© 1997 American Heart Association, Inc.
Articles |
Remodeling With Neointima Formation in the Mouse Carotid Artery After Cessation of Blood Flow
From Pharmacia and Upjohn, Cardiovascular Pharmacology, Kalamazoo, Mich (A.K.), and the Department of Surgery, Maine Medical Center Research Institute, South Portland, ME (V.L.).
Correspondence to Volkhard Lindner, MD, PhD, Maine Medical Center Research Institute, 125 John Roberts Rd, Suite 8, South Portland, ME 04106. E-mail lindnv{at}poa.mmc.org
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Abstract |
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Abstract The ability of gene targeting in the mouse species presents a powerful tool to determine the role of specific molecules in vascular biology. Using a denuding-injury procedure, we recently reported that intimal lesions can be induced in the carotid artery of outbred mice. The technical challenge associated with achieving complete denudation and the relatively small size of the developing lesions prompted us to design the present model of neointima formation and vascular remodeling in the carotid artery of the inbred FVB mouse strain. Complete ligation of the vessel near the carotid bifurcation induced rapid proliferation of medial smooth muscle cells, leading to extensive neointima formation in the presence of an endothelial lining. Thrombus formation was not observed except in the most distal part of the vessel adjacent to the ligature. At 4 weeks after ligation, luminal area was reduced by
80% through a combination of decreased vessel
diameter and neointima formation. Ultrastructural
analysis provided evidence for cell death in the developing
neointima as well as the remodeling media. The present
model might be useful in identifying those genes important for
neointima formation and vascular remodeling.
Key Words: smooth muscle • endothelium • intimal hyperplasia • mice
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The ability to introduce transgenes or to disrupt endogenous gene expression has made the mouse an attractive species with which to study the function of specific genes in vascular biology. Unlike that in the rat, the study of SMC proliferation and intimal lesion formation in mice has been difficult owing to the lack of suitable experimental models. A few years ago, we developed a model in which the common carotid artery of mice was denuded with a flexible wire.1 Using an outbred strain, we found that within 2 weeks after injury, intimal lesions would form in areas that were still denuded. These intimal lesions, however, were not very extensive and usually did not exceed two or three cell layers in thickness. The relatively small proliferative response and the technical challenge to achieve complete denudation prompted us to explore other ways to induce extensive SMC proliferation in a reproducible manner.
A reduction in blood flow has been shown to increase intimal lesion formation in vascular grafts and balloon-injured vessels,2 3 4 thus indicating that alterations in blood flow will affect the proliferative response of SMCs. Furthermore, a number of studies have demonstrated that vessels adapt to chronic changes in blood flow by undergoing compensatory adjustments in their lumen size.5 6 Together these findings stimulated the development of the murine model presented here, in which blood flow in the common carotid artery was disrupted by ligating the vessel near the distal bifurcation. These ligated vessels did not contain clots, and pulsation was present at all times. Luminal narrowing occurred by formation of an extensive SMC-rich neointima and a reduction in vessel diameter. This model might be useful for studying events in SMC proliferation and vascular remodeling at the molecular level.
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Methods |
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Animals
All animal studies were approved by the Institutional Animal Care and Use Committee. Forty female FVB mice (3 to 4 months old; The Jackson Laboratory, Bar Harbor, Me) weighing 22 to 30 g were used in all experiments. The animals were anesthetized by intraperitoneal injection of a solution of xylazine (5 mg/kg body weight, AnaSed; Lloyd Laboratories) and ketamine (80 mg/kg body weight, Ketaset; Aveco Co, Inc). The left common carotid artery was dissected and ligated near the carotid bifurcation. All animals recovered and showed no symptoms of a stroke. Groups of animals were killed at 0 and 3 hours and 2, 5, 8, 11, 14, 18, 21, and 28 days after ligation of the carotid artery. At least four mice were killed per time point. All animals received two subcutaneous injections of the thymidine analogue BrdU (2.5 mg per injection; Boehringer Mannheim). These injections were given 12 hours and 1 hour before the mice were killed. All animals were fixed for 3 minutes by perfusion with 4% p-formaldehyde in 0.1 mol/L sodium phosphate buffer (pH 7.3) as described.1 After excision of the left and right carotid arteries, the vessels were immersion fixed in 70% ethanol. Vessels used for electron microscopy were perfusion fixed with phosphate-buffered glutaraldehyde/p-formaldehyde (1%:4%, vol/vol). The common carotid arteries were
9 mm long, of
which the proximal and distal 2 mm were discarded and the
remaining portion (5 mm) was cut in half. The two segments were
embedded in paraffin, and serial sections (5 µm thick) were cut
for analysis by immunostaining and
hematoxylin-eosin staining for morphometry. Five or more sections
spanning most of the vessel segment were analyzed for
morphometry.
Immunostaining
Biotinylated secondary antibodies and the ABC-Elite kit (Vector
Labs, Inc) with 3,3'-diaminobenzidine as the color substrate were used
for all staining runs. Between incubations with antibodies and reagents
of the ABC kit, four washes (5 minutes each) with TBS (0.8% NaCl,
25 mmol/L Tris; pH 7.6) were carried out. Controls with
nonimmune immunoglobulins matching in species and concentration were
run in parallel with every antibody staining experiment.
The SMC replication indices in the media and intima were determined by staining the sections with a mouse monoclonal antibody against BrdU (1:200 dilution, Cappel). Before application of the antibody, the sections were treated with pepsin (0.1 mg/mL in 0.1N HCl) for 30 minutes at 37°C, washed with distilled water, and incubated in 1.5N HCl at 37°C for 15 minutes. The sections were rinsed in distilled water, washed twice for 5 minutes in 0.1 mol/L sodium tetraborate buffer (Borax, pH 8.5), and washed with TBS for 5 minutes before application of the anti-BrdU antibody (1 hour at 37°C). After three washes with TBS (5 minutes each), the sections were incubated for 30 minutes at room temperature with a biotinylated horse anti-mouse IgG (1:1000 dilution, Vector). Subsequent steps were carried out as described,7 except that the color reaction with diaminobenzidine was stopped after 30 to 45 seconds. The numbers of total and stained nuclei were counted separately for the media and intima, and the BrdU labeling indices [(stained nuclei/total nuclei)x100] were calculated for both the media and intima. At least three sections were analyzed per animal.
One question that we wished to answer was whether the endothelium would remain on the luminal surface of the carotid artery during intimal lesion formation. In addition to the ultrastructural analysis described below, a rabbit polyclonal antibody against factor VIII–related antigen (von Willebrand factor) was used to identify ECs. This antibody (Dako) was used at a 1:250 dilution, and subsequent steps of the staining protocol were carried out as described.8 At least 12 sections from each animal were stained.
The effects of carotid artery ligation on EC replication were determined in the ligated vessel as well as the contralateral carotid artery at 2, 5, and 8 days after ligation. The animals were injected with BrdU as described above, and the vessels were stained en face with the anti-BrdU antibody. Whole mounts were prepared, and the total number as well as the number of labeled endothelial nuclei was counted. Results were expressed as a replication index as described for SMCs.
The presence of inflammatory cells in this model was determined by using a rat monoclonal antibody against the mouse leukocyte common antigen CD45 (1:100 dilution, PharMingen). Mouse monocytes/macrophages were identified by immunostaining with a specific rat monoclonal antibody (1:200 dilution, BMA BM8; Accurate Chemical and Scientific Corp). A biotinylated mouse anti-rat antibody (adsorbed against mouse serum proteins, Jackson ImmunoResearch) was used at a 1:100 dilution. At least 12 sections from each animal were analyzed.
SMCs were identified by staining with a mouse monoclonal antibody
specific for 
-smooth muscle actin (clone 1A4, Sigma). This antibody
was used at a 1:8000 dilution. A biotinylated horse anti-mouse
immunoglobulin (Vector) was used as the secondary antibody at a 1:1000
dilution. At least 12 sections from each animal were stained.
Morphometry
Morphometric analysis was carried out on carotid
arteries from unmanipulated mice and on carotid arteries harvested 4
weeks after ligation. In some animals morphometric analysis was
also carried out on the contralateral vessel of the ligated carotid
artery 4 weeks after ligation. All animals were perfusion fixed under
physiological pressure. Digitized images of these
vessels were analyzed with image analysis software for
the Apple Macintosh computer (NIH Image 1.60). The circumferences
(lengths) of the lumen, IEL, and EEL were determined by tracing along
the luminal surface, IEL, and EEL. Under the assumption that the
structures were circular, these measurements were used to calculate
luminal area, intimal area, and medial area. The medial area was
calculated by subtracting the area defined by the IEL from the area
defined by the EEL, and intimal area was determined by subtracting the
luminal area from the area defined by the IEL.
Statistical Analysis
Student's t test was used to compare the values
between normal vessels and ligated vessels (intimal area, luminal
area). ANOVA followed by Scheffés F test were used to compare the
means of multiple groups (cell number). Means were considered
significantly different if P<.05.
Transmission Electron Microscopy
For ultrastructural analysis, ligated carotid arteries
from two or three animals per time point (2, 5, 8, 14, and 28 days
after ligation) were examined. After perfusion fixation and immersion
fixation with phosphate-buffered
glutaraldehyde/p-formaldehyde (1%:4%,
vol/vol), the specimens were placed in 1% OsO4 for
2 hours, dehydrated en bloc, stained with 3% uranyl acetate, and
embedded in Epon. Thin sections were cut and poststained with uranyl
acetate and Reynolds' lead citrate.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Morphological Changes After Cessation of Blood Flow
The common carotid artery in mice does not have side branches, and thus, vessels ligated near the bifurcation will have no net forward flow. Vessels were obtained from mice 4 weeks after ligation of the common carotid artery, and because of the ligature, blood components were still present in the lumen after perfusion fixation (Fig 1b
and 1c). Sections were cut from the
entire length of the vessel. It was found that no intimal lesion had
formed within the proximal 2 to 3 mm of the vessel adjacent to the
aortic arch. Distal from the arch, the vessels consistently
formed a neointima (Fig 1b and 1c), and for all subsequent
studies, sections from the middle portion of the vessel were
analyzed. Compared with control vessels (Fig 1a), the entire
vessel diameter had decreased (Fig 1c), as quantified by the outer
circumference of the media.
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SMC Proliferation
The formation of an intimal lesion in response to ligation of the
carotid artery suggested that SMC proliferation was a prominent feature
of the model. To characterize the time course of SMC replication, mice
were injected with BrdU and the replication index determined (Fig 2a). Within 5 days after flow reduction,
the SMC replication index in the media averaged 23.4%, and cells
present in the intima also revealed high replication rates
(27.6%). While cell replication in the media decreased dramatically
after 8 days, intimal cells continued to replicate at a high rate until
2 weeks after flow reduction. Replicating SMCs were still found in the
intima 4 weeks after carotid ligation.
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Because cell death has been demonstrated in other models of intimal
hyperplasia,9 10 we determined whether the increased SMC
proliferation did indeed result in an increase in cell number by
counting the number of cells present in the media and intima at
various time points after vessel ligation (Fig 2b
). Because the vessels
had not been denuded, cell counts in the intima included ECs. Within 2
days after ligation, a marked loss of SMCs from the media was evident.
At 8 days and all later time points, the number of medial SMCs was not
significantly different from that in control vessels. Cell numbers in
the intima increased after ligation of the vessel, reaching the highest
levels at 2 weeks. Intimal cell numbers were significantly increased
over control values at 2 and 4 weeks after flow reduction.
Morphometry
The changes in vessel wall geometry in response to flow reduction
were determined by measuring the luminal area of carotid arteries
harvested 4 weeks after vessel ligation (Fig 3a). The reduction in luminal area
averaged nearly 80% in the ligated vessels compared with that in
control vessels. To further determine whether this reduction in luminal
area was the result of intimal lesion formation, vessel constriction,
or both, we measured the intimal area as well as the outer
circumference of the vessel as determined by the EEL. As shown in Fig 3b, there was an 25% reduction in the circumference of the ligated
vessel. This decrease in circumference represented a fixed
change in vessel structure as opposed to active SMC contraction, since
topical application of nitroglycerin prior to perfusion
fixation did not relax the vessel (data not shown). In addition to the
decrease in vessel diameter, there was also a thick intimal lesion (Fig 3c) that led to narrowing of the lumen. Therefore, the adjustment of
luminal area in response to the loss of net flow occurred due to both a
decrease in vessel diameter and neointima formation. There
was also a significant increase in cross-sectional area of the media in
the ligated vessel (Fig 3d). No significant change in vessel diameter
was seen in the contralateral, unligated right carotid artery 4 weeks
after ligation compared with vessels from unmanipulated animals (Fig 3e).
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Morphology and Immunocytochemistry
The mice were killed at various time points after ligation
of the left common carotid artery to analyze the cellular
composition and morphological changes in the vessel in response to
blood flow reduction. SMCs were identified with an antibody against
-smooth muscle actin. Similar to the findings reported previously
for proliferating SMC in the denuded mouse carotid
artery,1 immunoreactivity for -smooth muscle actin was
reduced when SMCs were rapidly replicating (5 to 14 days; Fig 4a and 4b). The mature 4-week-old intimal
lesion, however, stained strongly for -smooth muscle actin (Fig 4c).
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Inflammatory cells identified with an antibody directed against the
common leukocyte antigen CD45 were frequently found in the adventitia
and outer layer of the media (Fig 4d). Some leukocytes were also
present in the developing intima and near the luminal surface. At 4
weeks after ligation, inflammatory cells were usually not detectable.
Immunostaining with an antibody that recognizes mouse
macrophages and monocytes revealed similar results, indicating
that the majority of inflammatory cells present were derived from
this cell lineage.
The presence of endothelium on the luminal surface was
verified by immunostaining for von Willebrand
factor (factor VIII–related antigen). Whole mounts of ligated and
contralateral carotid arteries were prepared and stained en face with
an anti-BrdU antibody to determine EC replication. No replicating cells
were seen in normal vessels, but increased EC replication was apparent
in vessels 5 and 8 days after ligation (Fig 5). Examination of
endothelial replication at later time points was
hampered by increased narrowing of the lumen, which made it difficult
to prepare whole mounts. Although the intimal lesions were covered by
the endothelium (Fig 4e), it was frequently found to
have become detached from the underlying IEL, thereby forming spaces
that were filled with red blood cells (Fig 4b and Fig 6a). By transmission electron microscopy,
evidence for SMC death was apparent, as indicated by the presence of
condensed nuclei and vacuolized cytoplasm (Fig 6b). Cells undergoing
cell death were found in both the media and neointima. The
electron micrograph in Fig 6c shows a thick, intimal lesion on top of a
contracted IEL 4 weeks after ligation.
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Discussion |
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Proliferation of SMCs plays an important role in the failure of angioplasty procedures; more recently, the remodeling of vascular structures has also been implicated in restenosis after angioplasty.11 12 13 To study the molecular mechanisms that contribute to SMC proliferation and remodeling, the present study sought to establish an animal model in the mouse because this species is genetically well characterized and can be genetically manipulated. The chances of identifying key factors are more likely to succeed in a model that is aimed toward maximizing the adaptive changes and proliferative responses of SMCs. In the model described here, we chose to completely disrupt blood flow in the common carotid artery by ligation near the bifurcation, thus causing the lumen to decrease to
20% of its original size. Because the ligated vessel was still
subject to arterial blood pressure, pulsation persisted in
these vessels. With the exception of the most distal part of the vessel
(within 1 to 2 mm of the ligature), clot formation did not occur within
1 to 2 mm of the ligature. However, when complete
endothelial denudation was performed before ligation of
the vessel, an occluding thrombus formed over the entire length of the
carotid artery (data not shown). Thus, one role of the
endothelium in this model is to maintain a
nonthrombogenic surface. We observed two mechanisms that contributed to
luminal narrowing in this model: one was by constriction or shrinkage
of the vessel diameter and the other by neointima
formation. Initial constriction has been described as a vasoactive
response14 that is thought to depend on the presence of
the endothelium.6 The fact that this
constriction could not be reversed by topical application of
nitroglycerin after 4 weeks demonstrates a fixed change
in the vessel wall structure. The endothelium was
present at all times, as evident by the presence of von
Willebrand factor–immunoreactive cells on the luminal surface.
Focal detachment of ECs from the underlying IEL, however, was observed
during lesion formation. Detachment of the endothelium
may in part result from persistent vessel constriction, as indicated by
the presence of "wavy" elastic laminas. It is conceivable that
endothelial detachment may lead to discontinuities in
the endothelial sheet, which may allow penetration of
blood cells and platelets into the subendothelial
space (Fig 5a). Large-scale endothelial degeneration
and denudation have been reported in rat models of vessel segments
isolated between two ligatures.15 16 17 These models,
however, differ from the one described here in that they were no longer
exposed to hemodynamic forces.
When SMC replication rates and numbers in the intima are compared
at 14 and 28 days, it is apparent that there is no further increase in
cell number in the intima despite the fact that the intimal cell
replication index is still 11% at 4 weeks. Between days 5 and 14,
cell replication rate in the intima exceeded 22% per day. This would
amount to an approximate sixfold increase in cell number
(1.229) during this 9-day period, an amount that was
considerably more than actually determined by counting cell numbers in
the intima. Thus, these data strongly argue for ongoing cell death and
turnover. Apoptosis has also been reported in the
balloon-injured rat carotid artery,9 10 in which we and
others have observed numerous inflammatory cells, particularly in the
adventitia (Lindner, 1995, unpublished data).18 Therefore,
the presence of inflammatory cells in the present model does not
necessarily contradict ongoing apoptosis, despite the fact that
apoptosis is not usually associated with inflammation.
In our mouse model the endothelium was not removed, and it is possible that the altered flow conditions might have played a role in expression of endothelial-leukocyte adhesion molecules and chemokines, with a subsequent influx of inflammatory cells. This explanation is supported by a recent study by Walpola and coworkers,19 who demonstrated that a reduction in flow caused upregulation of vascular cell adhesion molecule-1 expression in a rabbit model. It was interesting to note that a neointima did not develop in the proximal part of the ligated vessel adjacent to the aortic arch. Because the common carotid artery is an elastic vessel and does not possess side branches, it is likely that oscillations of blood flow and therefore shear stress (bidirectional) are higher at this location than at regions closer to the ligature. The near-stasis conditions in more distal segments of the ligated vessel may have additional implications for platelet and leukocyte activation, which in turn may affect SMC proliferation at this site. Complete blood stasis is more likely to prevail only in the immediate vicinity of the ligature where thrombus formation is seen.
The initial loss of SMCs from the media 2 days after ligation raises the question of whether hypoxia may have been a contributing factor. Although we cannot rule out this possibility, there are several reasons that argue against it. One is that a thick neointima can be supported in the absence of flow, and second, blood within the ligated vessels consistently had the color of arterial blood. A significant amount of cell death can also be expected to occur in the endothelial population of the ligated vessel, since replication of these cells was increased despite the fact that the reduction in luminal area would require a net loss of ECs.
The histology of neointima formation in a single-ligation model of the rat carotid artery has previously been described by Wexler.20 The morphological findings reported for normotensive rats are similar to those that we observed in the mouse model with regard to intimal lesion formation. These models differ from others in that they do not require mechanical trauma and widespread endothelial denudation to induce SMC proliferation. For example, in the balloon-injury model of the rat carotid artery, proliferation of SMCs stops in the denuded vessel as soon as reendothelialization occurs. Similarly, in the denudation model of the mouse carotid artery, no SMC replication was seen underneath regenerated endothelium.1 On the other hand, development of intimal lesions in atherosclerosis models and in human vascular disease occurs in the absence of noticeable endothelial denudation.21 The model presented here may not mimic a physiological situation. However, it should be pointed out that vascular lesions in humans often develop at sites of altered hemodynamics associated with low shear stress.22 23 Therefore, it is conceivable that the factors responsible for intimal lesion formation at these sites might differ from those involved in intimal hyperplasia after arterial injury associated with endothelial denudation. Further studies are required to determine how the present model relates to clinical situations of vascular disease and restenosis in humans.
In summary, the present study describes a model of vascular remodeling in the FVB mouse strain that is characterized by rapid proliferation of SMCs in an endothelialized artery in response to cessation of mean flow. It should be a useful model to study events in SMC proliferation and vascular remodeling at the molecular level.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a Grant-in-Aid from the American Heart Association and funds contributed in part by the American Heart Association, Alaska Affiliate, Inc, awarded to Dr Lindner. The excellent technical assistance provided by Veronica Poppa and Rei Port is greatly appreciated.
Received January 22, 1997; accepted April 8, 1997.
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References |
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 M. M. P. C. Donners, L. Beckers, D. Lievens, I. Munnix, J. Heemskerk, B. J. Janssen, E. Wijnands, J. Cleutjens, A. Zernecke, C. Weber, et al. The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling Blood, May 1, 2008; 111(9): 4596 - 4604. [Abstract] [Full Text] [PDF]
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L. J. Sommerville, S. E. Kelemen, and M. V. Autieri Increased Smooth Muscle Cell Activation and Neointima Formation in Response to Injury in AIF-1 Transgenic Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 47 - 53. [Abstract] [Full Text] [PDF]
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 T. Shimizu, T. Nakazawa, A. Cho, F. Dastvan, D. Shilling, G. Daum, and M. A. Reidy Sphingosine 1-Phosphate Receptor 2 Negatively Regulates Neointimal Formation in Mouse Arteries Circ. Res., November 9, 2007; 101(10): 995 - 1000. [Abstract] [Full Text] [PDF]
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R. Moura, M. Tjwa, P. Vandervoort, K. Cludts, and M. F. Hoylaerts Thrombospondin-1 Activates Medial Smooth Muscle Cells and Triggers Neointima Formation Upon Mouse Carotid Artery Ligation Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2163 - 2169. [Abstract] [Full Text] [PDF]
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J. V. Welser, N. Lange, C. A. Singer, M. Elorza, P. Scowen, K. D. Keef, W. T. Gerthoffer, and D. J. Burkin Loss of the {alpha}7 Integrin Promotes Extracellular Signal-Regulated Kinase Activation and Altered Vascular Remodeling Circ. Res., September 28, 2007; 101(7): 672 - 681. [Abstract] [Full Text] [PDF]
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V. A. Korshunov, S. M. Schwartz, and B. C. Berk Vascular Remodeling: Hemodynamic and Biochemical Mechanisms Underlying Glagov's Phenomenon Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1722 - 1728. [Abstract] [Full Text] [PDF]
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Y. Yuan and J. Xu Loss-of-Function Deletion of the Steroid Receptor Coactivator-1 Gene in Mice Reduces Estrogen Effect on the Vascular Injury Response Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1521 - 1527. [Abstract] [Full Text] [PDF]
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R. J. LeClair, T. Durmus, Q. Wang, P. Pyagay, A. Terzic, and V. Lindner Cthrc1 Is a Novel Inhibitor of Transforming Growth Factor-{beta} Signaling and Neointimal Lesion Formation Circ. Res., March 30, 2007; 100(6): 826 - 833. [Abstract] [Full Text] [PDF]
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O. Dumont, L. Loufrani, and D. Henrion Key Role of the NO-Pathway and Matrix Metalloprotease-9 in High Blood Flow-Induced Remodeling of Rat Resistance Arteries Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 317 - 324. [Abstract] [Full Text] [PDF]
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E. Falk, S. M. Schwartz, Z. S. Galis, and M. E. Rosenfeld Neointimal Cracks (Plaque Rupture?) and Thrombosis in Wrapped Arteries Without Flow Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 248 - 249. [Full Text] [PDF]
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V. A. Korshunov, A. M. Mohan, M. A. Georger, and B. C. Berk Axl, A Receptor Tyrosine Kinase, Mediates Flow-Induced Vascular Remodeling Circ. Res., June 9, 2006; 98(11): 1446 - 1452. [Abstract] [Full Text] [PDF]
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J. Sainz and M. Sata Maintenance of Vascular Homeostasis by Bone Marrow-Derived Cells. Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1196 - 1197. [Full Text] [PDF]
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L.-N. Zhang, D. W. Wilson, V. da Cunha, M. E. Sullivan, R. Vergona, J. C. Rutledge, and Y.-X. Wang Endothelial NO Synthase Deficiency Promotes Smooth Muscle Progenitor Cells in Association With Upregulation of Stromal Cell-Derived Factor-1{alpha} in a Mouse Model of Carotid Artery Ligation Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 765 - 772. [Abstract] [Full Text] [PDF]
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C. M. Matter, M. T. Wyss, P. Meier, N. Spath, T. von Lukowicz, C. Lohmann, B. Weber, A. R. de Molina, J. C. Lacal, S. M. Ametamey, et al. 18F-Choline Images Murine Atherosclerotic Plaques Ex Vivo Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 584 - 589. [Abstract] [Full Text] [PDF]
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R. D. Rudic, D. Brinster, Y. Cheng, S. Fries, W.-L. Song, S. Austin, T. M. Coffman, and G. A. FitzGerald COX-2-Derived Prostacyclin Modulates Vascular Remodeling Circ. Res., June 24, 2005; 96(12): 1240 - 1247. [Abstract] [Full Text] [PDF]
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Y. Li, T. Minamino, O. Tsukamoto, T. Yujiri, Y. Shintani, K.-i. Okada, Y. Nagamachi, M. Fujita, A. Hirata, S. Sanada, et al. Ablation of MEK Kinase 1 Suppresses Intimal Hyperplasia by Impairing Smooth Muscle Cell Migration and Urokinase Plasminogen Activator Expression in a Mouse Blood-Flow Cessation Model Circulation, April 5, 2005; 111(13): 1672 - 1678. [Abstract] [Full Text] [PDF]
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 J. A. Spencer, S. L. Hacker, E. C. Davis, R. P. Mecham, R. H. Knutsen, D. Y. Li, R. D. Gerard, J. A. Richardson, E. N. Olson, and H. Yanagisawa Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration PNAS, February 22, 2005; 102(8): 2946 - 2951. [Abstract] [Full Text] [PDF]
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 H. Li, S. Telemaque, R. E. Miller, and J. D. Marsh High Glucose Inhibits Apoptosis Induced by Serum Deprivation in Vascular Smooth Muscle Cells via Upregulation of Bcl-2 and Bcl-xl Diabetes, February 1, 2005; 54(2): 540 - 545. [Abstract] [Full Text] [PDF]
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V. A. Korshunov and B. C. Berk Strain-Dependent Vascular Remodeling: The "Glagov Phenomenon" Is Genetically Determined Circulation, July 13, 2004; 110(2): 220 - 226. [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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R. H.P. Hilgers, P. M.H. Schiffers, W. M. Aartsen, G. E. Fazzi, J. F.M. Smits, and J. G.R. De Mey Tissue Angiotensin-Converting Enzyme in Imposed and Physiological Flow-Related Arterial Remodeling in Mice Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 892 - 897. [Abstract] [Full Text]
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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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P.-K. Tran, K. Tran-Lundmark, R. Soininen, K. Tryggvason, J. Thyberg, and U. Hedin Increased Intimal Hyperplasia and Smooth Muscle Cell Proliferation in Transgenic Mice With Heparan Sulfate-Deficient Perlecan Circ. Res., March 5, 2004; 94(4): 550 - 558. [Abstract] [Full Text] [PDF]
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B. Kerlin, B. C. Cooley, B. H. Isermann, I. Hernandez, R. Sood, M. Zogg, S. B. Hendrickson, M. W. Mosesson, S. Lord, and H. Weiler Cause-effect relation between hyperfibrinogenemia and vascular disease Blood, March 1, 2004; 103(5): 1728 - 1734. [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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S. C.G. Hollestelle, M. R. de Vries, J. K. van Keulen, A. H. Schoneveld, A. Vink, C. F. Strijder, B. J. van Middelaar, G. Pasterkamp, P. H.A. Quax, and D. P.V. de Kleijn Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling Circulation, January 27, 2004; 109(3): 393 - 398. [Abstract] [Full Text] [PDF]
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D. L. Myers and L. Liaw Improved Analysis of the Vascular Response to Arterial Ligation Using a Multivariate Approach Am. J. Pathol., January 1, 2004; 164(1): 43 - 48. [Abstract] [Full Text] [PDF]
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V. A. Korshunov and B. C. Berk Flow-Induced Vascular Remodeling in the Mouse: A Model for Carotid Intima-Media Thickening Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2185 - 2191. [Abstract] [Full Text] [PDF]
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K. Tanaka, M. Sata, Y. Hirata, and R. Nagai Diverse Contribution of Bone Marrow Cells to Neointimal Hyperplasia After Mechanical Vascular Injuries Circ. Res., October 17, 2003; 93(8): 783 - 790. [Abstract] [Full Text] [PDF]
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M. Kuzuya, S. Kanda, T. Sasaki, N. Tamaya-Mori, X. W. Cheng, T. Itoh, S. Itohara, and A. Iguchi Deficiency of Gelatinase A Suppresses Smooth Muscle Cell Invasion and Development of Experimental Intimal Hyperplasia Circulation, September 16, 2003; 108(11): 1375 - 1381. [Abstract] [Full Text] [PDF]
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B. S. Buetow, K. A. Tappan, J. R. Crosby, R. A. Seifert, and D. F. Bowen-Pope Chimera Analysis Supports a Predominant Role of PDGFR{beta} in Promoting Smooth-Muscle Cell Chemotaxis after Arterial Injury Am. J. Pathol., September 1, 2003; 163(3): 979 - 984. [Abstract] [Full Text] [PDF]
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J. E. Leidenfrost, M. F. Khan, K. P. Boc, B. R. Villa, E. T. Collins, W. C. Parks, D. R. Abendschein, and E. T. Choi A Model of Primary Atherosclerosis and Post-Angioplasty Restenosis in Mice Am. J. Pathol., August 1, 2003; 163(2): 773 - 778. [Abstract] [Full Text] [PDF]
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D. L. Myers, K. J. Harmon, V. Lindner, and L. Liaw Alterations of Arterial Physiology in Osteopontin-Null Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 1021 - 1028. [Abstract] [Full Text] [PDF]
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 R. Wessely, L. Hengst, B. Jaschke, F. Wegener, T. Richter, R. Lupetti, M. Paschalidis, A. Schomig, R. Brandl, and F.-J. Neumann A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia Hum. Mol. Genet., January 15, 2003; 12(2): 177 - 187. [Abstract] [Full Text] [PDF]
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V. de Waard, T. A.E. van Achterberg, N. J. Beauchamp, H. Pannekoek, and C. J.M. de Vries Cardiac Ankyrin Repeat Protein (CARP) Expression in Human and Murine Atherosclerotic Lesions: Activin Induces Carp in Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 64 - 68. [Abstract] [Full Text] [PDF]
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S. Konstantinides, K. Schafer, and D. J. Loskutoff Do PAI-1 and Vitronectin Promote or Inhibit Neointima Formation?: The Exact Role of the Fibrinolytic System in Vascular Remodeling Remains Uncertain Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 1943 - 1945. [Full Text] [PDF]
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V. de Waard, E. K. Arkenbout, P. Carmeliet, V. Lindner, and H. Pannekoek Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 1978 - 1983. [Abstract] [Full Text] [PDF]
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S. Taurin, V. Seyrantepe, S. N. Orlov, T.-L. Tremblay, P. Thibault, M. R. Bennett, P. Hamet, and A. V. Pshezhetsky Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na+]i/[K+]i Ratio in Cultured Vascular Smooth Muscle Cells Circ. Res., November 15, 2002; 91(10): 915 - 922. [Abstract] [Full Text] [PDF]
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Z. S. Galis, C. Johnson, D. Godin, R. Magid, J. M. Shipley, R. M. Senior, and E. Ivan Targeted Disruption of the Matrix Metalloproteinase-9 Gene Impairs Smooth Muscle Cell Migration and Geometrical Arterial Remodeling Circ. Res., November 1, 2002; 91(9): 852 - 859. [Abstract] [Full Text] [PDF]
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N. Murakoshi, T. Miyauchi, Y. Kakinuma, T. Ohuchi, K. Goto, M. Yanagisawa, and I. Yamaguchi Vascular Endothelin-B Receptor System In Vivo Plays a Favorable Inhibitory Role in Vascular Remodeling After Injury Revealed by Endothelin-B Receptor-Knockout Mice Circulation, October 8, 2002; 106(15): 1991 - 1998. [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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E. K. Arkenbout, V. de Waard, M. van Bragt, T. A.E. van Achterberg, J. M. Grimbergen, B. Pichon, H. Pannekoek, and C. J.M. de Vries Protective Function of Transcription Factor TR3 Orphan Receptor in Atherogenesis: Decreased Lesion Formation in Carotid Artery Ligation Model in TR3 Transgenic Mice Circulation, September 17, 2002; 106(12): 1530 - 1535. [Abstract] [Full Text] [PDF]
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C. J. Sullivan and J. B. Hoying Flow-Dependent Remodeling in the Carotid Artery of Fibroblast Growth Factor-2 Knockout Mice Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1100 - 1105. [Abstract] [Full Text] [PDF]
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Y. Yuan, L. Liao, D. A. Tulis, and J. Xu Steroid Receptor Coactivator-3 Is Required for Inhibition of Neointima Formation by Estrogen Circulation, June 4, 2002; 105(22): 2653 - 2659. [Abstract] [Full Text] [PDF]
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E. Ivan, J. J. Khatri, C. Johnson, R. Magid, D. Godin, S. Nandi, S. Lessner, and Z. S. Galis Expansive Arterial Remodeling Is Associated With Increased Neointimal Macrophage Foam Cell Content: The Murine Model of Macrophage-Rich Carotid Artery Lesions Circulation, June 4, 2002; 105(22): 2686 - 2691. [Abstract] [Full Text] [PDF]
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L. Peng, N. Bhatia, A. C. Parker, Y. Zhu, and W. P. Fay Endogenous Vitronectin and Plasminogen Activator Inhibitor-1 Promote Neointima Formation in Murine Carotid Arteries Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 934 - 939. [Abstract] [Full Text] [PDF]
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D. G. Kuhel, B. Zhu, D. P. Witte, and D. Y. Hui Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 955 - 960. [Abstract] [Full Text] [PDF]
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S. M. Lessner, H. L. Prado, E. K. Waller, and Z. S. Galis Atherosclerotic Lesions Grow Through Recruitment and Proliferation of Circulating Monocytes in a Murine Model Am. J. Pathol., June 1, 2002; 160(6): 2145 - 2155. [Abstract] [Full Text] [PDF]
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M. D. Layne, S.-F. Yet, K. Maemura, C.-M. Hsieh, X. Liu, B. Ith, M.-E. Lee, and M. A. Perrella Characterization of the Mouse Aortic Carboxypeptidase-Like Protein Promoter Reveals Activity in Differentiated and Dedifferentiated Vascular Smooth Muscle Cells Circ. Res., April 5, 2002; 90(6): 728 - 736. [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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T. Tolbert, J. A. Thompson, P. Bouchard, and S. Oparil Estrogen-Induced Vasoprotection Is Independent of Inducible Nitric Oxide Synthase Expression: Evidence From the Mouse Carotid Artery Ligation Model Circulation, November 27, 2001; 104(22): 2740 - 2745. [Abstract] [Full Text] [PDF]
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M. Sata, S. Sugiura, M. Yoshizumi, Y. Ouchi, Y. Hirata, and R. Nagai Acute and Chronic Smooth Muscle Cell Apoptosis After Mechanical Vascular Injury Can Occur Independently of the Fas-Death Pathway Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1733 - 1737. [Abstract] [Full Text] [PDF]
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H. Weiler, V. Lindner, B. Kerlin, B. H. Isermann, S. B. Hendrickson, B. C. Cooley, D. A. Meh, M. W. Mosesson, N. W. Shworak, M. J. Post, et al. Characterization of a Mouse Model for Thrombomodulin Deficiency Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1531 - 1537. [Abstract] [Full Text] [PDF]
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S. S. Smyth, E. D. Reis, W. Zhang, J. T. Fallon, R. E. Gordon, and B. S. Coller {beta}3-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 Circulation, May 22, 2001; 103(20): 2501 - 2507. [Abstract] [Full Text] [PDF]
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J. A. McPherson, K. G. Barringhaus, G. G. Bishop, J. M. Sanders, J. M. Rieger, S. E. Hesselbacher, L. W. Gimple, E. R. Powers, T. Macdonald, G. Sullivan, et al. Adenosine A2A Receptor Stimulation Reduces Inflammation and Neointimal Growth in a Murine Carotid Ligation Model Arterioscler. Thromb. Vasc. Biol., May 1, 2001; 21(5): 791 - 796. [Abstract] [Full Text] [PDF]
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T. Kawasaki, M. Dewerchin, H. R. Lijnen, I. Vreys, J. Vermylen, and M. F. Hoylaerts Mouse Carotid Artery Ligation Induces Platelet-Leukocyte-Dependent Luminal Fibrin, Required for Neointima Development Circ. Res., February 2, 2001; 88(2): 159 - 166. [Abstract] [Full Text] [PDF]
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S. Kawashima, T. Yamashita, M. Ozaki, Y. Ohashi, H. Azumi, N. Inoue, K.-i. Hirata, Y. Hayashi, H. Itoh, and M. Yokoyama Endothelial NO Synthase Overexpression Inhibits Lesion Formation in Mouse Model of Vascular Remodeling Arterioscler. Thromb. Vasc. Biol., February 1, 2001; 21(2): 201 - 207. [Abstract] [Full Text] [PDF]
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D. Godin, E. Ivan, C. Johnson, R. Magid, and Z. S. Galis Remodeling of Carotid Artery Is Associated With Increased Expression of Matrix Metalloproteinases in Mouse Blood Flow Cessation Model Circulation, December 5, 2000; 102(23): 2861 - 2866. [Abstract] [Full Text] [PDF]
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J. E. Rectenwald, L. L. Moldawer, T. S. Huber, J. M. Seeger, and C. K. Ozaki Direct Evidence for Cytokine Involvement in Neointimal Hyperplasia Circulation, October 3, 2000; 102(14): 1697 - 1702. [Abstract] [Full Text] [PDF]
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J. L. Hall, C. M. Matter, X. Wang, and G. H. Gibbons Hyperglycemia Inhibits Vascular Smooth Muscle Cell Apoptosis Through a Protein Kinase C-Dependent Pathway Circ. Res., September 29, 2000; 87(7): 574 - 580. [Abstract] [Full Text] [PDF]
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J. M. Miano and B. C. Berk Retinoids : Versatile Biological Response Modifiers of Vascular Smooth Muscle Phenotype Circ. Res., September 1, 2000; 87(5): 355 - 362. [Full Text] [PDF]
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A. A.-R. Higazi, T. Nassar, T. Ganz, D. J. Rader, R. Udassin, K. Bdeir, E. Hiss, B. S. Sachais, K. J. Williams, E. Leitersdorf, et al. The alpha -defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis Blood, August 15, 2000; 96(4): 1393 - 1398. [Abstract] [Full Text] [PDF]
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C. Emanueli, M. B. Salis, J. Chao, L. Chao, J. Agata, K.-F. Lin, A. Munao, S. Straino, A. Minasi, M. C. Capogrossi, et al. Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Inhibits Neointima Formation Induced by Interruption of Blood Flow in Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1459 - 1466. [Abstract] [Full Text] [PDF]
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K. J. Harmon, L. L. Couper, and V. Lindner Strain-Dependent Vascular Remodeling Phenotypes in Inbred Mice Am. J. Pathol., May 1, 2000; 156(5): 1741 - 1748. [Abstract] [Full Text] [PDF]
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P. M. H. Schiffers, D. Henrion, C. M. Boulanger, E. Colucci-Guyon, F. Langa-Vuves, H. van Essen, G. E. Fazzi, B. I. Levy, and J. G. R. De Mey Altered Flow-Induced Arterial Remodeling in Vimentin-Deficient Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 611 - 616. [Abstract] [Full Text] [PDF]
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M. Roque, J. T. Fallon, J. J. Badimon, W. X. Zhang, M. B. Taubman, and E. D. Reis Mouse Model of Femoral Artery Denudation Injury Associated With the Rapid Accumulation of Adhesion Molecules on the Luminal Surface and Recruitment of Neutrophils Arterioscler. Thromb. Vasc. Biol., February 1, 2000; 20(2): 335 - 342. [Abstract] [Full Text] [PDF]
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N. J. McCarthy and M. Bennett The regulation of vascular smooth muscle cell apoptosis Cardiovasc Res, February 1, 2000; 45(3): 747 - 755. [Abstract] [Full Text] [PDF]
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C. Shi, A. Patel, D. Zhang, H. Wang, P. Carmeliet, G. L. Reed, M.-E. Lee, E. Haber, and N. E. S. Sibinga Plasminogen Is Not Required for Neointima Formation in a Mouse Model of Vein Graft Stenosis Circ. Res., April 30, 1999; 84(8): 883 - 890. [Abstract] [Full Text] [PDF]
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S. R. Bryant, R. J. Bjercke, D. A. Erichsen, A. Rege, and V. Lindner Vascular Remodeling in Response to Altered Blood Flow Is Mediated by Fibroblast Growth Factor-2 Circ. Res., February 19, 1999; 84(3): 323 - 328. [Abstract] [Full Text] [PDF]
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M. R Bennett Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture Cardiovasc Res, February 1, 1999; 41(2): 361 - 368. [Abstract] [Full Text] [PDF]
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V. Fuster, M. Poon, and J. T. Willerson Learning From the Transgenic Mouse : Endothelium, Adhesive Molecules, and Neointimal Formation Circulation, January 13, 1998; 97(1): 16 - 18. [Full Text] [PDF]
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R. Singh, S. Pan, C. S. Mueske, T. Witt, L. S. Kleppe, T. E. Peterson, A. Slobodova, J.-Y. Chang, N. M. Caplice, and R. D. Simari Role for Tissue Factor Pathway in Murine Model of Vascular Remodeling Circ. Res., July 6, 2001; 89(1): 71 - 76. [Abstract] [Full Text] [PDF]
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M. D. Layne, S.-F. Yet, K. Maemura, C.-M. Hsieh, X. Liu, B. Ith, M.-E. Lee, and M. A. Perrella Characterization of the Mouse Aortic Carboxypeptidase-Like Protein Promoter Reveals Activity in Differentiated and Dedifferentiated Vascular Smooth Muscle Cells Circ. Res., April 5, 2002; 90(6): 728 - 736. [Abstract] [Full Text] [PDF]
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