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DOI: 10.4172/2329-9495.1000145
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Angiology: Open Access
Berezin, Angiol 2015, 3:3
http://dx.doi.org/10.4172/2329-9495.1000145
Mini Review
Open Access
Small-size Endothelial-derived Micro Particles as Novel Predictive Biomarkers
in Cardiovascular Diseases
Alexander E. Berezin*
Consultant of Cardiology Unit, Internal Medicine Department, State Medical University, 26, Mayakovsky av, Zaporozhye, Ukraine
*Corresponding author: Alexander E. Berezin, Consultant of Cardiology Unit, Internal Medicine Department, State Medical University, 26, Mayakovsky av.,
Zaporozhye, Ukraine, 69035; Tel: +380612894585; E-mail: dr_berezin@mail.ru
Received date: July 07, 2015; Accepted date: July 17, 2015; Published date: July 26, 2015
Copyright: © 2015 Berezin AE. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The role of micro particles (MPs) as biological messengers is widely discussed. MPs demonstrate an ability to
involve in the different stages of pathophysiology of cardiovascular diseases mediating endothelial dysfunction,
atherogenesis, thrombosis, vascular remodeling, and low grading inflammation. Endothelial MPs are defined as
small (100-1000 nm) a nucleoid phospholipid vesicles released due to activated and / or apoptotic endothelial cells.
Small-size endothelial-derived MPs have low dimensions (less 100 nm usually about less 50 nm) and exert
biological effects corresponding cell-to-cell cooperation regulation of immunity, cell differentiation and growth,
modulating apoptosis, coagulation, and inflammation. These effects might mediate through MP surface proteins,
cytoplasmic material of the parental cells, including signal molecules, active proteins, coagulation and growth
factors, mRNA/miRNA. Wide spectrum of biological effects of small-size MPs confirms that they are not just a
passive messengers accompanying cellular function, but a tightly regulated mechanism implicated in the interactions
between various cells. Small-size MPs are poor detectable in serum, although there are various commercial analytic
system for its determination. Recent clinical studies have shown that small-size endothelial-derived MPs might be a
surrogate biomarker of vascular integrity and endothelial dysfunction with predictive value. The mini review is
clarified the role of number of small-size endothelial-derived MPs in cardiovascular diseases.
Keywords: Small-size endothelial-derived
Cardiovascular diseases; Biomarkers; Prognosis
micro
particles;
Abbreviations
MPs: Micro Particles; ACS: Acute Coronary Syndrome; MI:
Myocardial Infarction; TIA: Transient Ischemic Attack
Introduction
Endothelial dysfunction (ED) is well known cardiovascular (CV)
risk factor that contributed CV events and closely corresponded
mortality and morbidity in general population, subjects with classical
CV risk factors with and documented CV diseases [1-3]. Therefore,
ED is closely related to atherosclerosis and its risk factors, the natural
history of coronary artery disease (CAD), heart failure, and frequently
affecting clinical outcomes [4-6]. It is well known that apart from
vascular tone modulating vascular endothelium actively regulates
molecule traffic between blood and tissues, contributes reparative
mechanisms, and plays a crucial role in cell-to-cell cooperation,
immunity, coagulation, and inflammation [7].
Endothelial-derived micro particles (MPs) are recognized as vesicles
with dimensions ranged from 100 to 1000 nm secreted endothelial
cells resulting in activation or apoptosis of parental cells [8]. Elevated
or inversely decreased levels of circulating endothelial-derived MPs
were found in various CV diseases and it was extremely distinguished
from those that were reported in healthy volunteers [9-11]. Biological
role of endothelial-derived MPs are not fully understood and probably
depends on origin of the vesicles from parent cells [12-14]. There is
large body of evidence that MPs might contribute cell-to-cell
communication, transfer biological information, promote tissue repair
Angiol
ISSN:2329-9495 AOA, an open access journal
and angiogenesis, induce tissue injury, activate apoptosis, mediate
coagulation and effect negatively on vascular integrity [13,14].
Moreover, MPs may link to deleterious effects on target cells from
adipose tissue and antigen-presenting cells. Although wide spectrum
of biological effects of endothelial-derived MPs confirms that they are
not just a passive messengers accompanying cellular function, but a
tightly regulated mechanism implicated in the interactions between
various cell types, majority evidences dos not relate to small-size
endothelial-derived MPs. The aim of the mini review is consideration
of possible role of small-size endothelial-derived MPs in
cardiovascular diseases.
Definition and biological role of MPs
MPs are defined a heterogeneous population (small size MPs and
MPs with greater diameter are around less 50 nm and 100–1000 nm
respectively) of vesicles that are released by cellular vesiculation and
fission of the membrane of cells [15]. This mechanism affects genome
of parent cells and may mediate by wide spectrum triggers [16]. MPs
appear to be found into circulation in response to many situational
changes (physiological and pathological conditions, stress) micro
environmental stimulation, coagulation/thrombosis, endotoxinemia,
endothelial shear stress, activated cells or those undergoing apoptosis,
ischemic injury, hypoxia, and malignancy [17,18]. Biological role of
MPs are not fully understood and depends on origin of the vesicles.
MPs are released (in vivo and in vitro) following apoptosis and cell
activation of the various originated cells, i.e. mononuclears, platelets,
endothelial cells, erythrocytes, oligodendrocytes, antigen-presenting
cells, and even tumor cells. The most clinical significance probably has
MPs originated from platelets, mononuclears, endothelial cells, and
Volume 3 • Issue 3 • 1000145
Citation:
Berezin AE (2015) Small-size Endothelial-derived Micro Particles as Novel Predictive Biomarkers in Cardiovascular Diseases. Angiol 3:
145. doi:10.4172/2329-9495.1000145
Page 2 of 4
antigen-presenting cells (Figure 1) presented evidences regarding
biological role of MPs originated from differenced cells.
Figure 1: Evidences regarding biological role of MPs originated
from differenced cells.
MPs are not just disseminated storage pool of bioactive effectors
required for cell-to-cell communication, which is mediated through
delivering various peptides, lipids, active proteins and molecules,
mRNA and microRNA (miRNA), but they are direct effectors for
several biological processes, i.e. inflammation, tissue injury, vascular
integrity enhance, coagulation and thrombosis. Probably, not just an
origin of MPs, but their size might have sufficient value for the effect
on various target cells.
Circulating endothelial-derived MPs are a marker of endothelial
dysfunction and they are discussed as integrated effectors of target
cells, endothelium, and CVD risk factors. However, immune
phenotypes of circulating endothelial-derived MPs in various CV
diseases and metabolic states may be variable (Table 1). Moreover,
EMPs derived from activated endothelial cells may play a pivotal role
in the vascular remodeling and endothelial reparation [12]. In
opposite, EMPs originated from apoptotic endothelial cells are
considered a direct trigger of vascular injury [13,14]. It has suggested
that heart failure development might be the result of both diseasespecific and traditional CV risk factors contributed in imbalance
between apoptotic endothelial cell-derived MPs and activated
endothelial cell-derived MPs forming impaired phenotype.
CV risk and diseases
Immune phenotypes of endothelial-derived MPs
Hypertension
↑CD31+CD42-
Heart failure
↑CD31+ annexin V+
Asymptomatic atherosclerosis
↑CD105+; ↑CD31+ annexin V+
Stable coronary artery disease
↑CD31+CD42-; ↑CD144+;
ACS / MI
↑CD31+CD42-; ↑CD144+;↑CD31+ annexin V+
Ischemic stroke / TIA
↑CD62E+
Type two diabetes mellitus
↑CD31+CD42-; ↑CD144+; ↑Annexin-V
Metabolic syndrome
↑CD31+ CD42b; ↑CD31+CD42-; ↑CD144+
Obesity
↑CD31+ CD42b
Table 1: Immune phenotypes of circulating endothelial-derived MPs in patients with CV risk and diseases.
Recently small-size MPs originated from endothelial cells were
considered cell debris and their clinically significance was under
discussion, because a large of body of evidences regarding MPs related
to MP size more 100 nm. Whether small-size endothelial cell-derived
MPs specifically expressed apoptotic and activated cell antigens are
diagnostic tool with likely predictive value in heart failure patients is
still not understood.
Analytical measurements of MPs
Morphology, transcriptomics, and proteomics of circulating MPs
are still not fully investigated [19, 20]. The difficulty of separating MPs
realized from other types of cells limits or efforts to extend actual
cognitions in features affected biogenesis, secretion, and subsequent
biological role of MPs.
Angiol
ISSN:2329-9495 AOA, an open access journal
The conventional approach for measuring the MPs is based on
commonly used flow cytometry (FCM) and nano-particle tracking
analysis (NTA), Western blot analysis and electron microscopy. All
methods have crucial limitations regarding complicated assay and
suffers from relatively low sensitivity and accuracy because of
resolution problems occurring for the majority of commercially
available FCM [21,22]. FCM is the most commonly used method for
analyzing MPs; however, accurate characterization of MPs remains
challenging due to their small size and lack of discrete positive
populations. Small-size MP counts should be determined by highresolution FCM technique. However, the utilization of FCM
specifically designed for analysis of small-size MPs is probably to
provide considerable methodological advantages and should be the
preferable options. NTA is able to acquire both diffraction and
absorption images from a single grating-modulated projection image
through analysis in the spatial frequency domain. The serious barrier
Volume 3 • Issue 3 • 1000145
Citation:
Berezin AE (2015) Small-size Endothelial-derived Micro Particles as Novel Predictive Biomarkers in Cardiovascular Diseases. Angiol 3:
145. doi:10.4172/2329-9495.1000145
Page 3 of 4
created surmountable problems for NTA is sizing of small MPs (50
nm and less). In addition, problems with concentration limits of NTA
measurements restrict the use of this method for clinical samples [23].
Western blot analysis and electron microscopy allow investigators to
recognize MPs depending on determination of different markers,
represents a useful tool for examining particles. However, Western
blot analysis and electron microscopy require subsequent technical
efforts and are much expensive. Overall, measurement of small-size
MPs is not standardized and appears to be much difficult.
The small-size endothelial-derived MPs as biomarker
of endothelial dysfunction: results of clinical
investigations
Recent studies indicate that endothelial-derived MPs are biomarker
of endothelial dysfunction with possible predictive value. However,
similar data for small-size endothelial-derived MPs are limited. Hu et
al. [24] reported that small-size endothelial-derived MPs expressed
CD62E antigen showed a high accuracy to monitor endothelial
dysfunction in CAD patients (sensitivity of 76.9% and specificity of
88.9%). Because of CD62E antigen belongs to the selectin family of
adhesion molecules and its expression is related to inflammation,
endothelial dysfunction, and coagulation, obtained result confirm an
assumption regarding role of small-size CD62E+ MPs originated from
activated endothelial cells in pathogenesis of CAD. In a cross-sectional
study Montoro-García et al. [25] suggested that low count of Annexin
V-binding and CD144+ small-size endothelial-derived MPs could be
potentially implicated in the modulation of the post-acute coronary
syndrome reparative response to injury. Moreover, this immune type
of MPs might possible have prognostic implications. Therefore, several
investigations have shown that increased numerous of apoptoticendothelial cell-derived small-size MPs are biomarkers of vascular
dysfunction in clinical settings i.e. diabetes mellitus, metabolic
syndrome, obesity, associated with high CV risk, asymptomatic
atherosclerosis and newly appeared CV events [26-28], where they
could appear indicative of a poor clinical outcomes. Moreover, in heart
failure patient population Montoro-García et al. [28] found that
counts of annexin V-binding small-size endothelial-derived MPs
might constitute valuable hallmarks of acute decompensated state.
Interestingly that imbalance between numerous of both circulating
endothelial-derived MP populations labeled as activated endothelial
cell-derived (CD144+, CD131+, CD62+) and apoptotic endothelial
cell-derived (annexin V+) [29,30]. All these findings support a
hypothesis that small-size endothelial-derived MPs originated from
activated and apoptotic cells are indispensable biomarkers for
endothelial dysfunction and could provide valuable information for
risk stratification. Future perspectives regarding identification of
different immune phenotypes of circulating small-size endothelialderived MPs appear to be attractive. More clinical investigations with
large sample size are required to understand the predictive role of
these biomarkers in various patient populations.
In conclusion, small-size endothelial-derived MPs might be a
surrogate biomarker of vascular integrity and endothelial dysfunction
with likely predictive value. Therefore, they are probably a key tool for
personalization of risk stratification, while this assumption needed to
be extendedly investigated.
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