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Page 8 of 13 Berezin et al. Vessel Plus 2020;4:15 I http://dx.doi.org/10.20517/2574-1209.2020.03

the Agatston coronary calcium score were all inversely correlated with the number of endothelial cell-
[77]
derived EVs . However, a recent clinical study based on positron emission tomography/computed
tomography imaging has shown that early microvascular calcifications can be identified frequently, even
[78]
in high-risk patients with plaques . Early microvascular calcification was found to be associated with
atherosclerotic plaque instability and rupture, whereas advanced macrovascular calcification can potentially
contribute to plaque stability [79,80] . There is a suggestion that M1 macrophages that have accumulated in
a plaque may release EVs enriched in S100A9 and annexin A5 as a result of weakly activated endothelial
cell-derived EVs’ stimulation. This contributes to accelerated trans-differentiation of SMCs into osteogenic
[79]
cells, and the potentiation of microvascular calcification . Notably, endothelial cell-derived EVs contain
bone-related matricellular proteins (osteopontin, osteonectin, osteoprotegerin) and the deficiency of
these EVs in the circulation may impair the migration of and cell fusion required for osteoclast formation
in the vasculature [81,82] . Moreover, the immune phenotype and the number of cells accumulating into an
atheroma, as well as the extracellular environment are all under the control of endothelial cell-derived
[83]
EVs . In fact, EVs originating from progenitor and mature endothelial cells have the unique ability of
regulating the osteogenic transformation of SMCs and the activation of fibroblasts in the vasculature.
The endothelial cell-derived EVs support microvascular calcification in the collagen-poor fibrous cap,
and promote plaque rupture by acting through the TGF-β/SMAD signaling and platelet-derived growth
[84]
factor-BB pathway . Interestingly, endothelial cell senescence may increase the release of EVs as carriers
of molecular information, which then contributes to the development and calcification of atherosclerotic
plaques. The role of senescent EVs in microvascular calcification is not certain however, and requires
[85]
further investigation . Whether the altered balance between EVs produced by activated and apoptotic EVs
is a cause of microvascular calcification, or if the adaptive reaction prevents inflammatory-related injury of
the vasculature and thereby reduce the risk of calcification, is not fully understood.

Endothelial dysfunction and EVs
[86]
Endothelial cell-derived EVs are established biomarkers of endothelial dysfunction . The interplays
between cell components that are embedded into the pathogenesis of vascular tone impairment and
vascular remodeling in atherosclerosis are mutually activated and sophisticated. There is a wide range
of evidence that foam cells and both progenitor and mature endothelial cells may work with each other
by releasing exosomes and ABs. Foam cells may secrete exosomes that suppress endogenous activity of
endothelial cells and their precursors to modulate endothelial-dependent vasodilatation and prevent
[87]
intravascular blood cell adhesion and thrombosis . Moreover, the foam cell-derived EVs promote
migration and proliferation of SMCs by regulating the actin cytoskeleton and focal adhesion via ERK and
[87]
Akt pathways, thereby acting as a trigger of atherosclerosis .

There are findings that demonstrate a causative impact of EV-packaged microRNA-145, microRNA-150
[88]
and microRNA-126 on the progression of endothelial dysfunction and atherosclerosis in vivo . These
microRNAs appear to respect tissue specificity and are both expressed in and released from endothelial cells
due to several stimuli including shear stress, inflammatory cytokines, cell adhesion and thrombosis. Down-
regulated microRNA-145, which plays a key role in the control of SMC differentiation, promotes lesion
formation. The endothelial cell-specific microRNA-126 is a powerful signal transducer, which is essential
for endothelial repair through its transfer from apoptotic endothelial cells derived EVs. Interestingly,
splicing of the X-box binding protein 1 (XBP1) in vascular SMCs may control endothelial cell migration via
EVs-mediated transfer of microRNA-150 and microRNA-150-driven vascular endothelial growth factor-
[89]
dependent PI3K/Akt pathway activation, thereby supporting homeostasis of the vasculature . In fact,
XBP1 deficiency in vascular SMCs and endothelial progenitor cells significantly attenuate angiogenesis
and neovascularization, as well as maintain endothelial integrity and resistance to apoptosis [90,91] . Foam
cell shaping driven by CD36 mediated internalization of oxidized LDL activates mononuclear cells and
endothelial cells, and the subsequent release of EVs embedded with pro-inflammatory leukotriene B4,