(Circulation. 2001;103:1128.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Recombinant Soluble P-Selectin Glycoprotein Ligand-1-Ig Reduces Restenosis Through Inhibition of Platelet-Neutrophil Adhesion After Double Angioplasty in Swine
From the Research Center, Montreal Heart Institute (J.-G.B., J.-F. Tanguay, J-F. Théorêt, Y.M.), the University of Montreal (J.-G.B., J.-F. Tanguay, J-F. Théorêt, Y.M.), Montreal, Quebec, Canada; and Wyeth/Genetics Institute (A.K., R.G.S.), Andover, Mass.
Correspondence to Yahye Merhi, Laboratory of Experimental Pathology, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada, H1T 1C8. E-mail merhi{at}icm.umontreal.ca
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Abstract |
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Background—P-selectin mediates leukocyte recruitment to activated platelets and endothelium through its high-affinity receptor P-selectin glycoprotein ligand-1 (PSGL-1). Platelet and leukocyte activation and binding have been reported after coronary angioplasty and were correlated with restenosis. We investigated the effect of a recombinant soluble PSGL-1 (rPSGL-Ig) on the adhesion of platelets and neutrophils and the development of restenosis after double arterial injury.
Methods and Results—Four weeks after angioplasty of both carotid arteries in pigs, a second angioplasty was performed at the same sites, 15 minutes after a single administration of vehicle or rPSGL-1 (1 mg/kg IV). Animals were euthanized 1 hour, 4 hours, 1 week, or 4 weeks later. Adhesion of autologous 51Cr-platelets and 111In-neutrophils was quantified and histological/morphometric analyses were performed. Although rPSGL-Ig did not affect adherence of these cells 1 hour after injury, it significantly reduced the adhesion of platelets (50% at 4 hours and 85% at 1 week) and neutrophils (50% at 4 hours and 78% at 1 week) to deeply injured arteries. At 4 weeks, the residual lumen was 63% larger in rPSGL-Ig–treated arteries as compared with control arteries (6.1±0.6 versus 3.8±0.1 mm2; P<0.002). The neointimal area was slightly reduced (0.5 in rPSGL-Ig versus 0.7 mm2 in control). The ratio of the external elastic lamina of injured to uninjured reference segments was >1 in treated arteries and <1 in control arteries.
Conclusions—P-selectin antagonism with rPSGL-Ig inhibits early platelet/leukocyte adhesion on injured arteries and reduces restenosis through a positive impact on vascular remodeling. Hence, rPSGL-Ig may have potential in the prevention of restenosis.
Key Words: restenosis • remodeling • glycoproteins • platelets • leukocytes
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Introduction |
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Restenosis after successful coronary angioplasty constitutes a significant limitation to the long-term success of this procedure. Shortly after injury to the vessel wall, elastic recoil, thrombotic and inflammatory responses, and secretion of cytokines and growth factors contribute to thrombus organization. These early reactions are followed, in turn, by neointimal hyperplasia derived from medial cell proliferation and migration toward the intima with formation of extracellular matrix and eventual reduction in vascular lumen or restenosis.1 2 This process also involves chronic and adaptive changes in vascular structure resulting in changes to arterial size or remodeling. These include alterations in hemodynamic conditions and locally mediated vasoactive and growth factors with production/degradation of extracellular matrix.3 4 5 6
The acute response to arterial injury induced by angioplasty involves the adhesion of platelets and leukocytes, which react with the damaged arterial wall in proportion to the degree of injury.7 8 9 Activated platelets promote mural thrombus formation, vasoconstriction, and restenosis.7 10 Neutrophils are also activated after PTCA11 12 13 and contribute to the upregulation of platelet reactivity.14 These reactions of platelets and neutrophils are also accompanied by monocyte/macrophage accumulation that amplify the inflammatory reactions leading to the progression of restenosis.15 Interactions between platelets and leukocytes are facilitated by platelet P-selectin and its high-affinity counterreceptor on leukocytes, P-selectin glycoprotein ligand-1 (PSGL-1 or CD162).16
P-selectin–mediated platelet-leukocyte interactions17 18 19 allow tethering of leukocytes by activated platelets, thus facilitating metabolic cooperation and mutual activation.19 20 21 22 Increased platelet-leukocyte activation and interactions have been reported in unstable angina, after myocardial ischemia, and in coronary angioplasty.11 12 13 23 24 Indeed, inhibition of platelet/leukocyte binding with anti–P-selectin antibodies or a recombinant soluble form of PSGL-1 has been beneficial in animal models of deep-vein thrombosis,25 myocardial ischemia-reperfusion,26 27 intimal hyperplasia after angioplasty,28 and arterial thrombosis.29 30
In this study, we sought to demonstrate that administration of rPSGL-Ig would inhibit platelet-leukocyte interactions at the sites of injury and reduce restenosis in a porcine model involving double arterial angioplasty.
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Methods |
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Animal Preparation
Fourteen cross-bred Yorkshire swine (mean weight, 17.3±0.3 kg) were prepared according to the Canadian Council on Animal Care regulations. As described previously,8 9 31 the animals were sedated with an intramuscular injection of ketamine (Rogarsetic, 15 mg/kg) and azaperone (Stresnil, 3 mg/kg). They were then intubated, mechanically ventilated with medical air and O2, and anesthetized with 0.5% to 1% halothane. Intravenous heparin (100 U/kg) was given before the angioplasty procedure.
Double Arterial Injury by Angioplasty and
Experimental Groups
Carotid injury was performed with a 7F polyethylene
balloon dilation catheter (8 mmx3 cm), as previously
described.31 The balloon was
positioned under fluoroscopic control into the left and right common
carotid arteries. Five 30-second inflations were performed at a
pressure of 6 atm, with resting intervals of 60 seconds between each
inflation. Angiograms were obtained immediately before and during
dilation.
The animals were allowed to recover for 4 weeks, during which time neointimal lesions developed at injury sites. They were then subjected to a second angioplasty procedure at the previously injured sites. Approximately 15 minutes before the second angioplasty, a single intravenous bolus of vehicle (formulation buffer) or rPSGL-Ig30 (Wyeth/Genetics Institute), which has a half-life of 10 days in pigs, was administered at a dose of 1 mg/kg. The dose of rPSGL-Ig was chosen on the basis of our experience with this molecule in other animal studies and in cell-based in vitro assays. In a concentration-dependent manner, rPSGL-Ig inhibited the adhesion of thrombin-activated porcine platelets to neutrophils in a flow cytometry–based assay. The IC50 was found to be 25 µg/mL. Animals were euthanized 1 hour, 4 hours, 1 week, or 4 weeks after the second injury. Before and within 10 minutes of treatment administration, heart rate, blood pressure, hematological parameters, activated clotting time (ACT), and platelet aggregation were determined in each animal, as described previously.31
Isolation and Labeling of Neutrophils and
Platelets
Autologous blood was used for the isolation and
radiolabeling of neutrophils and platelets with
111indium-oxine
(111In) and
51chromium
(51Cr), respectively, as detailed
elsewhere.8 9 31
Briefly, a low-speed centrifuge yielded platelet-rich plasma, from
which platelets were isolated and incubated with 300 µCi of
51Cr for 30 minutes. Next, the suspension
was centrifuged to remove unbound 51Cr,
resuspended in platelet-poor plasma, and reinjected into the
animal.
Neutrophils were isolated from a leukocyte-rich suspension, obtained after red blood cell sedimentation with 4% dextran. Leukocytes were layered on Ficoll-Paque gradient and centrifuged to obtain a neutrophil-rich fraction. Next, contaminated red blood cells were lysed, and neutrophils were incubated with 250 µCi of 111In for 15 minutes. Finally, the suspension was centrifuged to remove unbound 111In, resuspended in platelet-poor plasma, and reinjected into the animal.
Quantification of Neutrophil and Platelet
Adhesion
At the end of the experiments, the carotid arteries
were fixed in situ under physiological pressure with 1 L of saline
followed by 2 L of a buffered formalin (10%) solution. The fixed
arteries were then removed and cleaned of surrounding tissue. The
dilated injured areas and the reference uninjured areas were each
divided into 4 segments. After length and internal area surface
measurements, these segments and the reference blood samples were
placed in a gamma counter equipped with a multinuclide analysis program
for 111In and
51Cr radioactivity determination. The amount
of neutrophils and platelets per square centimeter adhering to arterial
segments was calculated from the radioactivity of the segment and from
the cellular count and radioactivity of a reference blood sample,
corrected for the luminal surface of each arterial segment, as
described
previously.31 32
The results are presented as platelet and neutrophil adhesion values
from injured segments minus the adhesion on uninjured distal reference
segments.
Histopathology
Representative transverse sections from each arterial
segment were stained with hematoxylin-phloxin-safran and Movat’s
pentachrome, thereby allowing for identification of both the internal
elastic lamina (IEL) and the demarcation between the neointima and the
media, as reported
previously.33 All specimens
were evaluated microscopically for the presence of mild or deep
arterial wall injury, the latter being characterized by a breached IEL
and a lacerated media. Results from deeply injured arterial segments
are reported.
Morphometry
Sections from the injured arterial segments and the
distal (reference) segments were analyzed by computer-assisted
histomorphometry and NIH Image 1.60 imaging software. The lengths of
the external elastic lamina (EEL) and IEL were calculated. The areas
within these laminae and the area of the residual lumen were also
measured. Neointimal area was obtained by subtracting the residual
lumen area from the area within the
IEL.34 Vascular stenosis was
calculated as [(reference lumen-dilated lumen)/reference
lumen]x1003. Restenotic segments were
defined as those with vascular stenosis >50%. To minimize
animal-to-animal variations, normalized data were obtained by dividing
the measurement of the dilated injured segments by the corresponding
distal, uninjured reference segment values.
Immunohistochemistry
In the 4-week group, we showed the presence of
endothelial cells on the neointima of the arterial segments by using
peroxidase-labeled Dolichos biflorus agglutinin (DBA)
lectin.35 In
addition, we assessed the expression of P-selectin by the
neoendothelium in paraffin-embedded sections by immunostaining with an
affinity-purified polyclonal rabbit antibody to P-selectin from
Pharmingen. Using flow cytometry, we have shown that this antibody
reacts with porcine P-selectin expressed on isolated activated
platelets. The percentage of positive platelets expressing P-selectin
increases from 5% at baseline to 45% on thrombin-activated porcine
platelets.
Statistical Analysis
Results are reported as mean±SEM. Intragroup and
intergroup differences were compared by means of paired and unpaired
Student’s t tests,
respectively, and followed, when applicable, by 1-way ANOVA with
Bonferroni comparisons. A value of
P<0.05 was considered
statistically significant.
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Results |
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Animal Characteristics
Both control and rPSGL-Ig–treated animals had similar initial body weight (17.6±1.9 and 16.9±0.4 kg, respectively). Their hematological and hemodynamic parameters were within the normal range both before and after the injection of either rPSGL-Ig or the vehicle. As shown in Table 1
, which summarizes the characteristics of the
dilated arteries in each group, 1 artery was occluded in each of the
control groups at 4 hours, 1 week, and 4 weeks. No such occlusion was
noted in the arteries of treated animals. For each time point, the
number of deeply injured segments, the length of injured area, and the
percentage of fracture/IEL length were similar in control and treated
animals.
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Effect of rPSGL-Ig on Platelet and
Neutrophil Adhesion
The adhesion of platelets and neutrophils to uninjured
distal arterial segments (reference, nondilated) was low and similar
for the control and rPSGL-Ig–treated animals
(plateletsx106/cm2:
0.54±0.15 versus 0.51±0.17,
neutrophilsx103/cm2:
19.5±3.2 versus 14.1±2.8, respectively).
As shown in
Figures 1A and 2A, 1 hour after the second angioplasty,
rPSGL-Ig treatment did not significantly influence platelet and
neutrophil adhesion to the injured arteries. Four hours after
angioplasty, the adhesion of both platelets
(Figure 1A) and neutrophils
(Figure 2A) had increased significantly in the control group
but was significantly reduced by 
50% in the rPSGL-Ig–treated
animals. A significant 85% and 78% inhibition of platelet
(Figure 1B) and neutrophil
(Figure 2B) adhesion was maintained at 1 week after
angioplasty in the rPSGL-Ig–treated animals. At 4 weeks after injury,
the adhesion of platelets and neutrophils was reduced (but not
significantly) in rPSGL-Ig–treated animals as compared with
control.
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Morphometric Analyses and Restenosis
Reference distally uninjured arterial segments of
control and rPSGL-Ig–treated animals in the 4-week groups showed
similar morphometric values for areas within the EEL (7.1 versus 7.2
mm2) and IEL (5.1 versus 5.1
mm2) and the lengths of the EEL (9.6 versus
9.3 mm) and IEL (8.2 versus 8.4 mm). Because the uninjured segments had
no neointima, these were considered reference values. Similarly, the
area within the IEL in each group was considered the reference vascular
lumen.
As shown in
Table 2, the vascular lumen was significantly larger (by
63%) in rPSGL-Ig–treated arteries (6.08±0.58
mm2) as compared with control arteries
(3.84±0.06 mm2), whereas the neointima in
treated arteries (0.52±0.09 mm2) was only
26% smaller than that in control arteries (0.7±0.09
mm2). In addition, the vascular lumen was
reduced by 29% in control arteries, whereas in treated arteries it was
increased by 22%. Moreover, the lengths of the EEL and IEL and the
areas within them were also increased in rPSGL-Ig–treated arteries
when compared with control arteries.
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As shown in
Figure 3A, in both control and rPSGL-Ig–treated animals, a
negative significant correlation was obtained between vascular stenosis
and the area within EEL. In addition, although 43% of the control
arterial segments were restenotic (vascular stenosis >50%), none of
the treated arterial segments were restenotic.
Figure 3 also indicates that 52% of the arterial segments
in the control group showed inadequate compensatory enlargement
(normalized sub-EEL area <1), whereas 90% of the arterial segments in
the treated group showed adequate compensatory enlargement (normalized
sub-EEL area >1).
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When vascular stenosis is plotted against neointimal area
(Figure 3B
), a positive significant correlation was obtained
in the control group but not in the rPSGL-Ig–treated group. These
results and those of
Figure 3A suggest that in the control arteries, both
neointimal tissue formation and constrictive remodeling were
responsible for the vascular stenosis observed 4 weeks after double
angioplasty. On the other hand, it appears that rPSGL-Ig treatment
permitted positive remodeling of the arterial wall. Furthermore, this
positive remodeling probably occurs between 1 and 4 weeks after injury,
as suggested by the results shown in
Figure 4. Although the normalized values of area within the
EEL and residual lumen were similar between control and treated
arteries at 1 week, they had increased significantly at 4 weeks in the
rPSGL-Ig–treated arteries.
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Pathological Analysis and
Immunostaining
Neointima in both control and treated arteries was
characterized by various amounts of spindle-shaped cells and organized
mural thrombus in the extracellular matrix. As shown in
Figure 5, the rPSGL-Ig–treated arteries demonstrated a
dramatically increased overall vessel size and vascular lumen when
compared with the control arteries. In addition, immunostaining for the
DBA lectin indicated that complete neointimal
reendothelialization was achieved 4 weeks after injury in both control
and treated arteries. This newly formed endothelium expressed
P-selectin at almost the same level in control and treated arteries.
Endothelium of naive carotid arteries, however, did not express
P-selectin or showed few isolated positive cells (data not
shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we investigated the effects of rPSGL-Ig on platelet and neutrophil adhesion in a porcine model involving double injury by angioplasty to the carotid arteries. We also assessed the effect of such treatment on the development of restenosis. In this model, a single administration of rPSGL-Ig before the second angioplasty significantly reduced the adhesion of platelets and neutrophils during the first 4 hours after injury. This effect was maintained at 1 week after injury (Figures 1
and 2). As compared with the adhesion at 1 hour, a
sharp increase in the number of platelets
(Figure 1A) and neutrophils
(Figure 2A) adhering to and within the damaged sites of
control arteries was noted at 4 hours after injury. This finding is in
agreement with previous studies reporting concurrent accretion of
platelets and neutrophils within the first hours after
angioplasty.36 The reactions
of platelets are mostly integrin-dependent, involving the binding of
platelet glycoprotein Ia/IIa to collagen and glycoprotein IIb/IIIa to
fibrinogen, which results in shape change, release of granule contents,
and aggregation, leading to thrombus growth at the sites of arterial
injury. The adhesion of neutrophils, however, is predominantly mediated
by their binding to P-selectin expressed on adherent activated
platelets.9 18 20 21 22 37
This adhesive interaction between platelets and neutrophils promotes
mutual activation and secretion of vasoactive substances, which, in
turn, amplifies the inflammatory and thrombotic responses. Indeed, it
has been shown that platelet and neutrophil activation and binding
occur after angioplasty and are predictors of subsequent
restenosis.12 38
The blockade of selectins has been found to be beneficial in reducing
platelet-neutrophil interactions and vascular stenosis in experimental
models of
angioplasty.28 31
In this study, treatment with rPSGL-Ig, a recombinant
soluble form of PSGL-1 (the high-affinity ligand for
P-selectin),16 15 minutes
before the second angioplasty significantly reduced the adhesion of
neutrophils and platelets to deeply injured arterial surfaces out to 1
week after angioplasty
(Figures 2B and 3B). This result is consistent with rPSGL-Ig
having a long half-life of 10 days in swine and with its ability to
inhibit porcine platelet-neutrophil binding in a
concentration-dependent
manner.30
At 4 weeks after angioplasty, the level of platelet and
neutrophil adhesion to injured arteries was similar to the levels
observed 1 week after injury. By this time, these injured arteries were
completely reendothelialized in both control and rPSGL-Ig groups.
Previous reports have indicated that reendothelialization after
angioplasty in pig carotid arteries, as evaluated by
immunohistochemistry with DBA
lectin,35 can be achieved 21
days after injury.39 In our
study, treatment with rPSGL-Ig still reduced (but not significantly)
the adhesion of platelets and neutrophils to the neointima 4 weeks
after injury as compared with control. P-selectin expression was
observed on the newly formed endothelium in both control and
rPSGL-Ig–treated arteries
(Figure 5), which suggests an ongoing proinflammatory state
that continues to contribute to neutrophil and platelet adhesion. Four
weeks after a single administration of rPSGL-Ig, its plasma
concentration (around 2 µg/mL) may have been too low to efficiently
block these reactions.
The inhibitory effect of rPSGL-Ig on platelet and neutrophil accumulation at the site of injury until 1 week after injury, when reendothelialization of the injured arteries is in progress and incomplete, probably was caused by its interference with neutrophil PSGL-1 binding to platelet P-selectin. In addition, P-selectin antagonism with rPSGL-Ig in conjunction with tissue-type plasminogen activator has been shown to accelerate thrombolysis in a porcine model.30 The activity of other leukocytes, such as monocytes, which bear PSGL-1, also may be affected by rPSGL-Ig. Neutrophil and monocyte/macrophage infiltration of the damaged arterial wall release free radicals, cytokines, metalloproteinases, and growth factors, which induce smooth muscle cell migration and proliferation, leading to the amplification of restenosis.15
The early inhibition with rPSGL-Ig of platelet and
neutrophil adhesion at the site of injury was associated with a
subsequent 63% increase in vascular lumen in treated arteries as
compared with untreated arteries 4 weeks after injury
(Table 2). In fact, although 43% of control arterial
segments were restenotic (>50% stenosis), no rPSGL-Ig–treated
arteries showed restenosis
(Figure 3A). Reduced restenosis in rPSGL-Ig–treated arteries
was mainly related to positive remodeling (normalized sub-EEL area >1,
mean=1.5±0.1), resulting in an adequate compensatory enlargement of
the arterial wall. Furthermore, our results
(Figure 4) revealed that the remodeling process occurred at
least 1 week after angioplasty injury. These results are in agreement
with studies in experimental
models4 5 40
and in
humans,41 42
which have suggested that remodeling may be more important then
neointimal growth in the arterial response to
angioplasty.6 Further studies
are needed to assess more precisely the mechanism through which
rPSGL-Ig favors positive remodeling.
Conclusions
This study highlights the importance of platelet
P-selectin binding to neutrophil PSGL-1 in platelet-neutrophil
interactions at the sites of arterial injury produced by double
angioplasty in swine. It indicates, too, that selectin antagonism with
rPSGL-Ig reduced the thrombotic and inflammatory reactions and
inhibited restenosis by favoring positive remodeling of the arterial
wall, which may represent a unique mechanism of action. Our findings at
the cellular and pathophysiological levels add new insights to the
significance of platelet binding to neutrophils in thrombogenesis and
restenosis. They also provide a rationale for exploring the efficacy of
P-selectin antagonism with rPSGL-Ig in the clinical management of
restenosis.
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Acknowledgments |
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This work was supported by the Medical Research Council of Canada and the Heart and Stroke Foundation of Canada. We wish to thank Dr Martin Sirois for immunostaining and Nathalie Jacob and Dominique Lauzier for excellent technical assistance.
Received July 31, 2000; revision received September 5, 2000; accepted September 8, 2000.
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