(Circulation. 1997;96:1809-1818.)
© 1997 American Heart Association, Inc.
Articles |
vß3) Mediates Platelet Adhesion to the Luminal Aspect of Endothelial Cells
From the 1. Medizinische Klinik der Technischen Universität München, Germany.
Correspondence to Dr Meinrad Gawaz, 1. Medizinische Klinik der Technischen Universität München, Klinikum rechts der Isar, Ismaninger Straße 22, 81675 München, Germany.
| Abstract |
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|
|
|---|
vß3) in
platelet/endothelium adhesion.
Methods and Results We investigated the effect on
platelet/endothelium adhesion of plasma obtained
from patients with acute myocardial infarction during reperfusion
(before and 8, 24, 48, and 72 hours and 5 to 7 days after direct
angioplasty) and with pretreatment with
-thrombin (2 U/mL) and
recombinant human interleukin-1ß.
Platelet/endothelium adhesion was significantly
enhanced by
20% after pretreatment of endothelium
with patient plasma for 4 hours (P<.05) compared with
endothelium treated with pooled control plasma.
Plasma-induced platelet/endothelium adhesion was,
in part, RGD peptide dependent. Pretreatment of
endothelial cells with
-thrombin or recombinant
human interleukin-1ß enhanced
platelet/endothelium adhesion and surface
expression of
vß3 on the luminal aspect of
endothelium (P<.05). The adhesion of
platelets, isolated platelet microparticles, and Chinese
hamster ovary cells bearing human recombinant
IIbß3 (platelet
glycoprotein IIb-IIIa) to activated
endothelial cells was inhibited by antiadhesive
peptides GRGDSP and c(RGDfV) and monoclonal antibodies 4F10, LM609, and
7E3.
Conclusions The expression of vitronectin receptor exposed on the luminal aspect of activated endothelium is enhanced and mediates platelet/endothelium adhesion. Vitronectin receptormediated platelet attachment to activated endothelium during reperfusion may contribute to reperfusion injury and could be a target for antiadhesive therapy.
Key Words: platelets endothelium myocardial infarction reperfusion integrins
| Introduction |
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Recently, we found that plasma obtained from patients with AMI during
reperfusion promotes platelet/endothelium adhesion
in vitro.7 Previously, we showed that recombinant human
ß3 integrins
vß3 and
IIbß3 expressed in nuclear cells mediate
heterotypic cell adhesion in the presence of
fibrinogen.8 9 Thus, fibrinogen bridging platelet
GPIIb-IIIa (
IIbß3) to
endothelial
vß3 could have
a pathophysiological relevance in
platelet/endothelium adhesion during
reperfusion.
vß3 is the major integrin expressed on
endothelial cells, and it binds RGD-containing
glycoproteins.10
vß3 operates in concert with other
adhesion receptors to promote endothelial cell adhesion
to the vascular matrix10 11 12 as well as white blood cell
adhesion to and transmigration across endothelial
cells.13 Recently,
vß3 has
been a subject of considerable interest because experimental and
clinical studies suggest that
vß3 is
involved in mechanisms of angiogenesis,14
apoptosis of proliferating vascular cells,11 15
smooth muscle cell migration,11 16 neointimal
hyperplasia,16 and restenosis.17 It
has been suggested that
vß3 is involved in
disturbances of endothelial barrier function
and promotes edema in lung tissue.18
In the present study, we focused on the role of
vß3 in platelet adhesion to
activated cultured endothelium. Specifically,
we investigated the effect of plasma obtained from patients with AMI
during reperfusion on platelet adhesion and
vß3 surface exposure on cultured
endothelial cells. Moreover, we assessed the role of
vß3 for interaction of platelets with
activated HUVECs.
| Methods |
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|---|
|
Monoclonal Antibodies, Peptides, and Reagents
Anti-CD51 (IgG1 mouse, clone AMF7, Immunotech) recognizes the
v subunit, and anti-CD61 (IgG1 mouse, clone SZ21,
Immunotech) recognizes the ß3 subunit of the
vitronectin receptor
vß3. mAb
LM609 (IgG1 mouse, generously provided by Dr David Cheresh, Scripps
Clinic, La Jolla, Calif) is a blocking antibody directed against
vß3 and binds to the receptor only in its
complexed form.10 mAb 7E3 (IgG1 mouse, a gift from Dr
Barry Coller, Mount Sinai Hospital, New York, NY) blocks the fibrinogen
binding site on GPIIb-IIIa and also recognizes the complexed form of
vß3.19 mAb 4F10 (IgG1 mouse)
inhibits fibrinogen binding to GPIIb-IIIa
(
IIbß3) (a gift from Dr Virgil Woods,
University of California San Diego).20 mAb anti-LIBS1
(IgG1 mouse, kindly provided by Dr Mark Ginsberg, Scripps Clinic) is a
conformation-dependent antibody that induces a high-affinity state of
platelet GPIIb-IIIa.21 Anti-CD42b binds to
platelet GP-Ib (IgG1 mouse, clone SZ2, Immunotech), and anti-CD54,
a phycoerythrin-conjugate (IgG1 mouse, clone 84H10, Immunotech) binds
to ICAM-1. In all immunostaining studies, an irrelevant
isotype-matched control antibody was used (anti-
M, IgG1 mouse, clone
Bear1, Immunotech). For flow cytometric analysis, all mAbs were
conjugated with FITC to obtain fluorescence-to-protein ratios
of 2.5 to 3.0.22
The peptides GRGDSP and GRGESP were purchased from Calbiochem. GRGDSP
is recognized by both GPIIb-IIIa and
vß3,
whereas GRGESP is biologically inactive and was used as a control
peptide. c(RGDfV) (kindly provided by Prof Dr J. Kessler, Institut
für Biochemie, Technische Universität München,
Germany) is a cyclic pentapeptide with high selectivity for
vß3.23 Fibronectin-depleted
fibrinogen was purified according to described methods. The
RGD-containing polypeptide echistatin (Sigma Chemical) binds with high
affinity to
vß324 and was
conjugated for flow cytometric binding studies with FITC according to a
standard protocol to obtain a fluorescence-to-peptide ratio of
3.4.22
Cells
Primary HUVECs were harvested using collagenase
digestion (Worthington) and cultured as previously
described.25 ECV-304, an immortal HUVEC cell line
(American Type Culture Collection), was cultured in complete medium
M199 (10% FCS, 2 mmol/L glutamine, 100 U/mL penicillin,
and 100 mg/L streptomycin). The stable CHO cell line,
cotransfected with human ß3 and
IIb cDNA,
expresses functional recombinant human platelet GPIIb-IIIa (kindly
provided by Dr Mark Ginsberg, Scripps Clinic) and was cultivated as
previously described.9 26
Immunostaining of Endothelial Cells
Confluent monolayers of endothelial cells were
stimulated as indicated with human
-thrombin (Sigma; 2 U/mL) for 20
minutes or rhIL-1ß (R & D Systems; 100 pg/mL) for 4 hours,
respectively. After a washing step, cell layers were incubated with
saturating concentrations of FITC-conjugated mAbs (30 µg/mL)
and PE-conjugated antiICAM-1 mAb (20 µg/mL) for 20 minutes
at 37°C. After the addition of 2 mL M199 containing 1.67 mg/mL
LDS-751 (Styry 18, Exciton Inc), the mAb solution was diluted 1:20.
Endothelial cells were then mechanically detached and
separated into single-cell suspension by repetitive pipetting. For flow
cytometric analysis, endothelial cells were
identified by LDS-751 and ICAM-1 fluorescence; 10 000 events
were evaluated, and mean intensity of FITC
immunofluorescence was used as a
parameter of antigen expression. Immunoelectron microscopy
was performed as previously described.27 28 After
incubation with anti-
v mAb, the
endothelial monolayer was incubated for 30 minutes with
a second gold-conjugated goat anti-mouse antibody (gold particle size,
6 nm; Aurion). Fixation was then performed in 2.5%
glutaraldehyde followed by silver enhancement (Aurion
R-Gent) of the conjugates.
Effect of Patient Plasma on Platelet/Endothelium Adhesion
After incubation of endothelial monolayers for 4
hours with patient plasma diluted 1:2 in M199, the supernatant was
aspirated, and 100 µL of gel-filtered platelet suspension that
contained 300 µg/mL fibrinogen, 2 mmol/L
Ca2+, and 10 µmol/L ADP (final platelet
concentration, 108/mL) was added to each well. After a
60-minute incubation at 37°C without agitation in culture condition
atmosphere, the nonadherent platelets were removed by
centrifugation of the inverted culture plate
(500g for 5 minutes). Integrity of cell monolayer was
verified by direct microscopy. Thereafter, samples were fixed for 1
hour at room temperature by the addition of freshly prepared 4%
paraformaldehyde/PBS solution to each microtiter well.
The fixative was washed off, and 50 µL of platelet-specific mAb
anti-CD42b was then added in saturating concentration (20
µg/mL) to each well. Specific antibody binding was detected by
use of a secondary peroxidase-conjugated mAb (Sigma).
Echistatin Binding
Nonactivated or stimulated (
-thrombin, rhIL-1ß)
endothelial monolayers were incubated (2 hours at
37°C) with various concentrations of FITC-echistatin (0.1, 0.0625,
0.25, 0.5, 0.75, 1.0 µmol/L) diluted in M199 that
contained 1 mmol/L Ca2+. Binding experiments
were performed in the presence and absence of 1 mmol/L
GRGDSP. Thereafter, endothelial cells were stained with
LDS-751 and antiICAM-1 as described above. After mechanical
detachment and separation into a single-cell suspension, binding of
FITC-echistatin to endothelial cells was evaluated by
flow cytometry; 10 000 events were counted that were positive for
LDS-751 and ICAM-1.
Platelet/Endothelium Adhesion
Platelet adhesion to monolayers of cultured
endothelial cells (24-well plates) was evaluated by the
addition of 200 µL gel-filtered platelets (final platelet
concentration, 108/mL) resuspended in Tyrodes-HEPES buffer
(2.5 mmol/L HEPES, 150 mmol/L NaCl, 12
mmol/L NaHCO3, 2.5 mmol/L KCl, 1
mmol/L MgCl2, 5.5 mmol/L
D-glucose, and 1 mg/mL BSA, pH 7.4) that contained
1 mmol/L Ca2+, 300 µg/mL fibrinogen,
10 µmol/L ADP, and additional compounds as indicated.
After a 60-minute incubation at 37°C without agitation in culture
condition atmosphere, supernatant was aspirated, and 200 µL of M199
containing saturating concentrations of mAbs anti-CD42b and
PE-anti-CD54 was added to each well. After 20 minutes of incubation,
the cells were mechanically detached through repetitive pipetting, and
a single-cell suspension was evaluated by flow cytometry as described
above. In experiments with activated
endothelium, the adherent monolayers were conditioned
for the indicated time with
-thrombin (2 U/mL) or rhIL-1ß (100
pg/mL) and washed three times with M199 until the addition of
platelet suspension. In experiments with
-thrombin, activation
was stopped by the addition of excess (10 U/mL) of hirudin to
neutralize thrombin activity (Sigma).
Platelet-endothelium adhesion was verified by laser
scanning and raster electron microscopy as previously
described.7 27 28
Platelet microparticles were purified and characterized as previously described.29 Platelet microparticles (100 µg/mL) were resuspended homogeneously in Tyrodes-HEPES buffer supplemented with 1 mmol/L Ca2+ and 300 µg/mL fibrinogen. Monolayers of cultured endothelial cells were incubated after the addition of 100 µL membrane suspension to each well for 60 minutes at 37°C. Thereafter, microparticles bound to endothelial cells were detected as described above for intact platelets.
Adhesion of
IIbß3 Transfectants
to HUVECs
Preparation of cell suspensions and fluorescent labeling
of the transfected CHO cells were performed as previously
described.8 CHO transfectants were labeled with the red
fluorochrome hydroethidine (Polysciences), and HUVECs were labeled with
the green fluorochrome sulfofluorescein diacetate
(Molecular Probes). Equal volumes of labeled cells (4x106
cells/mL) in suspension were mixed, and coadhesion was evaluated as
previously described.8 9 The appearance of two-color
particles (red-green) was used as parameter of coadhesion
between
IIbß3 transfectants and
HUVECs.
Statistical Analysis
The Kolmogorov-Smirnov test showed that the data were not
normally distributed. Differences were tested by Friedman's test
followed by Wilcoxon's matched-pairs signed rank test.
Differences between unpaired samples were tested by the
Mann-Whitney-Wilcoxon rank sum test. A value of
P<.05 was regarded as statistically significant.
| Results |
|---|
|
|
|---|
|
In the presence of the synthetic peptide GRGDSP (500
µmol/L), induced adhesion of ADP-activated
platelets to endothelium was markedly reduced with
maximal inhibition 48 and 72 hours and 5 to 7 days after direct PTCA
(Table 2
).
Activation of Endothelium and Surface Expression of
Vitronectin Receptor
vß3
We tested whether activation of endothelium
affects expression of
vß3 on the luminal
aspect of cultured endothelial cells.
-Thrombin (2
U/mL) and rhIL-1ß (100 pg/mL) significantly enhanced surface
exposure of both subunits of the vitronectin receptor by
10% to 40%, as demonstrated by enhanced binding of mAb
anti-ß3 or anti-
v (P<.05) (Fig 1
). Similarly, binding of both mAb LM609,
which recognizes exclusively the functional and complexed form of the
receptor
vß3, and of mAb LIBS1, which
recognizes conformational changes in ß3 integrins, was
enhanced on activated endothelium compared with
untreated cells (P<.05) (Fig 1
). No significant changes in
binding of an isotype-matched control mAb, anti-
M, was found on
activated endothelium (Fig 1
).
Activation-dependent expression of
vß3 was
observed on both cultured HUVECs and ECV-304 monolayers (Fig 1A
and 1B
). The presence of significant amounts of vitronectin
receptor on the luminal surface of endothelial cells
was verified by transmission electron microscopy (Fig 2
).
|
|
To assess functional aspects of
vß3, we
performed binding experiments with echistatin, a polypeptide that
contains the RGD recognition motif and that binds to
vß3.24 Binding of echistatin
to cultured endothelium was saturable (Fig 3
) and was inhibited through GRGDSP
(1 mmol/L). Pretreatment of endothelial
cells with
-thrombin or rhIL-1ß resulted in significantly enhanced
GRGDSP-dependent echistatin binding (P<.05) (Fig 3
).
|
Platelet Adhesion to Nonstimulated and Activated
Endothelium
Adhesion of ADP-activated platelets to
-thrombinor rhIL-1ßpretreated endothelial
monolayers was significantly enhanced compared with
nonactivated endothelium (P<.05)
(Fig 4A
). Platelet adhesion to both
-thrombin and rhIL-1ßpretreated endothelial
cells was reduced in the presence of 500 µmol/L GRGDSP
(P<.05) but not in the presence of the biologically
inactive GRGESP peptide (500 µmol/L) (Fig 4A
). The cyclic
peptide c(RGDfV), which has a high selectivity for
vß3, also considerably reduced
platelet adhesion to activated endothelium
(P<.05) (Fig 4A
). As shown by direct microscopy, primarily
single platelets underwent significant morphological changes and
adhered to endothelial cells (Fig 5
).
|
|
Similar to intact platelets, adhesion of microparticles to
activated endothelium was significantly
enhanced (P<.05) (Fig 4B
). Platelet
membrane/endothelium adhesion was inhibited by GRGDSP
and c(RGDfV) but not by GRGESP (500 µmol/L)
(P<.05) (Fig 4B
).
Heterotypic Adhesion of CHO Cells Expressing Recombinant Human
Fibrinogen Receptor
IIbß3 (GPIIb-IIIa)
and HUVECs
CHO cells bearing the recombinant human platelet
fibrinogen receptor
IIbß3 (GPIIb-IIIa)
adhered to HUVECs in the presence of soluble fibrinogen (300
µg/mL), Ca2+ (2 mmol/L), and mAb
anti-LIBS1 (20 µg/mL) (Fig 6
). The adhesion was specific for
IIbß3 because it was inhibited by blocking
antiGPIIb-IIIa mAb 4F10 (50 µg/mL) (Fig 6
). Heterotypic
adhesion of transfectants and HUVECs was also
vß3 specific because it was inhibited by
mAb LM609 (50 µg/mL) (Fig 6
). mAb 7E3 (50 µg/mL),
which inhibits ligand recognition of both ß3
receptors, also reduced adhesion of transfectants to HUVECs (Fig 6
). No
inhibition of heterotypic coadhesion was found in the presence of mAb
anti-
v (anti-CD51) (30 µg/mL) or of an
irrelevant isotype-matched control antibody anti-
M (30
µg/mL) (Fig 6
).
|
As described above for platelets, adhesion of CHO cells bearing
IIbß3 to activated (
-thrombin,
rhIL-1ß) HUVECs was enhanced compared with nonstimulated HUVECs
(P<.05) (Fig 7
). Heterotypic
adhesion was inhibited by
IIbß3 -specific
mAb 4F10,
vß3-specific mAb LM609, or mAb
7E3 (P<.05) (Fig 7
). GRGDSP (500 µmol/L) but
not GRGESP inhibited adhesion of
IIbß3
transfectants to activated HUVECs (Fig 7
).
|
| Discussion |
|---|
|
|
|---|
-thrombin or rhIL-1ß enhances
adhesion of ADP-activated platelets to
endothelial cells and surface expression of
vitronectin receptor on the luminal aspect of cultured
endothelium; and (3) nuclear cells expressing
recombinant human platelet GPIIb-IIIa
(
IIbß3) adhere to monolayers of HUVECs in
the presence of soluble fibrinogen. Coadhesion of
IIbß3 transfectants can be inhibited
through antagonists of ß3 integrins. These findings imply that platelet/endothelium adhesion is enhanced during reperfusion. Inhibition of vitronectin receptor function by specific antiadhesive compounds during reperfusion may be beneficial for patients with AMI.
Surface Expression of Vitronectin Receptor
vß3 on the Blood-Facing Endothelial
Surface
The function of the luminal-facing integrin is still poorly
understood.
vß3 is a receptor for a
variety of plasmatic adhesive glycoproteins such as
fibrinogen, vitronectin, or thrombospondin. Soluble forms
of these proteins do not bind to endothelial
ß3 integrins.11 29 In contrast,
vitronectin immobilized on microbeads binds
significantly to endothelium in an RGD-dependent
manner.31 Luminal surface expression of
vß3 has been shown to support monocyte
adhesion to endothelium.13
Our present study shows that expression of
vß3 is enhanced on the luminal aspect of
activated endothelial cells, as demonstrated by
increased binding of
vß3-specific mAbs and
of echistatin after pretreatment of endothelial cells
with
-thrombin or rhIL-1ß. These results are in concert with
studies that show enhanced vitronectin binding and
RGD-dependent tumor cell adhesion to Il-1ßtreated
endothelial cells.32 Large amounts of
vß3 are stored intracellularly, and
vß3 receptors are translocated to the
membrane surface on activation.31 32 33 34 Thus, luminal surface
expression of endothelial
vß3 is activation dependent and might
contribute substantially to altered adhesive properties.
Platelet/Endothelium Adhesion in
Reperfusion
In vitro experiments suggest that enhanced
platelet/endothelium adhesion plays a role in a
variety of pathophysiological
conditions.35 36 37 38
In the present study, we found that plasma obtained from patients during reperfusion promotes adhesion of ADP-activated platelets to cultured endothelial cells. Plasma-induced adhesion could be inhibited, in part, through use of the antiadhesive peptide GRGDSP throughout reperfusion.
Numerous mediators (eg, complement factors, cytokines, reactive oxygen) are released during reperfusion.1 2 39 Because these mediators alter endothelial function,40 it seems likely that patient plasma contains compounds that are released during reperfusion. The presence of proinflammatory substances in plasma derived from patients during reperfusion may activate endothelial cells in culture and change their phenotype into a proadhesive one.
To evaluate the role of activation on
vß3-mediated platelet adhesion,
endothelial cells were stimulated with
-thrombin or
rhIL-1ß and the effect of antiadhesive RGD peptides on platelet
adhesion was studied. In the presence of GRGDSP, a peptide that binds
to a variety of integrins, including
vß3
and platelet fibrinogen receptor GPIIb-IIIa
(
IIbß3), adhesion of ADP-activated
platelets to pretreated endothelium was
significantly decreased. Similar effects were shown for the cyclic
synthetic peptide c(RGDfV), which is characterized by high selectivity
for the
vß3 receptor.23 This
indicates that
vß3 mediates platelet
adhesion to the activated endothelial cell
surface.
Adhesion to endothelium was not limited to intact platelets because isolated platelet membranes that lack intracellular structures also adhered to activated endothelium in an RGD-dependent manner. This suggests that the mechanism of platelet/endothelium adhesion is independent of endothelial-derived products (eg, nitric oxide, prostacyclin) that are released into the extracellular compartment and that can modulate activation-dependent processes within the intact platelet. Moreover, enhanced interaction of platelet membranes with endothelium may be of pathophysiological importance. Platelet-derived membrane fragments contain procoagulative compounds and are formed during reperfusion.7 Entrapment of these particles may support procoagulant activities on the endothelial monolayer.41
To further analyze the mechanisms of platelet adhesion to
endothelial cells, we used a CHO cell line that
expresses functional recombinant human platelet GPIIb-IIIa
(
IIbß3).8 26 We found that in
the presence of fibrinogen, CHO cells adhered to cultured HUVECs. This
interaction was specifically mediated by both ß3
integrins; it could be inhibited by blocking mAbs directed to
IIbß3 (4F10, 7E3) or
vß3 (LM609). Activation of HUVECs by
-thrombin and rhIL-1ß promoted coadhesion of
IIbß3 transfectants and HUVECs. Again,
this effect was dependent on enhanced surface expression of
vß3 in that it was blocked by specific mAb
LM609. Thus, fibrinogen bridging between platelet GPIIb-IIIa and
endothelial
vß3 is a
likely mechanism involved in
vß3-mediated
platelet adhesion to activated
endothelium.
Study Limitations
Mechanisms other than the one described above may also contribute
to platelet/endothelium adhesion. Platelets
expose significant amounts of thrombospondin on their activated
surface, which is able to bind
vß3.11 12 Activated
platelets also degranulate fibronectin, which is recognized by
fibronectin receptor
6ß1 on
endothelial cells.42 It has been shown
that the presence of ICAM-1 on endothelium binds
fibrinogen that is immobilized on cell
surfaces.43 Endothelial cells synthesize
large amounts of von Willebrand factor that, in part, remain
associated with the cell surface.37 Thus, interaction of
platelet GPIb with cell-surfaceimmobilized von
Willebrand factor might be another candidate for
platelet/endothelium adhesion.
Studies on platelet adhesion to endothelium have been criticized for the possibility of platelet contact to extracellular structures after damage of the confluent monolayer. For example, thrombin induces retraction of cultured endothelial cells, which results in loosening cell contact of the monolayer.36 In our study, in all experiments the integrity of the endothelial layer was verified by direct microscopy. Moreover, flow cytometric analysis of detached cells allowed us to directly study platelet adhesion to single endothelial cells.
Endothelial cells derived from different blood vessel
districts have specific adhesive properties.42
Endothelial cells isolated from the coronary
circulation may also be functionally different. In our experiments, we
used primary cultures of HUVECs and the stable
endothelial cell line ECV-304. Both cell types are
widely used to study endothelial cell function.
Integrin exposure on the apical aspect of the membrane, however, is not
a specific property of HUVECs or ECV-304 because cultured
endothelium from saphena magna and adrenal gland
microvessels also showed these characteristics.32 33 In
situ staining of human tissues showed that
vß3 is present in large vessel
endothelium and, to a lesser extent, expressed in the
microcirculation.32 Further experiments with
endothelial cells derived from coronary
macrovessels and microvessels will clarify whether
vß3 is differentially surface exposed in
response to activation and whether it promotes adhesion of
platelets.
Pathophysiological Considerations and
Therapeutic Implications
The adhesion of platelets to endothelium has
been described in a variety of pathophysiological
conditions.7 28 36 37 38 44 The biological relevance of
platelet adhesion is of interest. Adhering platelets might (1)
facilitate attachment and transmigration of leukocytes to and across
the endothelial layer, (2) change the
endothelial cell surface into a prothrombotic and
proadhesive phenotype, and (3) induce inflammatory reaction
within the endothelium. Activation and adhesion of
platelets result in release of P-selectin (CD62P) on the surface, a
central receptor for leukocyte tethering.45 Adherent
platelets to the vessel wall have been shown to promote
leukocyte-dependent fibrin deposition via P-selectin.46
Moreover, vitronectin receptor has been shown to promote in
concert with P-selectin monocyte migration across
endothelium.13 Thus, platelet
attachment to endothelium might be a potent mechanism
of targeting leukocyte sequestration toward the tissue of interest.
Platelets release a variety of mediators that support platelet
aggregation and coagulation.47 Moreover, platelet
membranes that are sheered off platelets during activation are
generated during reperfusion7 and possess significant
procoagulant activities by activating the prothrombinase
complex.41 In the present study, we found that
microparticles are able to bind to endothelium and thus
may promote fibrin generation localized at the site of adhesion. In
addition to their role in adhesion, integrins act as outside-in
signaling receptors.48 Integrins have been shown to
mediate increases of cellular Ca2+, tyrosine
phosphorylation of cell proteins, and induction of gene
expression.48 49 Thus, anchorage of platelets to
endothelial cells might induce inflammatory responses
via integrins. The importance of platelet adhesion in inflammatory
reactions is supported by experiments showing that P-selectin enhances
production of monocytic-chemotactic peptide 1 (MCP-1) in
neutrophils.45 Moreover, platelet-associated IL-1
activity induces ICAM-1 surface expression and IL-6 and IL-8
production50 51 ; all cytokines have been
suggested to be involved in pathophysiological
mechanisms of reperfusion.39 We (the present study)
and others52 showed that IL-1ß stimulates
endothelial surface expression of
vß3, which may further support
platelet adhesion.
Although in the present study we could not address the potential
clinical relevance of platelet/endothelium adhesion
in reperfusion, results showed mechanisms that may stimulate clinical
studies in this field, with the goal of improving therapy during
reperfusion. The availability of reagents that modulate
vitronectin receptor function, such as mAb
7E319 53 or LM60912 or
vß3-specific peptides such as
c(RGDfV),23 may be of interest in upcoming studies.
| Selected Abbreviations and Acronyms |
|---|
|
| Acknowledgments |
|---|
| Footnotes |
|---|
Received November 21, 1996; revision received April 8, 1997; accepted April 18, 1997.
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