Inflamm. res. 58 (2009) 1–8
© Birkhäuser Verlag, Basel, 2009
Abstract. Microvesicles (MVs) are membrane-covered cell
fragments released by most cell types during apoptosis or
activation. They are increasingly considered to play a pivotal
role in information transfer between cells. Their presence
and role have been proven in several physiological and path-
ological processes, such as immune modulation in inflamma-
tion and pregnancy, or blood coagulation and cancer. MVs
represent a newly recognized system of intercellular com-
munications. They not only may serve as prognostic markers
in different diseases, but could also hold the potential to be
new therapeutic targets or drug delivery systems.
The present overview aims to highlight some aspects of
this new means of cellular communication: “microvesicular
Key words: Microvesicles – Microvesicular communication
– Microvesicle formation – Microvesicular functions
The recognition of small vesicles, shed from a large number
of cell types, has opened a new era in the understanding
of signal and molecule transfer between cells, not only lo-
cally, but over long distances as well. The nomenclature of
the membrane-covered small fragments is still controversial.
Exosomes, microvesicles, microparticles, ectosomes and
even apoptotic bodies are commonly used terms. Presently,
the term “exosome” comprises preformed vesicles, which are
mostly smaller than 100 nm, and originate from intracellular
multivesicular bodies. (Confusingly, the term “exosome” is
also currently used in the literature to describe a nucleocyto-
plasmic multi-protein complex, capable of degrading various
types of RNAs. This fact further urges the introduction of
a consensus non-overlapping terminology for MVs.) They
are secreted after the fusion of the multivesicular bodies and
the plasma membrane [1, 2]. Although a precise definition
of microparticles/microvesicles is still lacking, authors often
define them as a heterogenous population of small vesicles,
with a diameter of 100–1000 nm [2, 3]. In the present article
we use a nomenclature in which we use the collective term
“microvesicle” (MV) for all the subcellular vesicles between
50 and 1000 nm, considering that all vesicles under 1000 nm
fulfill very similar effects, that is signal transfer between
MVs have been identified to originate from a large
number of cell types in vivo and in vitro: from epithelial, fi-
broblast, haematopoetic, immune, placental and tumor cells
[4–9]. Besides a constitutive release of MVs by the cells,
their secretion is enhanced upon activation or apoptosis. In
the present review we do not discuss the so-called apoptotic
bodies, which are distinct from the other subcellular vesicles
on the basis of two well defined aspects: they are released
in the final stages of programmed cell death and their size is
usually larger than 1 µm. Other MV types bud off the apop-
totic cells at the very beginning of the apoptotic process and
their size is smaller than 1000 nm [10, 11]).
MVs display a variable spectrum of molecules, enclosed
inside the vesicles and in their membrane, a pattern specific
to the parental cell that secretes them. The size of the secret-
ed vesicles also strongly depends on the type of the secreting
cell. Therefore “packages” of informations can reach differ-
ent targets, allowing a special communication between cells.
Microvesicular information transfer plays a role in several
Correspondence to: E. Pap
Highlights of a new type of intercellular communication:
microvesicle-based information transfer
E. Pap1, É. Pállinger2, M. Pásztói1, A. Falus1,2
1 Department of Genetics, Cell- and Immunobiology, H-1089, Nagyvárad tér 4. Budapest, Hungary, Fax 36-1-3036968, e-mail email@example.com
2 Research Group for Inflammation Biology and Immunogenomics of Hungarian Academy of Sciences and Semmelweis University,
H-1089, Nagyvárad tér 4. Budapest, Hungary, Fax 36-1-3036968, e-mail firstname.lastname@example.org
Received 3 July 2008; returned for revision 17 July 2008; received from final revision 8 October 2008; accepted by M. Parnham 8 October 2008
Published Online First 8 January 2009
2 E. Pap et al. Inflamm. res.
physiological and pathological processes, such as immune
modulation in inflammation and during pregnancy, blood co-
agulation and cancer.
The present overview is not intended to be exhaustive,
rather aims to highlight some aspects of this newly recog-
nized way of cellular communication: the “microvesicular
Formation of MVs
The production and the release of MVs can be constitutive or
requires activating signals depending on the cell type. MVs
can be shed from normally functioning cells and/or at the be-
ginning of the apoptotic process. A constitutive secretion has
been described in the case of epithelial, EBV-transformed B-
cells and immature dendritic cells (DC) [1, 12]. On the other
hand, in many cells, MV release was observed during cell
activation: in platelets following thrombin, terminal comple-
ment complex C5b-9 or Ca-ionophore activation, in mono-
cytes, hepatocytes, endothelial and smooth muscle cells fol-
lowing lipopolysaccharide and cytokine activation [13, 14].
There are two distinct mechanisms resulting in vesicle pro-
duction and shedding.
1. The strictly called exosomes have an endosomal origin.
Their size is under 100 nm. These vesicles are released
via exocytosis, when multivesicular bodies leave the
lysosomal pathway and fuse with the plasma membrane.
Our knowledge is very limited in terms of the sorting
signals directing the appropriate proteins into vesicles
within multivesicular bodies. Currently there is no sort-
ing signal common for all cells  (Fig 1a).
2. On the release of most MVs between 100 and 1000 nm,
a so-called reverse budding occurs. Multiple pathways
may lead to vesicle formation, two of which seem pres-
ently to be the most relevant: a.) the elevation of intracel-
lular Ca2+ concentration and b.) the reorganization of the
cytoskeleton (Fig 1b).
a. The increase of intracellular Ca2+ level alters the
asymmetric phospholipid distribution of the plasma
membrane. Phosphatidylserine (PS) and phosphati-
dylethanolamine (PE) are found on the inner side of
the cell membrane. This balance is maintained by sev-
eral enzymes: scramblase, floppase and translocase.
The increase in the cytoplasmic Ca2+ level results in
the inhibition of translocase and in the activation of
scramblase, so that PS and PE will not be returned to
the inner side of the membrane. Therefore MVs dis-
play large amounts of PS on the outer surface of their
membrane, which allows the binding of Annexin V,
also attracts macrophages for the clearance of possible
cell fragments [12, 3].
MV formation is regulated in a Ca2+ dependent manner
in monocytes, in platelets, in red blood cells, in en-
dothelial cells, in T cells and in mast cells [2, 11, 12].
b. The reorganization of the cytoskeleton leads to the de-
tachment of the plasma membrane from the cortical
actin. A few processes which initiate this detachment
are discussed below.
Phosphatidylinositol 4,5-biphosphate (PIP2) has been de-
scribed to play an important role in the attachment of the
membrane to the cortical cytoskeleton . Indeed, incuba-
tion with PIP2 inhibited MV formation; meanwhile a PIP2 de-
cline increased the vesiculation in the case of platelets. Other
phospholipids did not interfere with MV formation .
Fig. 1. Schematic drawing of the mechanisms resulting in the formation of microvesicles (MVs).
a. Formation of exosomes via exocytosis.
b. Formation of MVs via reverse budding.
Activated cells produce MVs through the disruption of cortical cytoskeleton. This can be initiated by increased Ca++ levels activating calpain or by
inhibiting the synthesis of PIP2, which participates in the anchoring of the membrane to the cytoskeleton. Increased Ca++ concentration disturbs the
phospholipid balance of the cell membrane, inhibiting scramblase and floppase to return PS into the inner membrane surface.
Apoptotic signals promote MV budding via the initiation of actin-myosin sliding, resulting in the detachment of the membrane from the cyto-
Vol. 58, 2009 Highlights of a new type of intercellular communication: microvesicle-based information transfer 3
Ca2+ ions also contribute to the reorganization of the cy-
toskeleton, through the activation of cytosolic proteases, such
as calpain and gelsolin. Calpain cleaves talin and α-activin,
gelsolin, specific to platelets, cleaves actin-capping proteins.
This protein cleavage leads to the disruption of the cortical
cytoskeleton protein network, which allows membrane bud-
ding as a consequence [5, 2].
MV formation in the early stages of apoptosis is asso-
ciated with cortical myosin-actin movement. The cascade
starts with GTP-bound Rho proteins, which activate Rho-
associated kinase I. (ROCK-I). This kinase phosphorylates
myosin light chain kinase, and its activation ends up in ex-
change between myosin and actin. This movement enables
detachment of the plasma membrane from the cytoskeleton
to occur, resulting in MV release [3, 18].
Composition of MVs
The membrane of the MVs consists of lipids and proteins,
displaying some typical markers of the parental cell origin.
Both the membrane molecular pattern and the internal con-
tent of the vesicle depend on the original cell type and on the
mechanism of MV release .
In the case of secretion of vesicles smaller than 100 nm
(exosomes), all proteins analyzed so far have been found in
the cytosol and in the plasma membrane. They do not contain
any nuclear, mitochondrial, Golgi or endoplasmic reticulum
proteins, which also highlights the endocytic origin of these
vesicles. On the other hand, they do not contain any ATP-
ases or lysosomal proteases either, indicating that their for-
mation through multivesicular bodies made a detour from
the lysosomal pathway [8, 19].
The protein composition of MVs is specific, that is, the
proteins reflect the origin of the parental cell. Exosomes, se-
creted from antigen presenting cells such as B lymphocytes
and dendritic cells, contain a membrane, enriched in MHC-I,
MHC-II and in co-stimulatory molecules. The membranes of
reticulocyte MVs contain transferrin receptor [4, 10, 7, 19,
20]. Tumor cell-released MVs bear pre-apoptotic molecules
such as Fas Ligand (FasL) or TRAIL (TNF- related apopto-
sis inducing ligand) [6, 21, 22]. Trophoblast- derived MVs
display HLA-G antigen (9) and FasL . Besides the wide
spectrum of specifically displayed proteins, some proteins
seem to be common for the majority of the MVs. Chaperone
HSP70 has been found in a large number of MVs, just like
tetraspan proteins [24, 25, 26]. Tetraspan proteins are mem-
bers of a large, highly conserved family which have been
shown to be expressed in a variety of cells, regulating nu-
merous diverse cell functions through their interactions with
– among others – protein kinases, growth factor receptors
and membrane transporters. Taking into account that they
appear in microvesicular membranes as well, it is tempting
to assume, that the activity of MVs may also depend on these
molecules. The inner protein content of the MVs has been
much less studied. Heat shock proteins and enzymes are
typical. Microvesicle shedding is a major secretory pathway
for rapid interleukin-1beta (IL-1beta) release. The multive-
sicular secretion of this proinflammatory cytokine, lacking
signal peptide, may represent a general mechanism for the
secretion of similarly signal-lacking secretory proteins .
In contrast to the protein set, the multivesicular lipid con-
tent itself remains relatively constant as does the distribu-
tion of the phospholipid molecules on the two leaflets of the
vesicles. As described above, the negatively charged PS and
PE molecules are situated on the outer surface of the mem-
brane, as part of the membrane remodeling process during
vesiculation. Lipid rafts are also typically observed in MVs
Other than proteins and lipids, nucleic acids (mRNA, miR-
NA, DNA) also have been found to be present in MVs [30, 31].
In addition to the above mentioned molecules, some MVs
have been observed to transmit infectious particles, such as
HIV or prions [32, 33].
The measurement of MVs
Isolation of MVs
Isolation from cell-free samples occurs by differential centrif-
ugation. It is widely accepted that ultracentrifugation should
be performed at 100 000 g from 20 to 60 minutes. In order to
isolate MVs smaller than 100 nm (the so-called exosomes),
sucrose gradient ultracentrifugation is required. Different re-
search groups apply different conditions [11, 34, 35].
The exact identification of the purified vesicles based on
their size can be further studied by electron microscopy.
Flow cytometry is the conventional method for studying MVs
from platelet-free plasma. This is an appropriate method for the
investigation of the quantity and the size of MVs and also for
their characterization by immunophenotyping. Commercially
available flow cytometers are not capable of analyzing MVs
smaller than 300 nm. One of the generic staining procedures
for MV measurement is the detection of negatively charged
phospholipids by Annexin V, though not all MVs are positive
for this marker . Immunophenotyping of cell specific anti-
gens is commonly accepted for the identification of MV origin,
although it should be noted that the expression of an antigen on
the microvesicular membrane does not unequivocally certify
the cellular origin: soluble proteins can bind to MVs or cir-
culating MVs can fuse with different cells, which can further
release MVs containing the adopted proteins .
Functional MV assays
Procoagulant activities of circulating MVs can be detected
by the investigation of plasma recalcification time in the
presence or in the absence of anti-tissue factor (anti-TF)
monoclonal antibodies . MP-associated TF procoagulant
activity can also be measured by microplate assays. .
ELISA methods have been also described for MV detection.
Some of them use Annexin V coated plates, while the other
4 E. Pap et al. Inflamm. res.
applications are based on the binding of MV specific anti-
Although the above mentioned MV preparation tech-
niques are commonly used by different research groups,
some still unsolved problems represent potential sources of
confusion in the identification of the different microvesicu-
lar types. Larger vesicles may disperse into smaller ones, in
response to mechanical force. This was one reason why we
suggested in the Introduction the use of the collective term
“microvesicle” for subcellular vesicles generated in biologi-
Function of MVs
MVs target either cells of remote tissues or cells in the rela-
tively close neighborhood of the donor cells. They can in-
teract with cell membrane molecules, initiating a signalling
cascade. Furthermore, they can provide new phenotypes to
the recipient cell after membrane fusion. They can act as ac-
tivators or suppressors. For instance MVs derived from anti-
gen-presenting cells can deliver signals for T cell activation
, meanwhile MVs from tumor cells or trophoblast cells
mediate immunosuppression [13, 42]. Generally it can be
stated that MVs may provide beneficial or detrimental fea-
tures to the cells. Without describing all fields and all details,
here we summarize the effects of MVs on hemostasis/coagu-
lation, inflammation and pregnancy.
Coagulation and hemostasis
Platelet-derived MVs constitute approximately 70 % to 90 %
of circulating MVs in the plasma . Platelet MVs may
derive from activated and quiescent circulating thrombocytes
and also from megakaryocytes during megakaryopoiesis [44,
45]. Several potential pathways have been described for the
clearance of platelet MVs. One of them is phagocytosis,
which is facilitated by the recognition of phosphatidylser-
ine (PS) components of MV membranes and by opsonisation
with C3. Opsonised MVs bind to CR1-bearing cells, which
can transfer them to phagocytes . Another clearance
mechanism can be the destruction by circulating phospholi-
pases. The life span of platelet-derived MVs is about 30 min-
utes in the circulation.
The role of platelet-derived MVs in thrombus formation
is diverse: on the one hand, the impaired ability to generate
platelet MVs is decreased as the bleeding time is prolonged
(Castaman’s defect, Scott’s syndrome) [47, 48], on the other
hand, elevated platelet MV levels could be detected in pa-
tients with diseases associated with thrombosis, such as cer-
ebrovascular disorders , acute myocardial infarction [50,
51] and unstable angina . Elevated levels of circulating
MVs could be detected not only in patients with cardiovas-
cular diseases but also in high risk conditions of them, such
as hypertension , obesity , diabetes mellitus [55, 56]
or increased plasma cholesterol level .
The procoagulant activity of platelet derived MVs is well
known. Functional studies of non-platelet MVs suggest that
these MVs may be involved in the activation of the coagu-
lation cascade. The main initiator of normal coagulation is
TF. It is an integral membrane protein which is normally ex-
pressed at only very low levels on endothelial cells but its ex-
pression can rapidly rise in response to several inflammatory
or hormonal stimuli. TF forms a complex with factor VII.
This complex obtains proteolytic activity through activation
by factor Xa in a positive feedback mechanism. This acti-
vated TF-VIIa complex generates factors IXa and Xa, which
require negatively charged phospholipids (e.g. phosphatidyl
serine) for their activity. Outer membranes of MVs could be
the sources of negatively charged phospholipids. The proco-
agulant activity of MVs can be measured in different ways,
e.g. by thrombin generation assay  or by the investigation
of the effects of MVs on the plasma prothrombin time in the
presence or in the absence of anti-TF monoclonal antibodies
. Elevated levels of procoagulant circulating MVs could
be detected in patients with sepsis [31, 60, 61].
The recognition of the role of procoagulant MVs in the
pathogenesis of cardiovascular diseases may help to identify
new therapeutic targets. For example, the platelet aggrega-
tion inhibitor, anti-glycoprotein IIb/IIIa receptor monoclonal
antibody, Abciximab, has effects on platelet MV formation,
although the results are controversial [62, 63, 64].
Acute inflammation is characterized by vascular changes
(endothelial activation, vasodilatation and increased perme-
ability), extravasation of blood cells and exudation. All par-
ticipating cells activate and release MVs which work tightly
together and create a so-called MV-related network. Platelet
derived MVs, binding to endothelial cells, induce the produc-
tion of pro-inflammatory cytokines and products of the ara-
chidonic acid pathway. In turn, pro-inflammatory cytokines
(TNFa, IL-1b) or the terminal complement complex C5b-9
can induce MV shedding of inflammatory cells (like platelets
and endothelial cells) which play an important role in the
regulation of the process . Furthermore, these MVs up-
regulate adhesion molecules on endothelium and leukocytes
[65, 66], which results in increased extravasation and leuko-
cyte adhesion to the endothelium [67, 68].
The recruitment of leukocytes to the site of tissue dam-
age, including rolling, adhesion and transmigration is me-
diated by adhesion molecules, such as selectins. P-selec-
tin (CD62P) is stored in platelets a granules and rapidly
translocated to the membrane surface after stimulation.
Platelets and platelet-derived MVs can interact with leuko-
cyte PSGL-1 through their surface CD62P, forming plate-
let-leukocyte aggregates. Platelet adherence induces gene
expression of chemokines and cytokines in inflammatory
cells, while they release IL-1b, chemokines and other pre-
formed mediators and express chemokine receptors, and
also begin to synthesize the products of arachidonic acid
pathway [69, 70]. In vitro experiments demonstrate that
platelet-derived MVs can also modulate immunoglobulin
production through delivering CD154 protein to B cells
. All these functions are capable of modifying local
immune responses. Taken together, it can be concluded
that not only platelets but also platelet-derived MVs are
relevant mediators of intercellular communication during
immune response .
Vol. 58, 2009 Highlights of a new type of intercellular communication: microvesicle-based information transfer 5
Procoagulant MVs have an important role in local throm-
bus formation and the demarcation of tissue injury . The
role of MVs in sepsis is controversial. One research group
found elevated circulating MV level in meningicoccal septic
patients, indicating poor clinical prognosis. . Another re-
search group found negative correlation between circulating
endothelial MV level and the survival rate .
Several sets of data in the literature describe the role
of MVs in the pathogenesis of rheumatoid arthritis (RA),
a chronic inflammatory disease characterized by joint and
bone destruction that is mediated mostly by synovial fi-
broblasts or other synovial cells. MVs can represent a novel
stimulatory agent which can contribute to the activation of
Increased levels of platelet-derived MVs were found in
the serum of RA patients, which was suggested to be also a
prognostic marker of RA . In the synovial fluid, elevated
levels of granulocyte- and monocyte-derived MVs could be
observed. Moreover, T cell-, B cell-, platelet- and erythro-
cyte-derived MVs were also detected in the synovial fluid of
RA patients [77, 78].
Several studies demonstrate the role of MVs in the patho-
genesis of RA. Berckmans et al. reported that leukocyte-de-
rived MVs of the synovial fluid supported coagulation via the
factor VII-dependent pathway and thus contributed to the lo-
cal hypercoagulation and fibrin deposition in inflamed joints
of RA and also in some non-RA patients . In their further
study, fibroblasts were treated with synovial MVs, which in-
duced the production of several cytokines and chemokines,
such as MCP-1, IL-6, IL-8, ICAM-1, VEGF and RANTES
. In in vitro studies, it was also shown that T cell- and
monocyte-derived MVs can induce synovial fibroblast pro-
duction of cartilage degrading matrix metalloproteinases
(MMP) (MMP-1, MMP-3, MMP-9, MMP-13) . They
also upregulate the expression of prostaglandin E2 (PGE2)
in synovial fibroblasts by inducing cyclooxygenase 2 and
microsomal prostaglandin E synthase 1 .
In order to understand how MVs contribute to the patho-
genesis of RA, membrane molecules of plasma- and synovi-
al fluid-derived MVs were examined. Complement compo-
nents and activator molecules were found on their membrane,
which suggest that MVs may contribute to the pathogenesis
of RA by activation of the classical complement pathway,
especially in the inflamed synovium . Furthermore, it
was also shown that MVs, derived from synovial fibroblasts
of patients with RA but not OA (osteoarthritis), contain a
membrane bound form of TNF-a. Co-culture of CD4+ T
cells with them led to the blunting of activation-induced cell
death of T cells. However, the authors suggest that additional
microvesicular proteins may contribute to the apoptosis re-
sistance, too .
Only limited data are available on proteins in MVs
which may be involved in the induction of RA. Skriner et
al. found citrullinated proteins (well known autoantigens
in RA) in MVs of synovial origin . More interestingly,
the DEK autoantigen, which was previously described as a
nuclear protein, was found in MVs of inflammatory cells
and synovial fluid of juvenile idiopathic arthritis patients.
Since DEK can function as a chemoattractant molecule, its
presence suggests a possible role in mediating inflamma-
Taken together, at sites of inflammation (e.g. in the joints)
where both apoptosis and activation occur frequently, MV
release is presumably a common phenomenon. These vesi-
cles may be involved in the inflammation, cell activation and
joint destruction processes.
Pregnancy is a unique condition of the female organism. In a
broad sense, pregnancy itself can be considered as an inflam-
matory state, properly regulated and well-balanced through
specific immunological interactions between the mother and
the fetus. Trophoblast cells, in order to protect the fetus, ex-
press non-classical HLA molecules and Fas L. Furthermore,
Th1/Th2/Th3 cytokine balance is a key regulatory require-
ment in the maintenance of pregnancy. These events occur
at the placento-maternal interface and/or at the systemic
level [79, 80]. The phenomenon of microvesicular signalling
opens a new level in the understanding of the remote control
regulation of the gestational condition from both the fetal
and maternal side.
Normal pregnancy is accompanied by an overall in-
creased MV release . Our group detected a significantly
higher absolute number of MVs in pregnant plasmas. As for
the relative quantity of MVs in pregnant plasma samples, we
found a significant increase of CD14+ (monocyte-derived)
and a significant decrease of CD41+ / CD42+ (platelet-de-
rived) MVs. No significant changes could be detected in the
number of T- and B-cell derived MV-s .
In pregnancy, MVs originate from different tissues, from
platelets, from trophoblast, from endothelial and from im-
mune cells. The apoptotic degradation of trophoblast cells
is a constantly on-going process, from the very moment of
implantation until delivery. Apoptosis plays a prominent role
in the remodeling of the placenta. Considering that cells
release MVs at the beginning of their apoptotic activation,
it is not surprising that larger quantities of MVs appear in
the pregnant maternal circulation. The role of trophoblast-
derived MVs is diverse. On the one hand, they participate
in the establishment of immune tolerance against the fetus,
carrying Fas L in their membrane. They induce apoptosis
and enhance CD3 zeta chain loss of the maternal cytotoxic
T cells [81–83]. Also, they carry HLA-G, which contributes
to the immunosuppressive effect against NK cells . In
addition, they attract macrophages which remove cell debris
and which participate in the orchestrated regulation of the
inflammatory network .
It has been shown that syncytiotrophoblast-derived
MVs (STBMs) enhance IL-12, IL-18, TNF-a and IFN-g
synthesis in primed peripheral mononuclear cells in vitro
. Also, STBMs stimulate systemic inflammatory re-
sponses and induce granulocytes and peripheral blood leu-
kocytes in vitro [86, 87]. Recently, we found that trophob-
last-derived MVs bind to T cells, but not to B and NK cells
. Furthermore, MVs have been shown to modify T cell
responses. The total MV pool isolated from pregnant sera
 and from pregnant plasma decreased JAK3 expression
in Jurkat cells .
Since MVs can reach their targets across relatively large
distances, they can transfer their effect at the systemic level,
6 E. Pap et al. Inflamm. res.
helping to establish an overall systemic immune regulation
The outcome of pregnancy depends greatly on placen-
tal vascularization, in which the role of platelets has already
been recognized, as activated thrombocytes participate in en-
dothelial reactions as well as in several immune regulatory
steps . There is a marked increase in the procoagulant
activity in maternal blood in normal pregnancy. Endothelial,
platelet- and trophoblast-derived circulating MVs may con-
tribute to this procoagulant effect .
Pre-eclampsia is the best characterized and most com-
mon pregnancy complication. This multiorgan disorder is
associated with generalized endothelial dysfunction, result-
ing in hypertension, proteinuria and fetal growth delay. El-
evated plasma levels of T lymphocyte– and granulocyte–de-
rived MVs can be detected in the maternal circulation during
preeclampsia, and also circulating STBMs are at higher
levels, compared with normal pregnancy . In contrast,
the number of platelet-derived MVs is significantly reduced
in pathological pregnancies . Although the exact back-
ground of generalized endothelial dysfunction is not well
understood, some data suggest that circulating MVs play an
important role in its pathogenesis [93, 94]. Both in vitro and
in vivo experiments demonstrated that MVs isolated from
pre-eclamptic patients have effects on vessel wall. By upreg-
ulating inducible nitric oxide synthase (iNOS) and cyclooxy-
genase-2 (COX-2), they enhance NO and prostaglandin pro-
duction, leading to altered vascular reactivity.  Inversely,
in different pathophysiological conditions, such as cardio-
vascular diseases, endothelial injury increases the plasma
level of endothelial-derived MVs. It serves as a potential tool
to predict the cardiovascular risk of asymptomatic patients
. On the basis of these findings, circulating endotheli-
al MVs were observed in pre-eclamptic plasma. Although
significant elevation could be detected, no correlation was
found between their plasma concentration and the clinical
status of the patients .
It is conceivable that in normal pregnancy the overall MV
pool provides a regulatory signalling effect on the maternal
immune system and the whole maternal organism. In pre-
eclampsia the disequilibrium of this homeostatic balance
can be more or less associated with altered MV pattern and
nature (Fig 2.).
As this review indicates, MVs play a pivotal role in physi-
ological and pathological processes. They represent a new
field in intercellular communication, establishing a MV re-
lated network. MVs are more and more recognized as prog-
nostic markers in different diseases such as chronic inflam-
mation, pathological pregnancy, tumors or cardiovascular
disorders. The recognition of the importance of MVs may
also open a new era in the search for therapeutic strategies.
 Théry C, Zitvogel L, Amigorena S. Exosomes: composition, bio-
genesis and function. Nature Rewievs Immunology 2002; 2: 569–
 Redman CW, Sargent IL. Microparticles and immunomodulation
in pregnancy and pre-eclampsia. J Reprod Immunol 2007; 76: 61–
 Distler JH, Pisetsky DS, Huber LC, Kalden JR, Gay S, Distler O.
Microparticles as regulators of inflammation: novel players of cel-
lular crosstalk in the rheumatic diseases. Arthritis Rheum. 2005;
 Chaput N, Taïeb J, Schartz NE, André F, Angevin E, Zitvogel L.
Exosome-based immunotherapy. Cancer Immunol Immunother.
2004; 53: 234–9.
 Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L.
Tumor-released microvesicles as vehicles of immunosuppression.
Cancer Res. 2007; 67: 2912–5.
 Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Cor-
belli A, Fais S, Parmiani G, Rivoltini L. Human tumor-released
microvesicles promote the differentiation of myeloid cells with
transforming growth factor-beta-mediated suppressive activity on
T lymphocytes. Cancer Res. 2006; 66: 9290–8.
 Wieckowski E, Whiteside TL. Human tumor-derived vs dendritic
cell-derived exosomes have distinct biologic roles and molecular
profiles. Immunol Res. 2006; 36:247–54.
 VanWijk MJ, VanBavel E, Sturk A, Nieuwland R.Microparticles in
cardiovascular diseases. Cardiovasc Res. 2003; 59: 277–87.
 Pap E., Pállinger É., Falus A., Kiss AA., Kittel Á., Kovács P., Buzás
EI.T lymphocytes are targets for platelet- and trophoblast-derived
microvesicles during pregnancy. Placenta 2008; 29: 826–32
 Théry C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-
Castagnoli P, Raposo G, Amigorena S. Molecular characterization
of dendritic cell-derived exosomes. Selective accumulation of the
heat shock protein hsc73. J Cell Biol. 1999; 147: 599–610.
 Théry C, Boussac M, Véron P, Ricciardi-Castagnoli P, Raposo G,
Garin J, Amigorena S. Proteomic analysis of dendritic cell-derived
exosomes: a secreted subcellular compartment distinct from apop-
totic vesicles. J Immunol. 2001; 166: 7309–18.
 Piccin A, Murphy WG, Smith OP. Circulating microparticles:
pathophysiology and clinical implications. Blood Rev. 2007; 21:
 Freyssinet JM. Cellular microparticles: what are they bad or good
for? J Thromb Haemost 2003; 1: 1655–62.
 Jimenez JJ, Jy W, Mauro LM, Soderland C, Horstman LL, Ahn YS.
Endothelial cells release phenotypically and quantitatively distinct
microparticles in activation and apoptosis. Thromb Res 2003; 109:
 Johnstone RM. Exosomes biological significance: A concise re-
view. Blood Cells Mol Dis 2006; 36: 315–21.
 Raucher D, Stauffer T, Chen W, Shen K, Guo S, York JD, Sheetz
MP, Meyer T. Phosphatidylinositol 4,5-bisphosphate functions as
a second messenger that regulates cytoskeleton-plasma membrane
adhesion. Cell 2000; 100: 221–8.
 Flaumenhaft R. Formation and fate of platelet microparticles.
Blood Cells Mol Dis. 2006; 36: 182–7.
Fig. 2. Intercellular communication through microvesicular network in
Vol. 58, 2009 Highlights of a new type of intercellular communication: microvesicle-based information transfer 7
 Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF.
Membrane blebbing during apoptosis results from caspase-medi-
ated activation of ROCK I. Nat Cell Biol 2001; 3: 339–45.
 Keller S, Sanderson MP, Stoeck A, Altevogt P. Exosomes: from
biogenesis and secretion to biological function. Immunol Lett
2006; 107: 102–8.
 Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding
CV, Melief CJ, Geuze HJ.B lymphocytes secrete antigen-present-
ing vesicles. J Exp Med 1996; 183: 1161–72.
 Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P,
Squarcina P, Accornero P, Lozupone F, Lugini L, Stringaro A, Mo-
linari A, Arancia G, Gentile M, Parmiani G, Fais S. Induction of
lymphocyte apoptosis by tumor cell secretion of FasL-bearing mi-
crovesicles. J Exp Med 2002; 195: 1303–16.
 Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P, Zaccheddu
A, Colone M, Arancia G, Gentile M, Seregni E, Valenti R, Ballabio G,
Belli F, Leo E, Parmiani G, Rivoltini L. Human colorectal cancer cells
induce T-cell death through release of proapoptotic microvesicles:
role in immune escape. Gastroenterology 2005; 128: 1796–804.
 Abrahams VM, Straszewski-Chavez SL, Guller S and Mor G. First
trimester trophoblast cells secrete Fas ligand which induces im-
mune cell apoptosis. Mol Hum Reprod 2004; 10: 55–63.
 Hegmans JP, Bard MP, Hemmes A, Luider TM, Kleijmeer MJ,
Prins JB et al. Proteomic analysis of exosomes secreted by human
mesothelioma cells. Am J Pathol 2004; 164: 1807–15.
 Aoki N., Jin-no S., Nakagawa Y., Asai N., Arakawa E., Tamura N.,
Tamura T., Matsuda T. Identification and Characterization of
Microvesicles Secreted by 3T3-L1 Adipocytes: Redox- and
Hormone-Dependent Induction of Milk Fat Globule-Epidermal
Growth Factor 8-Associated Microvesicles. Endocrinology 2007;
 Fritzsching B., Schwer B., Kartenbeck J., Pedal A., Horejsi V., Ott
M. Release and Intercellular Transfer of Cell Surface CD81 Via
Microparticles. J. Immunol, 2002; 169: 5531–7.
 MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA,
Surprenant A. Rapid secretion of interleukin-1beta by microvesicle
shedding. Immunity 2001; 15: 825–35.
 Bénédicte Hugel, M. Carmen, Martínez, Corinne Kunzelmann,
Jean-Marie Freyssinet. Membrane Microparticles: Two Sides of
the Coin. Physiology 2005; 20: 22–7.
 Lopez J. A., Del Conde I., Shrimpton C. N. Receptors, rafts, and
microvesicles in thrombosis and inflammation J. of Thrombosis
and Haemostasis. 2005; 3: 1737–44.
 Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO.
Exosome-mediated transfer of mRNAs and microRNAs is a novel
mechanism of genetic exchange between cells. Nat Cell Biol 2007;
 Bergsmedh A, Szeles A, Henriksson M, Bratt A, Folkman MJ, Spetz
AL, Holmgren L. Horizontal transfer of oncogenes by uptake of
apoptotic bodies. Proc Natl Acad Sci U S A. 2001; 98: 6407–11.
 Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A,
Ratajczak MZ. Membrane-derived microvesicles: important and
underappreciated mediators of cell-to-cell communication. Leuke-
mia. 2006; 20: 1487–95.
 Kramer B, Pelchen-Matthews A, Deneka M, Garcia E, Piguet V,
Marsh M. HIV interaction with endosomes in macrophages and
dendritic cells. Blood Cells Mol Dis 2005; 35: 136–42.
 Raposo, G., Nijman, H. W., Stoorvogel, Liejendekker W. R., Hard-
ing CV, Melief CJ, Geuze HJ. B lymphocytes secrete antigen-pre-
senting vesicles. J. Exp. Med. 1996; 183: 1161.
 Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins
C5b-9 cause release of membrane vesicles from the platelet surface
that are enriched in the membrane receptor for coagulation factor
Va and express prothrombinase activity. J Biol Chem 1988; 263:
 Shet AS, Aras O, Gupta K. Sickle blood contains tissue factor–pos-
itive microparticles derived from endothelial cells and monocytes.
Blood 2003; 102: 2678–83.
 Trummer A, De Rop C, Tiede A, Ganser A, Eisert R. Isotype con-
trols in phenotyping and quantification of microparticles: A major
source of error and how to evade it.Thromb Res 2008.
 Nieuwland R, Berckmans RJ, McGregor S, Böing AN, Romijn
FPHThM, Westendorp RGJ, Hack CE, Sturk A. Cellular origin and
procoagulant properties of microparticles in meningococcal sepsis.
Blood 2000; 95: 930–5.
 Simak J, Gelderman MP. Cell Membrane Microparticles in Blood
and Blood Products: Potentially Pathogenic Agents and Diagnostic
Markers. Transf Med Rev 2006; 20: 1–26.
 Osumi K, Ozeki Y, Saito S, Nagamura Y, Ito H, Kimura Y, Ogura H,
Nomura S. Development and assessment of enzyme immunoassay
for platelet-derived microparticles. Thromb Haemost. 2001; 85:
 van Niel G, Porto-Carreiro I, Simoes S, Raposo G. Exosomes: a
common pathway for a specialized function. J Biochem. 2006;140:
 Redman CW, Sargent IL. Circulating Microparticles in Normal
Pregnancy and Pre-Eclampsia. Placenta 2008; 29: 73–7.
 Berckmans RJ, Neiuwland R, Böing AN, Romijn FP, Hack CE,
Sturk A. Cell-derived microparticles circulate in healthy humans
and support low grade thrombin generation, Thromb Haemost
2001; 85: 639–46.
 Horstman LL, Ahn YS. Platelet microparticles: a wide-angle per-
spective. Critical Reviews in Oncology:Hematology 1999; 30:
 Fox JE, Austin CD, Reynolds CC, Steffen PK. Evidence that ago-
nist induced activation of calpain causes the shedding of procoagu-
lant-containing microvesicles from the membrane of aggregating
platelets, J Biol Chem 1991; 266: 13289–95.
 Flaumenhaft R. Formation and fate of platelet microparticles.
Blood Cells, Molecules, and Diseases 2006; 36: 182–7.
 Castaman G, Yu-Feng L, Rodeghiero F. A bleeding disorder char-
acterised by isolated deficiency of platelet microvesicle generation.
Lancet 1996; 347: 700–1.
 Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of
the Platelet Prothrombinase Complex Is Linked to Vesiculation of
the Platelet Plasma Membrane. Studies in Scott Syndrome: an Iso-
lated Defect in Platelet Procoagulant Activity. J Biol Chem 1989;
 Geiser T, Sturzenegger M, Genewein U, Haeberli A, Beer JH.
Mechanisms of cerebrovascular events as assessed by procoagu-
lant activity,cerebral microemboli, and platelet microparticles in
patients with prosthetic heart valves. Stroke 1998; 29: 1770–7.
 Mallat Z, Benamer H, Hugel B, Benessiano J, Steg PG, Freyssinet
JM, Tedgui A. Elevated levels of shed membrane microparticles
with procoagulant potential in the peripheral circulating blood of
patients with acute coronary syndromes, Circulation 2000; 101:
 Gawaz M, Neumann JF, Ott I, Schiessler A, Schömig A. Platelet
function in acute myocardial infarction treated with direct angi-
oplasty. Circulation 1996; 93: 229–37.
 Singh N, Gemell CH, Daly PA, Yeo EL. Elevated platelet-derived
microparticle levels during unstable angina. Can J Cardiol 1995; 11:
 Preston RA, Jy W, Jimenez JJ, Mauro LM, Horstman LL, Valle M,
Aime G, Ahn YS. Effects of severe hypertension on endothelial and
platelet microparticles. Hypertension 2003; 41: 211–7.
 Goichot B, Grunebaum L, Desprez D, Vinzio S, Meyer L, Schlienger
JL, Lessard M, Simon C. Circulating procoagulant microparticles
in obesity. Diabetes Metab 2006; 32: 82–5.
 Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK.
Elevated numbers of tissue-factor exposing microparticles corre-
late with components of the metabolic syndrome in uncomplicated
type 2 diabetes mellitus. Circulation 2002; 106: 2442–7.
 Leroyer AS, Tedgui A, Boulanger CM. Microparticles and type 2
diabetes. Diab Metab 2008; 34: 27–31.
 Koga H, Sugiyama S, Kugiyama K, Fukushima H, Watanabe K,
Sakamoto T, Yoshimura M, Jinnouchi H, Ogawa H. Elevated levels
of remnant lipoproteins are associated with plasma platelet micro-
particles in patients with type-2 diabetes mellitus without obstruc-
tive coronary artery disease. European Heart Journal 2006; 27:
8 E. Pap et al. Inflamm. res. Download full-text
 Kessels H, Beguin S, Andree H, Hemker HC. Measurement of
thrombin generation in whole blood: the effect of heparin and aspi-
rin. Thromb Haemost 1994; 72: 78–83.
 Shet AS, Aras O, Gupta K, Hass MJ, Rausch DJ, Saba N, Koop-
meiners L, Key NS, Hebbel RP. Sickle blood contains tissue fac-
tor–positive microparticles derived from endothelial cells and
monocytes. Blood 2003; 102: 2678–83.
 Schuerholz T, SuÈmpelmann R, Piepenbrock S, Leuwer M, Marx
G. Ringer’s solution but not hydroxyethyl starch or modified fluid
gelatin enhances platelet microvesicle formation in a porcine model
of septic shock. Br J Anaesth. 2004; 92: 716–21.
 Zubairova LD, Zubairov DM, Andrushko IA, Svintenok GY, Mus-
tafin IG. Cell Microvesicles during Experimental Endotoxemia.
Bulletin of Experimental Biology and Medicine 2006; 142: 517–
 Morel O, Hugel B, Jesel L, Mallat Z, Lanza F, Douchet MP, Zupan
M, Chauvin M, Cazenave JP, Tedgui A, Freyssinet JM, Toti F.
Circulating procoagulant microparticles and soluble GPV in my-
ocardial infarction treated by primary percutaneous transluminal
coronary angioplasty. A possible role for GPIIb-IIIa antagonists. J
Thromb Haemost 2004; 2: 1118–26.
 Razmara M, Hu H, Masquelier M, Li N. Glycoprotein IIb/IIIa
blockade inhibits platelet aminophospholipid exposure by potenti-
ating translocase and attenuating scramblase activity. Cell Mol Life
Sci 2007; 64: 999–1008.
 Craft JA, Marsh NA. Increased generation of platelet-derived mi-
croparticles following percutaneous transluminal coronary angi-
oplasty. Blood Coag & Fibrinolysis 2003; 14: 719–28.
 Weyrich AS, Lindemann S, Zimmerman GA. The evolving role of
platelets in inflammation. J Thromb Haemost 2003; 1: 1897–905
 Wang HB, Wang JT, Zhang L, Geng ZH, Xu WL, Xu T, Huo Y,
Zhu X, Plow EF, Chen M, Geng JG. P-selectin primes leukocyte
integrin activation during inflammation. Nat Immunol. 2007; 8:
 Barry OP, Pratico D, Savani RC, Fitzgerald GA. Modulation of
monocyte-endothelial cell interactions by platelet microparticles.
J Clin Invest 1998; 102: 136–44.
 Bizios R, Lai LC, Cooper JA, Del Vecchio PJ, Malik AB. Thrombin-
induced adherence of neutrophils to cultured endothelial monolay-
ers: increased endothelial adhesiveness. J Cell Physiol 1988; 134:
 von Hundelshausen P, Weber C. Platelets as immune cells: bridg-
ing inflammation and cardiovascular disease. Circ Res. 2007; 100:
 Elzey BD, Sprague DL, Ratliff TL. The emerging role of platelets
in adaptive immunity. Cell Immunol 2005; 238: 1–9
 Sprague DL, Elzey BD, Crist SA, Waldschmidt TJ, Jensen RJ,
Ratliff TL. Platelet-mediated modulation of adaptive immunity:
unique delivery of CD154 signal by platelet-derived membrane
vesicles. Blood 2008; 111: 5028–36.
 Weyrich AS, Zimmerman GA. Platelets: signaling cells in the im-
mune continuum. TRENDS in Immunol 2004; 25: 489–95.
 Ardoin SP, Shanahan JC and Pisetsky DS. The Role of Micropar-
ticles in Inflammation and Thrombosis. Scandinavian Journal of
Immunology 2007; 66: 159–65.
 Nieuwland R., Berckmans R. J., McGregor S., Böing A. N., Romi-
jn F., Westendorp R.G. J., Hack C. E., Sturk A.. Cellular origin and
procoagulant properties of microparticles in meningococcal sepsis.
Blood. 2000; 95:930–5
 Soriano AO, Jy W, Chirinos JA, Valdivia MA, Velasquez HS,
Jimenez JJ, Horstman LL, Kett DH, Schein RM, Ahn YS.Levels of
endothelial and platelet microparticles and their interactions with
leukocytes negatively correlate with organ dysfunction and predict
mortality in severe sepsis.Crit Care Med. 2005; 33: 2540–6.
 Knedla A, Neumann E, Müller-Ladner U. Developments in the
synovial biology field 2006. Arthritis Research & Therapy 2007; 9:
 Knijff-Dutmer EA, Koerts J, Nieuwland R, Kalsbeek-Batenburg
EM, van de Laar MA. Elevated levels of platelet microparticles are
associated with disease activity in rheumatoid arthritis. Arthritis &
Rheum 2002; 46: 1498–1503.
 Berckmans RJ, Nieuwland R, Kraan MC, Schaap MCL, Pots D,
Smeets TJM, Sturk A, Tak PP. Synovial microparticles from ar-
thritic patients modulate chemokine and cytokine release by syn-
oviocytes. Arthritis Research & Therapy 2005; 7: 536–44
 Wegmann TG, Lin H, Guilbert L and Mosmann TR. Bidirectional
cytokine interactions in the maternal-fetal relationship: is success-
ful pregnancy a TH2 phenomenon? Immunol Today 1993; 14:
 Chaouat G, Ledee-Bataille N, Dubanchet S, Zourbas S, Sandra O
and Martal J. TH1/TH2 paradigm in pregnancy: paradigm lost?
Cytokines in pregnancy/early abortion: reexamining the TH1/TH2
paradigm. Int Arch Allergy Immunol 2004; 134: 93–119.
 Kauma SW, Huff TF, Hayes N, Nilkaeo A. Placental Fas ligand
expression is a mechanism for maternal immune tolerance to the
fetus. J Clin Endocrinol Metab 1999; 84: 2188–94.
 Sabapatha A, Gercel-Taylor C and Taylor DD. Specific isolation of
placenta-derived exosomes from the circulation of pregnant women
and their immunoregulatory consequences. Am J Reprod Immunol
2006; 56: 345–55.
 Taylor DD, Akyol S and Gercel-Taylor C. Pregnancy-associated
exosomes and their modulation of T cell signaling. J Immunol
2006; 176: 1534–42.
 Dorling A, Monk NJ and Lechler RI. HLA-G inhibits the transen-
dothelial migration of human NK cells. Eur J Immunol 2000; 30:
 Redman CW, Sargent IL. Placental debris, oxidative stress and pre-
eclampsia. Placenta 2000; 21: 597–602.
 Gupta AK, Hasler P, Holzgreve W, Gebhardt S, Hahn S. Induction
of neutrophil extracellular DNA lattices by placental microparticles
and IL-8 and their presence in preeclampsia. Hum Immunol. 2005;
 von Dadelszen P, Hurst G, Redman CW. Supernatants from co-cul-
tured endothelial cells and syncytiotrophoblast microvillous mem-
branes activate peripheral blood leukocytes in vitro. Hum Reprod
1999; 14: 919–24
 Taylor DD, Akyol S and Gercel-Taylor C. Pregnancy-associated
exosomes and their modulation of T cell signaling. J Immunol
2006; 176: 1534–42.
 VanWijk MJ, Nieuwland R, Boer K, van der Post JAM, VanBavel E
and Sturk A. Microparticle subpopulations are increased in preec-
lampsia: Possible involvement in vascular dysfunction? Am J Ob-
stet Gynecol 2002; 187: 450–6.
 Brenner B. Haemostatic changes in pregnancy. Thrombosis Re-
search 2004; 114: 409–14.
 Goswami D, Tannetta DS, Magee LA, Fuchisawa A, Redman CW,
Sargent IL and von Dadelszen P. Excess syncytiotrophoblast mi-
croparticle shedding is a feature of early-onset pre-eclampsia, but
not normotensive intrauterine growth restriction. Placenta 2006;
 Carp H, Dardik R, Lubetsky A, Salomon O, Eskaraev R, Rosenthal
E and Inbal A. Prevalence of circulating procoagulant microparti-
cles in women with recurrent miscarriage: a case-controlled study.
Human Reproduction 2004; 19: 191–5.
 VanWijk MJ, Boer K, Berckmans RJ,Meijers JC, van der Post JA,
Sturk A, et al. Enhanced coagulation activation in preeclampsia: the
role of APC resistance, microparticles and other plasma constitu-
ents. Thromb Haemost 2002; 88: 415–20.
 Hamad RR, Curvers J, Berntorp E, Eriksson MJ, Bremme K. In-
creased thrombin generation in women with a history of preec-
lampsia. Thromb. Res. 2008.
 Meziani F., Tesse A., David E., Martinez M. C., Wangesteen R.,
Schneider F., Andriantsitohaina R.. Shed Membrane Particles from
Preeclamptic Women Generate Vascular Wall Inflammation and
Blunt Vascular Contractility. Am J Pathol 2006, 169: 1473–83
 Boulanger C. M., Amabile N., Tedgui A.. Circulating Micropar-
ticles: A Potential Prognostic Marker for Atherosclerotic Vascular
Disease. Hypertension. 2006; 48: 180–6.
 Gonzalez-Quintero V. H., Jimenez J., Jy W., Mauro L. M., Hortman
L., O’Sullivan M. J., Ahn Y.. Elevated plasma endothelial micropar-
ticles in preeclampsia. Am J Obstet Gynecol 2003; 189: 589–93.