms (blebbing and budding of endosomal or plasma membranes) and include
[17]
exosomes, microvesicles and apoptotic bodies . EV subtypes are defined according to numerous physical
characteristics however, such as size (small, medium and large EVs with diameters < 100 nm, 100-200 nm
+
and > 200 nm), density (low, middle, and high, with each range defined), biochemical composition (CD63 /
CD81 , Annexin A5-stained), and descriptions of conditions or cell of origin (e.g., podocyte EVs, hypoxic
+
EVs, large oncosomes, apoptotic bodies). Although the terms “exosome” and “microvesicle” are historically
burdened by both manifold and inaccurate definitions, Table 1 reports both under the nomenclatures of
EVs to easily understand the basic characterictics of several subtypes of EVs.