(Circulation. 2001;103:1164.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Induction of Rapid Atherogenesis by Perivascular Carotid Collar Placement in Apolipoprotein E–Deficient and Low-Density Lipoprotein Receptor–Deficient Mice
From the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, Leiden, The Netherlands (J.H.v.d.T., T.J.C.v.B., E.A.L.B.); and the Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands (J.H.v.d.T.).
Correspondence to Jan H. von der Thüsen, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, Wassenaarseweg 72, PO Box 9503, 2300 RA Leiden, The Netherlands. E-mail thuesen{at}lacdr.leidenuniv.nl
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Abstract |
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Background—Perivascular collar placement has been used as a means for localized atherosclerosis induction in a variety of experimental animal species. In mice, however, atherosclerosis-like lesions have thus far not been obtained by this method. The aim of this study was the development of a mouse model of rapid, site-controlled atherogenesis.
Methods and Results—Silastic collars were placed around the carotid arteries of apolipoprotein E–deficient (apoE-/-) and LDL receptor–deficient (LDLr-/-) mice. The development of collar-induced lesions was found to occur predominantly in the area proximal to the collar and to be dependent on a high-cholesterol diet. Lesions were evident in apoE-/- mice after 3 weeks and in LDLr-/- mice after 6 weeks and were overtly atherosclerotic in appearance. Lumen stenosis reached 85% in apoE-/- mice and 61% in LDLr-/- mice 6 weeks after collar insertion. Expression levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were increased both proximal and distal to the collar, whereas endothelial nitric oxide synthase expression was downregulated at the proximal site.
Conclusions—We propose that this model of collar-induced acceleration of carotid atherogenesis is of hemodynamic cause. It may serve as a substrate for sequential mechanistic studies concerned with the underlying cause and pathogenesis of atherosclerosis. The rapidity of lesion development will also aid the efficient screening of new potentially antiatherogenic chemical entities and the evaluation of therapies with limited duration of effectiveness, such as adenoviral gene therapy.
Key Words: atherosclerosis • carotid arteries • cell adhesion molecules • hemodynamics
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Atherosclerosis is a common and complex pathological process characterized by intimal foam cell accumulation and extracellular matrix deposition in medium and large-sized arteries.1 In the pursuit of a representative, reproducible, and practical model for this disease, several animal species and atherogenic stimuli have been used. Systemic approaches have included diet-induced hypercholesterolemia2 and genetically modified mouse models, including LDL receptor knock-out (LDLr-/-),3 apolipoprotein E knockout (apoE-/-),4 and apolipoprotein E3-Leiden transgenic5 strains. Local lesion induction has been achieved by transluminal (eg, wire denudation)6 or extravascular (eg, perivascular collar placement)7 arterial manipulation. Perivascular collar placement offers the advantage of maintaining the structural integrity of the endothelium while inducing rapid, site-controlled lesion formation. The neointima in perivascular collar models tends to occur within the collar and is generally fibroproliferative in appearance, with limited foam cell formation and extracellular lipid deposition.8 9 Cholesterol feeding10 or local (oxidized) LDL application11 in conjunction with the placement of a perivascular Silastic collar have been shown to promote the development of more atherosclerosis-like lesions in the rabbit carotid artery. The underlying mechanism, however, appears to remain in essence fibroproliferative, and it could, therefore, be valuable to study the effect of perivascular collar placement in animals that are more susceptible to spontaneous and humanlike atherogenesis. The aforementioned transgenic mouse models are eminently suited to this purpose because they are predisposed to developing severe atherosclerotic lesions, particularly when fed a high-fat diet.
The aim of this study was to evaluate the intimal response of the carotid artery to Silastic collar placement in apoE-/- and LDLr-/- mice, which are known to spontaneously develop extensive and complex atherosclerotic lesions. On an atherogenic diet, LDLr-/- mice have relatively fibroproliferative intimal lesions at sites of hemodynamic predilection,3 whereas lesions in apoE-/- mice are more heterogeneous and lipid-rich, even when a regular chow diet is given.4 We hypothesized that the flow disturbance caused by the placement of a mildly constrictive perivascular collar could result in site-controlled atherogenesis in these mouse strains; therefore, we applied such collars to the midsection of the common carotid artery, an easily accessible site of low natural occurrence of atherosclerosis. The extent as well as the composition of the lesions thus obtained was assessed to identify any potential differences in lesion development between the strains, thereby validating their relative value as a substrate for focal induction of atherogenesis. In addition, we used immunohistochemistry to determine endothelial integrity (von Willebrand factor [vWF]) and the expression levels of endothelial cell nitric oxide synthase (eNOS) and two endothelial adhesion molecules that are known to be involved in the development of atherosclerosis in humans (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 [ICAM-1 and VCAM-1]) to further elucidate the underlying mechanisms of lesion formation in this model.
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Methods |
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Animals
All animal work was approved by the regulatory authority of Leiden University and carried out in compliance with Dutch government guidelines. Male LDLr-/- and apoE-/- mice were acquired from TNO-PG and were 10 to 12 weeks old at the time of entry into the study. Unless otherwise stated, the animals received a Western-type diet (0.25% cholesterol and 15% cocoa butter, Hope Farms) 2 weeks before surgery. Diet and water were provided ad libitum.
Carotid Collar Placement
Collars were prepared from Silastic tubing (Dow
Corning) and stored in 70% ethanol until further use. An inside
diameter of 0.5 mm was nonconstrictive, whereas an inside diameter of
0.3 mm resulted in a stenosis of 
30% because the average outside
diameter of the common carotid at 80 mm Hg perfusion pressure was 0.36
mm. Mice were anesthetized by subcutaneous injection of ketamine (75
mg/kg, Eurovet), droperidol (1 mg/kg), fluanisone (0.75 mg/kg), and
fentanyl (0.04 mg/kg) (all from Janssen-Cilag). Access to the anterior
cervical triangles was gained through a sagittal anterior neck
incision. Both carotid sheaths were opened, and the common carotid
arteries were dissected free from the surrounding connective tissue,
avoiding damage to the vagus nerves and the carotid bodies. In the
sham-operated animals, the neck wound was closed in one layer with
interrupted silk sutures at this point (6-0, Braun). In the remaining
animals, collars were placed bilaterally around the common carotid
arteries, and their axial edges were approximated by placement of 3
circumferential silk ties
(Figure 1
). Subsequently, the entry wound was closed and the
animals were returned to their cage for recovery from
anesthesia.
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Tissue Harvesting and Preparation
One to 18 weeks after collar placement, the
animals were anesthetized and exsanguinated by femoral artery
transection. In situ perfusion fixation through the left cardiac
ventricle was performed by PBS instillation for 15 minutes, followed by
constant-pressure infusion (at 80 mm Hg) of 10% neutral buffered
formalin (Shandon Inc) for 30 minutes. Subsequently, both carotid
bifurcations and common carotid arteries were removed. Formalin
fixation was omitted for arteries that were to be stained for vWF;
these were immediately snap-frozen in liquid nitrogen after having been
embedded in OCT compound (Tissue-Tek; Sakura Finetek), whereas the
remaining arteries were left in 10% formalin overnight before
freezing. The specimens were stored at -20°C until further use.
Transverse 5-µm cryosections were prepared in a proximal direction
from the carotid bifurcation and mounted in order on a parallel series
of slides.
Histology and Immunohistochemistry
Cryosections were routinely stained with
hematoxylin (Sigma Diagnostics) and eosin (Merck Diagnostica) and with
oil red O (Sigma Diagnostics) for lipid visualization. Corresponding
sections on separate slides were stained immunohistochemically with
antibodies against a macrophage-specific antigen (MOMA-2, polyclonal
rat IgG2b, diluted 1:10; Research Diagnostics
Inc), 
–smooth muscle cell actin (monoclonal mouse
IgG2a (clone 1A4), dilution 1:500; Sigma),
ICAM-1 (monoclonal rat IgG2a (clone BSA2),
dilution 1:200; R&D Systems), VCAM-1 (monoclonal rat
IgG2a (clone 429), dilution 1:100; Pharmingen),
eNOS (monoclonal rat IgG1 (clone 3), dilution
1:20; Transduction Laboratories), and vWF (peroxidase-conjugated
polyclonal rabbit Ig, dilution 1:100; Dako). The slides were incubated
with primary antibody for 2 hours at room temperature, except for
anti–VCAM-1 (4°C overnight). Goat anti-mouse IgG peroxidase
conjugate (dilution 1:100 and 1:500; Nordic) and goat anti-rat IgG
alkaline phosphatase conjugate (dilution 1:100; Sigma Diagnostics) were
used as secondary antibodies (1-hour incubation at room temperature),
with 3,3'-diamino-benzidine (Sigma Diagnostics), nitro blue tetrazolium
(Sigma Diagnostics), and 5-bromo-4-chloro-3-indolyl phosphate (Sigma
Diagnostics) as enzyme substrates.
Morphometry
Hematoxylin and eosin–stained sections were
used for morphometric analysis. Each vessel was assessed in cross
section at 3 levels: 0.5 mm proximal, in the mid-section, and 0.5 mm
distal to the collar
(Figure 1
). The images were analyzed with a Leica DM-RE
microscope and LeicaQwin software (Leica Imaging Systems). The intimal
surface area was calculated by subtracting the patent lumen area from
the area circumscribed by the internal elastic lamina, whereas the
medial surface area was defined as the area between the internal
elastic lamina and the external elastic lamina. The intima/media ratio
and the intima/lumen ratio were determined by dividing the intimal area
by the medial area and the total area confined by the internal elastic
lamina, respectively.
Cholesterol Assay
Nonfasting serum samples were obtained by
femoral artery transection. Total serum cholesterol levels were
quantified colorimetrically by enzymatic procedures (Roche), with
Precipath used as internal standard.
Statistical Analysis
All groups consisted of 3 animals. Values are
expressed as mean±SD. Data variance was analyzed by 1-way and 2-way
ANOVA. A 2-tailed Student’s t
test was used in the comparison of individual groups, which was used in
a nonpaired form when comparing different animals and paired when
comparing contralateral values in the same animal. A level of
P<0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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After recovery from anesthesia, the presence of perivascular collars did not affect normal functioning of the animals. This was corroborated by the absence of a difference in body weight or lipid levels between collar-treated animals and sham-operated control animals. There was no evidence of collar-induced thrombosis in the analyzed common carotid arteries at any time point of analysis (from 1 day to 18 weeks). The data discussed below were derived from the right carotid arteries; these were not found to differ significantly from the contralateral side.
Lesion Size
One week after bilateral insertion of a 0.3-mm diameter
collar, intimal thickening was not detectable in either strain
(Figure 2 and
Table 1). By 3 weeks, however, a neointima had
appeared in the area proximal to the collar in apoE-/- mice. Six
weeks after collar insertion, a significant increase in intimal surface
area had occurred in both strains, although this was more extensive in
the apoE-/- group
(1.46±0.50x105
µm2 in apoE-/-,
0.59±0.23x105
µm2 in LDLr-/-;
P<0.05 compared with
sham-operated in both strains). The increase with time in neointimal
surface proximal to the collar was found to be significant in both
apoE-/- and LDLr-/- mice
(P<0.01, 1-way ANOVA). The
intimal area within and distal to the collar remained virtually
unaltered at all time points examined; these values were confirmed to
differ significantly from the values obtained at the proximal site
(P<0.0001, 2-way ANOVA). The
medial surface area did not rise significantly with time at any site in
either strain, and medial SMC loss was not found to have occurred at
the time points examined (data not shown). No plaques were found in the
corresponding sites of the common carotid arteries of sham-operated
animals of either strain
(Figure 3). The intima-media ratios of the proximal site are
in agreement with the absolute data, being highest in both strains 6
weeks after insertion (apoE-/-, 2.96±1.72; LDLr-/-,
1.42±0.88). The degree of proximal lumen stenosis (as expressed by the
intima-lumen ratio) was highest in the apoE-/- mice, being 36±26%
at 3 weeks and approaching occlusion (85±5%) by 6 weeks. The
corresponding values for LDLr-/- mice were 9±7% and 61±23%.
Distal and midsection sites did not display a significant increase in
intima-media or intima-lumen ratio. A neointimal response was not
observed in animals of either strain 6 weeks after insertion of a
nonconstrictive 0.5-mm diameter collar
(Figure 3; 0.08±0.03x105
µm2 in apoE-/-,
0.02±0.0005x105
µm2 in LDLr-/-;
P<0.05). LDLr-/- mice on
chow diet had not developed collar-induced lesions by 6 weeks
(P<0.05; serum total
cholesterol [TC] 261.6±39.4 mg/dL as compared with 1281.2±298.4
mg/dL on Western-type diet). Lesions in chow-fed apoE-/- mice
(serum TC, 731.0±85.4 mg/dL) were found to be considerably but not
significantly smaller than in their Western-type diet–fed counterparts
(serum TC, 1126.6±29.5 mg/dL), as depicted in
Figure 3 (0.40± 0.53x105
µm2 versus
1.46±0.50x105
µm2). ApoE3-Leiden transgenic mice did not
develop collar-induced plaques for up to 6 months after collar
placement despite having been on a Western-type diet (serum TC,
229.6±48.6 mg/dL; 0.005±0.0001x105
µm2).
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Lesion Composition
The composition of the observed plaques was determined
by a variety of histological and immunohistochemical staining
techniques. Routine hematoxylin and eosin staining revealed that
collar-induced plaques in LDLr-/- mice remained homogeneous and
relatively cellular with advancing maturity, whereas plaques in
apoE-/- animals were seen to become increasingly heterogeneous,
consisting of an acellular necrotic core and a well-defined fibrous cap
by 6 weeks
(Figure 4). Significant extracellular matrix deposition was
demonstrated in mature plaques by Weigert’s staining method (data not
shown). Oil red O staining revealed extensive intracellular and
extracellular lipid deposits in the plaques of both strains, which
included abundant cholesterol crystal clefts. Early plaques contained a
particularly high number of foam cells; these were more numerous and
appeared to be more lipid-rich in apoE-/- mice than in LDLr-/-
mice
(Figure 5). On immunohistochemical staining, the majority of
these cells were positive for MOMA-2
(Figure 5), thus confirming their monocytic origin. Staining
for smooth muscle actin was restricted to the media in early lesions,
but differentiated smooth muscle cells (SMCs) appeared in the intima at
6 weeks, when positive cells were found to be primarily located in the
fibrous cap
(Figure 5).
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Endothelial Expression of Adhesion
Molecules and eNOS
Endothelial integrity was confirmed by staining for vWF
in all 3 sites examined
(Figure 6). Endothelial ICAM-1 expression was seen
circumferentially throughout the common carotid artery in both
collar-treated and sham-operated animals. Expression at the proximal
and distal sites, however, was strongly upregulated by placement of a
0.3-mm-diameter collar, whereas expression within the collar was
reduced
(Figure 6). ICAM-1 expression by endothelial cells overlying
collar-induced lesions decreased with increasing lesion maturity.
Furthermore, its expression did not appear to be dependent on the
administration of a high-cholesterol diet (data not shown). VCAM-1
expression was detected in a limited number of endothelial cells in the
proximal and distal sites and found to be downregulated in the
intracollar area
(Figure 7). eNOS expression was found to be limited to
several contiguous areas of the endothelium. Attenuation of eNOS
staining was observed proximal to the collar 1 week after collar
insertion
(Figure 7).
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Discussion |
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Since the initial studies by Booth et al,7 the rabbit has been the favored animal model for the investigation of collar-inflicted neointima formation. However, placement of a pericarotid or perifemoral collar has also been shown to induce intimal accumulation of SMCs in rats9 and mice,12 respectively. In all of these models, the neointima develops primarily in the collared section, with little involvement of the adjacent proximal or distal uncuffed artery. A range of causative mechanisms has been suggested for the source of these lesions. Thus, direct mechanical or chemical injury of the media by the collar may trigger the migration and proliferation of SMCs within the intima. Alternatively, indirect activation of the media might result from the disruption of its innervation and blood supply caused by damage to the perivascular nerve plexus13 and/or adventitial vasa vasorum.14 Furthermore, the presence of a collar has been found to attenuate endothelial NO synthesis and to reduce reactivity to NO.15 16 Finally, it may also elicit a localized inflammatory response, resulting in diapedesis and intimal accumulation of leukocytes.17
In contrast, the collar-related plaques formed in our
model are located primarily in the area proximal to the collar. Minor
effects are observed in the distal area, whereas the area inside the
collar remains unaffected
(Figure 2). These plaques are therefore presumed to differ in
pathogenesis from those seen in the above-mentioned models. The
location of the lesions, with maximal stenosis occurring at some
distance from the collar, implies that induction of atherosclerosis by
the collar through a direct mechanical or chemical injury is unlikely.
The absence of lesions at the level of the collar also indicates that
diminished removal of waste products from the vessel wall or disruption
of the perivascular nerve plexus are unlikely to play a major
pathogenic role. Moreover, the limited thickness of the murine carotid
media, which consists of 3 SMC layers, obviates the need for a
transmural blood supply.18
The initial lesions seen in our model contain mainly foam cells of
monocytic origin, in addition to extracellular lipid deposits. With
progressive maturation, SMCs appear in the cap of the lesion and
extracellular matrix is deposited. This suggests that the pathogenesis
of these lesions depends on lipid accumulation as an initial stimulus
rather than migration and proliferation of SMCs. This is corroborated
by the dependency of lesion development on high-cholesterol feeding,
which was found to be relative in apoE-/- mice and absolute in
LDLr-/- mice. The lesional distribution pattern found in our model
mirrors the distribution of lipid deposition in aortic coarctation
models in cholesterol-fed
rats19 and cynomolgus
monkeys,20 in which lipid
deposition was found to be highest proximal to the stenosis, with
relative sparing20 and
absence of lesion development distal from the stenotic segment.
The deposition of lipids in these models is known to be rheologically
determined in part,19
whereas it may also reflect a localized increase in endothelial
permeability and/or retention of
LDL.21 These lesions were
found to correspond to areas of low shear stress and disturbed laminar
flow. It is conceivable that equivalent hemorheological conditions
exist in our model, in which a collar of 0.3-mm inside diameter was
found to cause a stenosis of 30% and attenuation of flow
disturbance by placement of a nonconstrictive collar resulted in
considerably delayed atherogenesis. Hemodynamic factors also play an
important indirect role in human and experimental atherogenesis,
through modulation of vascular adhesiveness for leukocytes. The
endothelium assumes a pivotal role in these processes because the
expression of various endothelial genes known to be upregulated in the
endothelium of atherosclerotic plaques and lesion-prone sites in humans
and experimental animals22
have been found to be shear-stress responsive, including ICAM-1, eNOS,
and
VCAM-1.23 24 25
Atherogenesis is known to occur predominantly at sites of disturbed
flow, typified by low and oscillating shear
stress.23 26 27 28
The application of oscillatory shear stress to endothelial cells in
culture has been found to greatly enhance ICAM-1 expression and
downregulate eNOS expression in comparison with steady laminar flow as
well as inducing a transient rise in VCAM-1
levels.29 In our model, the
expression of ICAM-1 and VCAM-1 is in agreement with these findings,
being higher at sites of disturbed flow (proximal and distal to the
collar) than in the high laminar shear stress environment within the
collar
(Table 2 and
Figures 6 and 7). Conversely, downregulation of eNOS was
observed at the proximal site
(Table 2 and
Figure 7). It should be noted that besides shear stress,
circumferential deformation has also been found to augment ICAM-1 and
VCAM-1 expression, potentially through the generation of reactive
oxygen species.30 This type
of deformation is more likely to occur in the "free" proximal and
distal sites than within the collar, where the artery is prevented from
full extension by the "splinting" effect of the collar.
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Summary
Our model is characterized by site-controlled and
accelerated atherogenesis, which mirrors the differences seen between
apoE-/- and LDLr-/- mice in spontaneous atherosclerosis. The
differences in lesion composition reflect the more fibrocellular
plaques normally seen in LDLr-/- mice and the more lipid-rich and
heterogeneous plaques typical of apoE-/- mice. In addition, the
temporal pattern of lesion development is in agreement with the more
delayed and diet-dependent atherogenesis in LDLr-/- mice in
comparison with apoE-/- mice. It may offer several advantages over
conventional animal models of mechanically induced atherosclerosis.
First, closer resemblance to human plaque morphology, endothelial
expression pattern, and plaque pathogenesis should ensure its relevance
as a model of human atherosclerosis per se. This is of importance in
the validation of mechanistic studies and may improve the relevance of
in vivo assessment of potential therapeutic strategies. Second, rapid
atherogenesis will allow efficient screening of potentially
antiatherogenic new chemical entities and the evaluation of therapies
with a limited duration of effectiveness. The latter category includes
many adenoviral vectors, the expression of which often does not exceed
a few weeks. Last, the possibility of controlled lesion induction in
easily accessible sites is very much suited to further intraluminal
instrumentation and application of therapeutic agents. This will also
prove valuable in the development of a more representative murine model
for restenosis because a double-injury restenosis model based on
collar-inflicted atherosclerosis is likely to reflect the complex
pathogenesis seen in clinical
practice.
Received April 18, 2001; revision received August 25, 2001; accepted September 11, 2000.
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E. J.A. van Wanrooij, S. C.A. de Jager, T. van Es, P. de Vos, H. L. Birch, D. A. Owen, R. J. Watson, E. A.L. Biessen, G. A. Chapman, T. J.C. van Berkel, et al. CXCR3 Antagonist NBI-74330 Attenuates Atherosclerotic Plaque Formation in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 251 - 257. [Abstract] [Full Text] [PDF]
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 Q. Li, Y. Li, Z. Zhang, T. R. Gilbert, A. H. Matsumoto, S. E. Dobrin, and W. Shi Quantitative Trait Locus Analysis of Carotid Atherosclerosis in an Intercross Between C57BL/6 and C3H Apolipoprotein E-Deficient Mice Stroke, January 1, 2008; 39(1): 166 - 173. [Abstract] [Full Text] [PDF]
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F. E. Alkemade, A. C. Gittenberger-de Groot, A. E. Schiel, J. C. VanMunsteren, B. Hogers, L. S. J. van Vliet, R. E. Poelmann, L. M. Havekes, K. Willems van Dijk, and M. C. DeRuiter Intrauterine Exposure to Maternal Atherosclerotic Risk Factors Increases the Susceptibility to Atherosclerosis in Adult Life Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2228 - 2235. [Abstract] [Full Text] [PDF]
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A. D. Hauer, G. H.M. van Puijvelde, N. Peterse, P. de Vos, V. van Weel, E. J.A. van Wanrooij, E. A.L. Biessen, P. H.A. Quax, A. G. Niethammer, R. A. Reisfeld, et al. Vaccination Against VEGFR2 Attenuates Initiation and Progression of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 2050 - 2057. [Abstract] [Full Text] [PDF]
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 I. Bot, S. C.A. de Jager, A. Zernecke, K. A. Lindstedt, T. J.C. van Berkel, C. Weber, and E. A.L. Biessen Perivascular Mast Cells Promote Atherogenesis and Induce Plaque Destabilization in Apolipoprotein E-Deficient Mice Circulation, May 15, 2007; 115(19): 2516 - 2525. [Abstract] [Full Text] [PDF]
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L. Zhang, K. Peppel, P. Sivashanmugam, E. S. Orman, L. Brian, S. T. Exum, and N. J. Freedman Expression of Tumor Necrosis Factor Receptor-1 in Arterial Wall Cells Promotes Atherosclerosis Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1087 - 1094. [Abstract] [Full Text] [PDF]
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E. Falk, S. M. Schwartz, Z. S. Galis, and M. E. Rosenfeld Putative Murine Models of Plaque Rupture Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 969 - 972. [Full Text] [PDF]
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C. L. Jackson, M. R. Bennett, E. A.L. Biessen, J. L. Johnson, and R. Krams Assessment of Unstable Atherosclerosis in Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 714 - 720. [Abstract] [Full Text] [PDF]
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 S. Gross, P. Tilly, D. Hentsch, J.-L. Vonesch, and J.-E. Fabre Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors J. Exp. Med., February 19, 2007; 204(2): 311 - 320. [Abstract] [Full Text] [PDF]
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E. J.A van Wanrooij, G. H.M van Puijvelde, P. de Vos, H. Yagita, T. J.C. van Berkel, and J. Kuiper Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 204 - 210. [Abstract] [Full Text] [PDF]
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J. F. Bentzon, C. Weile, C. S. Sondergaard, J. Hindkjaer, M. Kassem, and E. Falk Smooth Muscle Cells in Atherosclerosis Originate From the Local Vessel Wall and Not Circulating Progenitor Cells in ApoE Knockout Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2696 - 2702. [Abstract] [Full Text] [PDF]
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G.H.M. van Puijvelde, A.D. Hauer, P. de Vos, R. van den Heuvel, M.J.C. van Herwijnen, R. van der Zee, W. van Eden, T.J.C. van Berkel, and J. Kuiper Induction of Oral Tolerance to Oxidized Low-Density Lipoprotein Ameliorates Atherosclerosis Circulation, October 31, 2006; 114(18): 1968 - 1976. [Abstract] [Full Text] [PDF]
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R. de Nooijer, C.J.N. Verkleij, J.H. von der Thusen, J.W. Jukema, E.E. van der Wall, Th. J.C. van Berkel, A.H. Baker, and E.A.L. Biessen Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 340 - 346. [Abstract] [Full Text] [PDF]
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 A.D. Hauer, P. de Vos, N. Peterse, H. ten Cate, Th.J.C. van Berkel, F.R.M. Stassen, and J. Kuiper Delivery of Chlamydia pneumoniae to the vessel wall aggravates atherosclerosis in LDLr-/- mice Cardiovasc Res, January 1, 2006; 69(1): 280 - 288. [Abstract] [Full Text] [PDF]
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E. J.A. van Wanrooij, H. Happe, A. D. Hauer, P. de Vos, T. Imanishi, H. Fujiwara, T. J.C. van Berkel, and J. Kuiper HIV Entry Inhibitor TAK-779 Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2642 - 2647. [Abstract] [Full Text] [PDF]
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 R. J. Dekker, J. V. van Thienen, J. Rohlena, S. C. de Jager, Y. W. Elderkamp, J. Seppen, C. J.M. de Vries, E. A.L. Biessen, T. J.C. van Berkel, H. Pannekoek, et al. Endothelial KLF2 Links Local Arterial Shear Stress Levels to the Expression of Vascular Tone-Regulating Genes Am. J. Pathol., August 1, 2005; 167(2): 609 - 618. [Abstract] [Full Text] [PDF]
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Q. Zhao, K. Egashira, K.-i. Hiasa, M. Ishibashi, S. Inoue, K. Ohtani, C. Tan, M. Shibuya, A. Takeshita, and K. Sunagawa Essential Role of Vascular Endothelial Growth Factor and Flt-1 Signals in Neointimal Formation After Periadventitial Injury Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2284 - 2289. [Abstract] [Full Text] [PDF]
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R. de Nooijer, J.H. von der Thusen, C.J.N. Verkleij, J. Kuiper, J.W. Jukema, E.E. van der Wall, Th.J.C. van Berkel, and E.A.L. Biessen Overexpression of IL-18 Decreases Intimal Collagen Content and Promotes a Vulnerable Plaque Phenotype in Apolipoprotein-E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2313 - 2319. [Abstract] [Full Text] [PDF]
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K.-Y. Chyu, S. M. Babbidge, X. Zhao, R. Dandillaya, A. G. Rietveld, J. Yano, P. Dimayuga, B. Cercek, and P. K. Shah Differential Effects of Green Tea-Derived Catechin on Developing Versus Established Atherosclerosis in Apolipoprotein E-Null Mice Circulation, May 25, 2004; 109(20): 2448 - 2453. [Abstract] [Full Text] [PDF]
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J. H. von der Thusen, M. L. Fekkes, R. Passier, A.J. van Zonneveld, V. Mainfroid, T. J.C. van Berkel, and E. A.L. Biessen Adenoviral Transfer of Endothelial Nitric Oxide Synthase Attenuates Lesion Formation in a Novel Murine Model of Postangioplasty Restenosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 357 - 362. [Abstract] [Full Text]
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B. E. Sobel, D. J. Taatjes, and D. J. Schneider Intramural Plasminogen Activator Inhibitor Type-1 and Coronary Atherosclerosis Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 1979 - 1989. [Abstract] [Full Text] [PDF]
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 I. Bot, J. H. von der Thusen, M. M.P.C. Donners, A. Lucas, M. L. Fekkes, S. C.A. de Jager, J. Kuiper, M. J.A.P. Daemen, T. J.C. van Berkel, S. Heeneman, et al. Serine Protease Inhibitor Serp-1 Strongly Impairs Atherosclerotic Lesion Formation and Induces a Stable Plaque Phenotype in ApoE-/- Mice Circ. Res., September 5, 2003; 93(5): 464 - 471. [Abstract] [Full Text] [PDF]
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T. J. Wang, B.-H. Nam, R. B. D'Agostino, P. A. Wolf, D. M. Lloyd-Jones, C. A. MacRae, P. W. Wilson, J. F. Polak, and C. J. O'Donnell Carotid Intima-Media Thickness Is Associated With Premature Parental Coronary Heart Disease: The Framingham Heart Study Circulation, August 5, 2003; 108(5): 572 - 576. [Abstract] [Full Text] [PDF]
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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K. Schafer, S. Konstantinides, C. Riedel, T. Thinnes, K. Muller, C. Dellas, G. Hasenfuss, and D. J. Loskutoff Different Mechanisms of Increased Luminal Stenosis After Arterial Injury in Mice Deficient for Urokinase- or Tissue-Type Plasminogen Activator Circulation, October 1, 2002; 106(14): 1847 - 1852. [Abstract] [Full Text] [PDF]
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M. W. Majesky Mouse Model for Atherosclerotic Plaque Rupture Circulation, April 30, 2002; 105(17): 2010 - 2011. [Full Text] [PDF]
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 M. Kaplan, T. Hayek, A. Raz, R. Coleman, L. Dornfeld, J. Vaya, and M. Aviram Pomegranate Juice Supplementation to Atherosclerotic Mice Reduces Macrophage Lipid Peroxidation, Cellular Cholesterol Accumulation and Development of Atherosclerosis J. Nutr., August 1, 2001; 131(8): 2082 - 2089. [Abstract] [Full Text] [PDF]
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J. H. von der Thusen, B. J.M. van Vlijmen, R. C. Hoeben, M. M. Kockx, L.M. Havekes, T. J.C. van Berkel, and E. A.L. Biessen Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E-/- Mice After Adenovirus-Mediated Transfer of p53 Circulation, April 30, 2002; 105(17): 2064 - 2070. [Abstract] [Full Text] [PDF]
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