(Circulation. 2001;103:2501.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
ß3-Integrin–Deficient Mice but Not P-Selectin–Deficient Mice Develop Intimal Hyperplasia After Vascular Injury
Correlation With Leukocyte Recruitment to Adherent Platelets 1 Hour After Injury
From the Department of Medicine (S.S.S., B.S.C.), Department of Surgery (E.D.R., W.Z.), and Department of Pathology (J.T.F., R.E.G.), Mount Sinai School of Medicine, New York, NY.
Correspondence to Barry S. Coller, MD, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. E-mail Barry.Coller{at}mssm.edu
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Abstract |
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Background—Intimal hyperplasia contributes to restenosis after percutaneous vascular interventions. Both ß3-integrins,
Vß3 and
IIbß3
(glycoprotein IIb/IIIa), and leukocytes have been
implicated in neointimal formation, based in part on the
results obtained using antagonists to 1 or both receptors
in animal models. Methods and Results—The responses in wild-type mice, ß3-integrin–deficient mice, and P-selectin–deficient mice were studied in a model of transluminal endothelial injury of the femoral artery. At 4 weeks, ß3-integrin–deficient mice were not protected from developing intimal hyperplasia, whereas P-selectin–deficient mice were protected. Within 1 hour of injury, several layers of platelets deposited on the arteries of wild-type mice and a single layer of platelets deposited on the vessels of ß3-integrin–deficient mice; in both cases, leukocytes were recruited to the platelet layer. In P-selectin–deficient mice, the platelet layer was less compact and extended further into the lumen but did not recruit leukocytes.
Conclusions—In a model of transluminal arterial injury, absence of early leukocyte recruitment and not deficiency of ß3-integrins correlated with a reduction in neointimal formation. Blockade of P-selectins may be an effective therapeutic strategy to decrease restenosis after percutaneous vascular interventions.
Key Words: cell adhesion molecules • leukocytes • platelets • receptors • restenosis
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Introduction |
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Percutaneous coronary interventions are increasingly being used to treat acute coronary syndromes, with an estimated 926 000 procedures performed in the United States in 1998.1 Despite improvements in technique, as well as the use of stents and new antiplatelet therapies, restenosis requiring repeat procedures continues to be an important complication, affecting
8% of patients at 6 months,
even with optimal treatment.2
Because intimal hyperplasia contributes to restenosis after
vascular injury,3
understanding the molecular mechanisms involved in its development is
particularly important. It is well established that platelet
deposition and leukocyte recruitment occur soon after vascular
damage,4 but their
contributions, if any, to the subsequent smooth muscle cell
proliferation and migration that result in intimal hyperplasia remain
unclear.
There is reason to hypothesize that both of the
ß3-containing integrins,
IIbß3
(glycoprotein [GP] IIb/IIIa), which is platelet
specific,5 and
Vß3, which is
present on endothelial cells and smooth muscle
cells in addition to other
cells,6 play important roles
in the development of intimal hyperplasia after vascular injury. Thus,
IIbß3 is necessary
for platelet aggregation induced by
physiological agonists, contributes to
platelet-mediated thrombin generation, and facilitates release of
platelet mediators (platelet-derived growth factor,
serotonin, and
ADP)4 7 8
that may promote smooth muscle cell proliferation and/or migration.
Similarly, a number of in vitro and in vivo studies implicate
Vß3 in smooth muscle
cell proliferation and
migration.6 9 10 11
In fact, antagonists to
Vß3 or to both
IIbß3 and
Vß3 significantly
inhibited intimal hyperplasia after vascular injury in all but 1 of a
large number of animal studies
(Table 1
). Given the wealth of theoretical and experimental
data implicating ß3-integrins in intimal
hyperplasia, we sought to determine whether
ß3-integrin null mice
(ß3-/-), which lack both
IIbß3 and
Vß3, are protected
from developing intimal hyperplasia after vascular injury. Because
leukocyte recruitment mediated by P-selectin has also been implicated
in facilitating intimal hyperplasia after vascular injury in
mice12 and, recently, in
rats,13 we also studied
P-selectin null mice (P-selectin-/-).
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Methods |
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Animals
The generation of ß3-integrin–deficient mice by homologous recombination in embryonic stem cells and their phenotype have been described previously.14 Wild-type (ß3+/+) and ß3-/- mice were descendants of F2 intercrosses and therefore had a mixed genetic background of C57Bl/6 and 129Sv strains. P-selectin–deficient mice backcrossed on the C57Bl/6 strain were obtained from Jackson Laboratories (Bar Harbor, Maine). Wild-type C57Bl/6 and 129Sv mice (Jackson Laboratories) served as controls for the effect of genetic background on the response to arterial injury. Mice were maintained on 12-hour light/12-hour dark cycles, fed standard rodent chow (5001; Purina Mills), and provided with water ad libitum. All procedures conformed to the recommendations of the Guide for the Care and Use of Laboratory Animals (Department of Health, Education, and Welfare publication number NIH 78-23, 1996) and were approved by the Mount Sinai Institutional Animal Care and Use Committee.
Arterial Injury
Male mice aged 8 to 10 weeks were
anesthetized with inhaled isoflurane, and wire injury of the
femoral artery was performed as described
previously.15 16
In brief, the femoral vessels were exposed by a longitudinal groin
incision and viewed with the aid of a surgical microscope (Carl Zeiss).
The distal portion of the femoral artery was encircled with an 8-0
nylon suture, a vascular clamp was placed proximally at the level of
the inguinal ligament, and a 0.010-in (0.25-mm) diameter angioplasty
guidewire (Advanced Cardiovascular Systems) was
introduced into the arterial lumen through an arteriotomy
made just distal to the suture. After release of the clamp, the
guidewire was advanced to the level of the aortic bifurcation and
immediately pulled back; this process was repeated 2 additional times
to denude the endothelium. The guidewire was then
removed, and the arteriotomy site was ligated by tying the previously
placed suture. In a previous
study,15 we demonstrated
that sham-operated mice that undergo all maneuvers (dissection,
vascular clamping, arteriotomy, and ligation) except passage of the
guidewire display no evidence of damage to the vessel wall and no
vascular reaction. The injury results in >99%
endothelial denudation, as judged by morphological and
immunohistochemical analysis with antibodies to von
Willebrand factor15
and intercellular adhesion molecule-1 (data not shown), and <2%
laceration of the internal elastic lamina (IEL).
Histology and Morphometry
Mice were killed 1 hour or 4 weeks after injury by
perfusion fixation with 4% paraformaldehyde in PBS, pH
7.4 at 100 mm Hg for 5 minutes, administered via a cannula
inserted in the left ventricle. Hindlimbs were excised en bloc, fixed
in 4% paraformaldehyde in PBS for 24 hours, and
decalcified in 10% formic acid overnight. Each limb was cut
transversely, dividing the common femoral artery into 2 segments, each
of which was 2 mm in length. Each segment was embedded in
paraffin. Sections (5 µm) were obtained for staining or
immunohistochemistry. Combined Mason-elastic stain was used for
measurements of the arterial wall layers. Sections were
analyzed by computerized morphometry and the different regions
of the vessel quantified with Image Pro Plus software. Measurements of
luminal area, area inside the IEL, and area beneath the external
elastic lamina were made on each section. Intimal area was calculated
by subtracting luminal area from the area inside the IEL; medial area
was calculated by subtracting the area inside the IEL from the area
inside the external elastic lamina. Results from the 2 segments of each
artery were averaged.
For immunohistochemical analysis, sections were deparaffinized, rinsed in xylene, rehydrated, and then blocked first with 3% hydrogen peroxide and then with 2% ovalbumin in PBS. The sections were incubated at 37°C with primary antibodies, followed by biotin-conjugated secondary antibodies (Biogenics). Staining was detected by reaction with horseradish peroxidase–streptavidin and diaminobenzidine; sections were counterstained with hematoxylin. Rabbit polyclonal anti-mouse platelet antibody was from Inner Cell Technologies; polyclonal anti–P-selectin antibody was from Pharmingen; polyclonal anti–von Willebrand factor antibody was from Dako; and polyclonal anti-fibrinogen antibody was from Behring.
Electron Microscopy
Animals (ß3+/+, n=4;
ß3-/-, n=4; P-selectin-/-, n=2;
C57Bl/6, n=2) underwent the standard vascular injury procedure and were
euthanized by perfusion fixation. With the aid of the surgical
microscope, a segment of the common femoral artery (from the takeoff of
the epigastric artery to the inguinal ligament) was dissected. The
isolated artery was immersed in 2%
paraformaldehyde/2.5% glutaraldehyde
in 0.1 mol/L cacodylate buffer and, after fixation, transected in the
center; 2-µm cross sections for transmission electron microscopy
(TEM) were obtained and then the remaining halves of the artery were
cut longitudinally to expose the lumen for scanning electron microscopy
(SEM). For TEM, the arteries were dehydrated in graded alcohols,
embedded in EMbed 812 (Electron Microscopy Sciences), and thin
sectioned. The sections were stained with uranyl acetate and lead
citrate and then viewed with a JEM 100 CX microscope (JEOL Ltd). For
SEM, the longitudinal sections were critical-point dried, mounted in
silver paint, coated with gold-palladium, and examined in a Hitachi
S350 microscope. For statistical analysis, a blinded
investigator selected 8 representative images of
platelet thrombi from each of 4 separate arteries per group. The
number of granules and platelets per micrometer of IEL
was obtained from digitized images.
Statistical Analysis
Results are expressed as mean±SD, unless otherwise
indicated. Comparisons were made between C57/129 wild-type and
ß3-/- mice and between C57Bl/6 wild-type
and P-selectin-/- mice by Mann-Whitney
U
test.
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Results |
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Early Platelet Deposition and Leukocyte Recruitment After Endothelial Denudation of the Femoral Artery
One hour after guidewire-induced endothelial denudation of the femoral arteries of wild-type C57Bl/6 and mixed C57/129Sv mice, platelets were found adherent to the blood vessel wall and leukocytes were found to adhere to the platelets (Figures 1
and 2). Platelets were identified by both TEM
and SEM. The platelet layer varied between 1 and 3 platelets
thick when viewed by TEM
(Figure 1A), and many of the platelets in contact with
the vessel were spread and at least partially degranulated. SEM
observations were consistent with the TEM data, with
platelets forming a nearly con-tinuous layer
(Figure 1B); in only a few areas, platelet thrombus
formation extended from the surface into the lumen.
Immunohistochemistry also demonstrated a platelet layer, with
positive reactions with polyclonal antibodies to whole mouse
platelets
(Figure 2C), as well as platelet-associated proteins
(P-selectin, fibrinogen, and von Willebrand factor; data not
shown). Leukocytes were readily identified attached to the luminal
surface of the adherent platelets by both electron microscopy
(Figure 1A and 1B)
and light microscopy
(Figure 2A).
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In ß3-null animals, the
platelet layer appeared to be restricted to only a monolayer of
platelets, many of which were extensively spread along the surface,
with few platelet-platelet interactions
(Figure 1C
through
1E).
Leukocytes were readily observed attached to the platelets, however
(Figures 1C, 1E, and 2B),
and there was no significant difference in the number of leukocytes
attached to platelets in the ß3-/-
mice compared with the wild-type mice
(Figure 2A versus
2B;
60±20% of the circumference of the ß3+/+
arteries versus 60±30% of the ß3-/-
arteries had attached leukocytes).
One hour after vascular injury to the femoral arteries of
P-selectin-/- mice, TEM revealed a platelet layer several
platelets thick that extended from the surface of the blood vessel
(Figure 3A through
3C;
Table 2). In contrast to the results with wild-type mice,
the platelet layer appeared less compact, and more of the
platelets retained their granules
(Figure 3A through
3C;
Table 2). By SEM, the platelets in the
P-selectin-/- mice
(Figure 3D and 3E)
appeared to extend further out from the vessel surface than did
platelets in the wild-type mice
(Figure 1B;
Table 2). In sharp contrast to the results with wild-type
and ß3-/- mice, there was a striking
decrease in leukocyte attachment to the platelets of
P-selectin-/- mice
(Figure 2D; 50±30% of the circumference of the C57B/l6
wild-type arteries had attached leukocytes versus <5% of the
circumference of P-selectin-/- arteries).
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Intimal Hyperplasia at 4 Weeks
Because strain differences have been reported to affect
neointimal development in response to vascular injury in
other
models,17 18 19
we studied separately wild-type C57Bl/6, wild-type 129Sv, and mixed
C57/129Sv mice. In accord with results published by others, we found
that the wild-type 129Sv mice had the most pronounced intimal
hyperplasia, the C57Bl/6 mice the least, and the mixed strain an
intermediate amount
(Table 3). The ß3-/-
mice are of mixed lineage, and so they were compared with the
mixed-lineage wild-type mice. The P-selectin-/- mice have a C57Bl/6
background, and so they were compared with the wild-type C57Bl/6
mice.
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The wild-type mixed C57/129Sv ß3+/+
and ß3-/- mice demonstrated similar levels
of neointimal growth as judged by neointimal
area, intima/media ratios, and residual luminal area
(Figure 4). In sharp contrast, the P-selectin-/- mice had
significantly less neointimal growth than the wild-type
C57Bl/6 mice (P=0.075 for
intimal area, P=0.003 for
intima/media ratio, and P=0.052
for luminal area;
Figure 4).
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Discussion |
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Using a model of transluminal endothelial injury designed to simulate the vascular injury induced by percutaneous coronary interventions in humans, we observed that ß3-integrin–deficient mice were not protected from developing intimal hyperplasia. In sharp contrast, and in accord with studies using different forms of vascular injury,12 13 P-selectin–deficient mice were protected from developing intimal hyperplasia. Our findings in the ß3-/- mice stand in stark contrast to a large body of data indicating that antagonists of integrin
Vß3 (and, in some
cases, IIbß3) reduce
intimal hyperplasia after vascular injury in other animal models
(Table 1). A number of factors may account for the
apparent discrepancy between our results and those obtained using
inhibitors to
Vß3 (and, in some
cases, IIbß3).
First, differences in animal species and/or technical features of the
models may influence the contribution of
ß3-integrins to intimal hyperplasia. Previous
models have involved balloon catheter injury induced in rabbits, rats,
and guinea pigs; catheter injury in hamsters; stent implantation in
pigs, monkeys, and baboons; and arterial cuff injury in
rabbits
(Table 1). In contrast to these models, our model utilizes
mice and involves a combination of guidewire-induced
endothelial denudation and arterial
ligation; the latter maneuver, which is known to enhance or produce
intimal hyperplasia in other
models,20 was not used in
the previous studies using antagonist to
Vß3. Nonetheless,
the protection from intimal hyperplasia we observed with the
P-selectin-/- mice is very similar to that obtained both in a mouse
model utilizing arterial ligation to initiate vascular
injury12 and in a rat model
involving balloon catheter
injury.13 Second, loss of
Vß3 on a genetic
basis may result in compensatory increases in the number and/or
affinity of other adhesion receptors, whereas such compensation
probably cannot occur with acute inhibition of
Vß3. For example, we
previously demonstrated that Glanzmann thrombasthenia patients with
abnormalities in IIb had increased numbers of
platelet Vß3
receptors.21 In addition, in
contrast to the effect of inhibiting an integrin receptor, the absence
of the receptor may affect signaling mediated by other integrins by
virtue of decreased binding of intracellular proteins involved in
signaling that ordinarily bind to the cytoplasmic domain of the missing
integrin.22 Finally, as
opposed to inhibiting the
Vß3 receptor, its
absence in ß3-/- mice may result in the
loss of transduction of signals initiated by
Vß3; such signals
may be initiated by the unliganded receptor, the liganded receptor, or
the antagonized receptor.
In sharp contrast to the failure of
ß3-integrin deficiency to protect against the
development of intimal hyperplasia after vascular injury, P-selectin
deficiency offered dramatic protection. Because this protection
correlated with nearly complete absence of leukocyte recruitment to the
platelets lining the vessel 1 hour after injury, it is possible
that leukocyte recruitment is a crucial element in the development of
intimal hyperplasia. However, the platelets that deposited on the
damaged blood vessel wall of the P-selectin-/- mice were less
compact and retained more of their granular contents than the
platelets that deposited on the blood vessel surface of wild-type
mice, which suggests that the platelets may be less
activated. Our observations on platelet thrombus formation
in P-selectin-/- mice are consistent with several other
observations that indicate that P-selectin plays an important role in
platelet function. Thus, P-selectin-/- mice have prolonged
bleeding times,23 and
P-selectin has been implicated in contributing to both
platelet-platelet interactions in
vitro24 and fibrin thrombus
formation in vivo.25
Moreover, Ruggeri et al26
presented evidence that platelet thrombi formed from
P-selectin-/- mice on collagen-coated surfaces ex vivo under shear
are taller and thinner than thrombi formed from wild-type mice. These
results are very similar to our in vivo data. Recently, P-selectin
glycoprotein ligand-1 (PSGL-1) was detected on
platelets,27 and the
platelet GP Ib/IX/V complex has been identified as a
counterreceptor for endothelial
P-selectin,28 which raises
the possibility that activated platelets expressing
P-selectin can interact with activated and unactivated
platelets via GP Ib/IX/V and/or PSGL-1. Such interactions may
contribute to platelet accumulation, platelet activation, and
platelet thrombus formation. Thus, it remains possible that at
least some of the protection from the development of intimal
hyperplasia in P-selectin-/- mice reflects abnormalities in
platelet function rather than abnormal leukocyte recruitment.
Nonetheless, a correlation between early leukocyte recruitment and
subsequent development of intimal hyperplasia has previously been
observed by several investigators using other
species,29 30 31 32 33
and studies by Simon et al34
recently demonstrated that
Mß2-deficient mice
(Mac1-/-) were protected from developing intimal hyperplasia after
vascular injury. There are a number of plausible links between
leukocyte recruitment and subsequent development of intimal
hyperplasia,31 including
direct involvement of macrophages and activation of smooth
muscle cells by leukocyte
elastase,10 but
causality between these phenomena and the mechanisms responsible remain
to be established.
Immunohistochemical analysis revealed that
platelets were deposited along the vessels in both wild-type and
ß3-integrin–deficient mice, and TEM
demonstrated a single layer of platelets in the
ß3-/- mice, which indicates that
platelet adhesion but not platelet-platelet interactions
occur in the absence of
IIbß3, presumably
via receptors such as GP Ib. ß3-/- mice
recruited leukocytes to the platelets adherent to the site of
vascular injury at 1 hour, but P-selectin-/- mice did not. Several
receptor pairs have been implicated in platelet-leukocyte
interactions4 : P-selectin on
the surface of activated platelets and its leukocyte
counterreceptor PSGL-1; platelet GP Ib and leukocyte
Mß2; platelet
intercellular adhesion molecule-2 and leukocyte
Lß2; platelet
IIbß3 and/or
Vß3 bridged by
fibrinogen to leukocyte
Mß2; and
platelet and leukocyte CD36 (GP IV) bridged by thrombospondin-1.
Our results indicate that neither
IIbß3 nor
Vß3 is necessary for
murine platelet-leukocyte interactions but that P-selectin
expression is required. In unpublished studies, we have confirmed that
as in humans, murine platelet P-selectin plays a major role in
platelet-leukocyte interactions, because antibodies to P-selectin
inhibit the binding of murine neutrophils to thrombin-activated
murine platelets in vitro (V. Evangelista, MD, S.S. Smyth, MD, PhD,
and B.S. Coller, MD, unpublished data, 1999).
In summary, the present study provides evidence that
ß3-integrin deficiency results in decreased
platelet deposition but no protection from intimal hyperplasia,
whereas P-selectin deficiency protects against the development of
intimal hyperplasia. Because antagonists of
IIbß3 have
demonstrated efficacy in preventing acute ischemic
complications of percutaneous coronary
interventions,35 our data
are of potential therapeutic importance, raising the possibility that
the addition of an antagonist to P-selectin may provide
additional protection against intimal hyperplasia and clinical
restenosis.
Note Added in Proof
After acceptance of this manuscript, Chico et al
(Circulation.
2001;103:1135–1141) reported that antagonists to
IIbß3,
Vß3, or both
IIbß3 and
Vß3 prevented
neointima formation after porcine coronary artery angioplasty when
administered for 14 days.
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Acknowledgments |
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This work was supported in part by grants 19278 and 54469 from the National Heart, Lung, and Blood Institute to Dr Coller.
Received October 25, 2000; revision received December 31, 2000; accepted January 10, 2001.
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 B. S. Coller and S. J. Shattil The GPIIb/IIIa (integrin {alpha}IIb{beta}3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend Blood, October 15, 2008; 112(8): 3011 - 3025. [Abstract] [Full Text] [PDF]
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 M. Panchatcharam, S. Miriyala, F. Yang, M. Rojas, C. End, C. Vallant, A. Dong, K. Lynch, J. Chun, A. J. Morris, et al. Lysophosphatidic Acid Receptors 1 and 2 Play Roles in Regulation of Vascular Injury Responses but Not Blood Pressure Circ. Res., September 12, 2008; 103(6): 662 - 670. [Abstract] [Full Text] [PDF]
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A. P. Reiner, C. S. Carlson, B. Thyagarajan, M. J. Rieder, J. F. Polak, D. S. Siscovick, D. A. Nickerson, D. R. Jacobs Jr, and M. D. Gross Soluble P-Selectin, SELP Polymorphisms, and Atherosclerotic Risk in European-American and African-African Young Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1549 - 1555. [Abstract] [Full Text] [PDF]
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 P. W. Bedard, V. Clerin, N. Sushkova, B. Tchernychev, T. Antrilli, C. Resmini, J. C. Keith Jr., J. K. Hennan, N. Kaila, S. DeBernardo, et al. Characterization of the Novel P-Selectin Inhibitor PSI-697 [2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h] Quinoline-4-carboxylic acid] in Vitro and in Rodent Models of Vascular Inflammation and Thrombosis J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 497 - 506. [Abstract] [Full Text] [PDF]
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G. Li, A. C. Keenan, J. C. Young, M. J. Hall, Z. Pamuklar, E. M. Ohman, S. R. Steinhubl, and S. S. Smyth Effects of Unfractionated Heparin and Glycoprotein IIb/IIIa Antagonists Versus Bivalirdin on Myeloperoxidase Release From Neutrophils Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1850 - 1856. [Abstract] [Full Text] [PDF]
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 T. Palmerini, A. Marzocchi, C. Marrozzini, L. B. Reggiani, C. Savini, G. Marinelli, R. Di Bartolomeo, and A. Branzi Preoperative C-reactive protein levels predict 9-month mortality after coronary artery bypass grafting surgery for the treatment of left main coronary artery stenosis Eur. J. Cardiothorac. Surg., April 1, 2007; 31(4): 685 - 690. [Abstract] [Full Text] [PDF]
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P. Liu, S. Patil, M. Rojas, A. M. Fong, S. S. Smyth, and D. D. Patel CX3CR1 Deficiency Confers Protection From Intimal Hyperplasia After Arterial Injury Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 2056 - 2062. [Abstract] [Full Text] [PDF]
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 G. Brevetti, V. Schiano, and M. Chiariello Cellular adhesion molecules and peripheral arterial disease Vascular Medicine, February 1, 2006; 11(1): 39 - 47. [Abstract] [PDF]
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 P. L. Gross, B. C. Furie, G. Merrill-Skoloff, J. Chou, and B. Furie Leukocyte-versus microparticle-mediated tissue factor transfer during arteriolar thrombus development J. Leukoc. Biol., December 1, 2005; 78(6): 1318 - 1326. [Abstract] [Full Text] [PDF]
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 G. Li, J. M. Sanders, E. T. Phan, K. Ley, and I. J. Sarembock Arterial Macrophages and Regenerating Endothelial Cells Express P-Selectin in Atherosclerosis-Prone Apolipoprotein E-Deficient Mice Am. J. Pathol., December 1, 2005; 167(6): 1511 - 1518. [Abstract] [Full Text] [PDF]
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 Y. Wang, M. Sakuma, Z. Chen, V. Ustinov, C. Shi, K. Croce, A. C. Zago, J. Lopez, P. Andre, E. Plow, et al. Leukocyte Engagement of Platelet Glycoprotein Ib{alpha} via the Integrin Mac-1 Is Critical for the Biological Response to Vascular Injury Circulation, November 8, 2005; 112(19): 2993 - 3000. [Abstract] [Full Text] [PDF]
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T. Palmerini, A. Marzocchi, C. Marrozzini, P. Ortolani, F. Saia, L. Bacchi-Reggiani, S. Virzi, S. Gianstefani, and A. Branzi Preprocedural Levels of C-Reactive Protein and Leukocyte Counts Predict 9-Month Mortality After Coronary Angioplasty for the Treatment of Unprotected Left Main Coronary Artery Stenosis Circulation, October 11, 2005; 112(15): 2332 - 2338. [Abstract] [Full Text] [PDF]
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O. Safa, C. T. Esmon, and N. L. Esmon Inhibition of APC anticoagulant activity on oxidized phospholipid by anti-{beta}2-glycoprotein I monoclonal antibodies Blood, September 1, 2005; 106(5): 1629 - 1635. [Abstract] [Full Text] [PDF]
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 S. Yokoyama, H. Ikeda, N. Haramaki, H. Yasukawa, T. Murohara, and T. Imaizumi Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1280 - 1286. [Abstract] [Full Text] [PDF]
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 B. Butler and S. D. Blystone Tyrosine Phosphorylation of {beta}3 Integrin Provides a Binding Site for Pyk2 J. Biol. Chem., April 15, 2005; 280(15): 14556 - 14562. [Abstract] [Full Text] [PDF]
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B. S. Coller Leukocytosis and Ischemic Vascular Disease Morbidity and Mortality: Is It Time to Intervene? Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 658 - 670. [Abstract] [Full Text] [PDF]
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A. S. Weyrich, M. M. Denis, J. R. Kuhlmann-Eyre, E. D. Spencer, D. A. Dixon, G. K. Marathe, T. M. McIntyre, G. A. Zimmerman, and S. M. Prescott Dipyridamole Selectively Inhibits Inflammatory Gene Expression in Platelet-Monocyte Aggregates Circulation, February 8, 2005; 111(5): 633 - 642. [Abstract] [Full Text] [PDF]
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A. Schober, A. Zernecke, E. A. Liehn, P. von Hundelshausen, S. Knarren, W. A. Kuziel, and C. Weber Crucial Role of the CCL2/CCR2 Axis in Neointimal Hyperplasia After Arterial Injury in Hyperlipidemic Mice Involves Early Monocyte Recruitment and CCL2 Presentation on Platelets Circ. Res., November 26, 2004; 95(11): 1125 - 1133. [Abstract] [Full Text] [PDF]
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 Z. Chen, J. F. Keaney Jr., E. Schulz, B. Levison, L. Shan, M. Sakuma, X. Zhang, C. Shi, S. L. Hazen, and D. I. Simon Decreased neointimal formation in Nox2-deficient mice reveals a direct role for NADPH oxidase in the response to arterial injury PNAS, August 31, 2004; 101(35): 13014 - 13019. [Abstract] [Full Text] [PDF]
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D. Manka, S. B. Forlow, J. M. Sanders, D. Hurwitz, D. K. Bennett, S. A. Green, K. Ley, and I. J. Sarembock Critical Role of Platelet P-Selectin in the Response to Arterial Injury in Apolipoprotein-E-Deficient Mice Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1124 - 1129. [Abstract] [Full Text] [PDF]
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Z. Chen, M. Sakuma, A. C. Zago, X. Zhang, C. Shi, L. Leng, Y. Mizue, R. Bucala, and D. I. Simon Evidence for a Role of Macrophage Migration Inhibitory Factor in Vascular Disease Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 709 - 714. [Abstract] [Full Text] [PDF]
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E. T. Choi, M. F. Khan, J. E. Leidenfrost, E. T. Collins, K. P. Boc, B. R. Villa, D. V. Novack, W. C. Parks, and D. R. Abendschein {beta}3-Integrin Mediates Smooth Muscle Cell Accumulation in Neointima After Carotid Ligation in Mice Circulation, March 30, 2004; 109(12): 1564 - 1569. [Abstract] [Full Text] [PDF]
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A. Schober, J. Bernhagen, M. Thiele, U. Zeiffer, S. Knarren, M. Roller, R. Bucala, and C. Weber Stabilization of Atherosclerotic Plaques by Blockade of Macrophage Migration Inhibitory Factor After Vascular Injury in Apolipoprotein E-Deficient Mice Circulation, January 27, 2004; 109(3): 380 - 385. [Abstract] [Full Text] [PDF]
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 M. Sajid, R. Zhao, A. Pathak, S. S. Smyth, and G. A. Stouffer {alpha}v{beta}3-Integrin antagonists inhibit thrombin-induced proliferation and focal adhesion formation in smooth muscle cells Am J Physiol Cell Physiol, November 1, 2003; 285(5): C1330 - C1338. [Abstract] [Full Text] [PDF]
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A. M. Taylor and C. A. McNamara Regulation of Vascular Smooth Muscle Cell Growth: Targeting the Final Common Pathway Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1717 - 1720. [Full Text] [PDF]
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H. Koyama, T. Maeno, S. Fukumoto, T. Shoji, T. Yamane, H. Yokoyama, M. Emoto, T. Shoji, H. Tahara, M. Inaba, et al. Platelet P-Selectin Expression Is Associated With Atherosclerotic Wall Thickness in Carotid Artery in Humans Circulation, August 5, 2003; 108(5): 524 - 529. [Abstract] [Full Text] [PDF]
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S. Weng, L. Zemany, K. N. Standley, D. V. Novack, M. La Regina, C. Bernal-Mizrachi, T. Coleman, and C. F. Semenkovich {beta}3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice PNAS, May 27, 2003; 100(11): 6730 - 6735. [Abstract] [Full Text] [PDF]
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J. W. Phillips, K. G. Barringhaus, J. M. Sanders, S. E. Hesselbacher, A. C. Czarnik, D. Manka, D. Vestweber, K. Ley, and I. J. Sarembock Single Injection of P-Selectin or P-Selectin Glycoprotein Ligand-1 Monoclonal Antibody Blocks Neointima Formation After Arterial Injury in Apolipoprotein E-Deficient Mice Circulation, May 6, 2003; 107(17): 2244 - 2249. [Abstract] [Full Text] [PDF]
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P. C. Burger and D. D. Wagner Platelet P-selectin facilitates atherosclerotic lesion development Blood, April 1, 2003; 101(7): 2661 - 2666. [Abstract] [Full Text] [PDF]
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M. Sajid, K. V. Vijayan, S. Souza, and P. F. Bray PlA Polymorphism of Integrin {beta}3 Differentially Modulates Cellular Migration on Extracellular Matrix Proteins Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1984 - 1989. [Abstract] [Full Text] [PDF]
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R. Kraemer Reduced Apoptosis and Increased Lesion Development in the Flow-Restricted Carotid Artery of p75NTR-Null Mutant Mice Circ. Res., September 20, 2002; 91(6): 494 - 500. [Abstract] [Full Text] [PDF]
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A. S. Weyrich, S. M. Prescott, and G. A. Zimmerman Platelets, Endothelial Cells, Inflammatory Chemokines, and Restenosis: Complex Signaling in the Vascular Play Book Circulation, September 17, 2002; 106(12): 1433 - 1435. [Full Text] [PDF]
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A. Schober, D. Manka, P. von Hundelshausen, Y. Huo, P. Hanrath, I. J. Sarembock, K. Ley, and C. Weber Deposition of Platelet RANTES Triggering Monocyte Recruitment Requires P-Selectin and Is Involved in Neointima Formation After Arterial Injury Circulation, September 17, 2002; 106(12): 1523 - 1529. [Abstract] [Full Text] [PDF]
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C. Kupatt, R. Wichels, J. Horstkotte, F. Krombach, H. Habazettl, and P. Boekstegers Molecular mechanisms of platelet-mediated leukocyte recruitment during myocardial reperfusion J. Leukoc. Biol., September 1, 2002; 72(3): 455 - 461. [Abstract] [Full Text] [PDF]
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T. Palmerini, M. A. Nedelman, L. E. Scudder, M. T. Nakada, R. E. Jordan, S. Smyth, R. E. Gordon, J. T. Fallon, and B. S. Coller Effects of abciximab on the acute pathology of blood vessels after arterial stenting in nonhuman primates J. Am. Coll. Cardiol., July 17, 2002; 40(2): 360 - 366. [Abstract] [Full Text] [PDF]
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M. Roque, W. J.H. Kim, M. Gazdoin, A. Malik, E. D. Reis, J. T. Fallon, J. J. Badimon, I. F. Charo, and M. B. Taubman CCR2 Deficiency Decreases Intimal Hyperplasia After Arterial Injury Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 554 - 559. [Abstract] [Full Text] [PDF]
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H. Konishi, Y. Katoh, N. Takaya, Y. Kashiwakura, S. Itoh, C. Ra, and H. Daida Platelets Activated by Collagen Through Immunoreceptor Tyrosine-Based Activation Motif Play Pivotal Role in Initiation and Generation of Neointimal Hyperplasia After Vascular Injury Circulation, February 26, 2002; 105(8): 912 - 916. [Abstract] [Full Text] [PDF]
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G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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M. Roque, W. J.H. Kim, M. Gazdoin, A. Malik, E. D. Reis, J. T. Fallon, J. J. Badimon, I. F. Charo, and M. B. Taubman CCR2 Deficiency Decreases Intimal Hyperplasia After Arterial Injury Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 554 - 559. [Abstract] [Full Text] [PDF]
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