(Circulation. 2001;103:3105.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Plasminogen Activator Inhibitor Type 1 Enhances Neointima Formation After Oxidative Vascular Injury in Atherosclerosis-Prone Mice
From the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
Correspondence to William P. Fay, MD, University of Michigan Medical Center, 7301 MSRB III, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0644. E-mail wfay{at}umich.edu
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Abstract |
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Background—Plasminogen activator inhibitor type 1 (PAI-1) inhibits neointima formation after vascular injury. Hyperlipidemia modulates the expression of multiple genes, however, and the effects of PAI-1 on the arterial response to injury under hyperlipidemic conditions are unknown. The purpose of this study was to examine the impact of PAI-1 on intimal hyperplasia and other vascular changes that develop after arterial injury in apolipoprotein E–deficient (apoE-/-) mice.
Methods and Results—Ferric chloride injury of the midportion of the common carotid arteries of apoE-/- mice (n=22) induced formation of a neointima that contained smooth muscle cells, foam cells, neutral lipid, tissue factor, and von Willebrand factor. Interactions between vascular injury and apolipoprotein E deficiency were strongly synergistic; either stimulus alone was insufficient to induce significant neointima formation. Mean intima/media ratios were significantly greater (P<0.03) in apoE-/-, PAI-1+/+ mice (5.6±1.8, n=12) than in apoE-/-, PAI-1-/- mice (1.2±0.55, n=12), as were the percentages of bromodeoxyuridine-positive cells in the intima and media (P<0.03). Transiently occlusive (<48 hours) and nonocclusive mural thrombi persisted longer in apoE-/-, PAI-1+/+ mice than in apoE-/-, PAI-1-/- mice.
Conclusions—In atherosclerosis-prone mice, PAI-1 promotes neointima formation after oxidative vascular injury. The apparent hyperlipidemia-dependent effect of PAI-1 may be mediated by its capacity to inhibit the clearance of platelet-fibrin thrombi that can deliver growth factors to the blood vessel wall or be incorporated into developing vascular lesions. Alternatively, hyperlipidemia may alter the pattern of gene expression in the blood vessel wall to enhance potential effects of PAI-1 on antiproliferative processes, such as transforming growth factor-ß activation and apoptosis.
Key Words: plasminogen activators • apolipoproteins • vascular biology
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Introduction |
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The arterial response to injury is characterized by cell proliferation and migration. This response plays a key role in several arterial disorders, including atherosclerosis and intimal hyperplasia after balloon angioplasty.1 The plasminogen activation system is an important determinant of vascular remodeling after injury.2 Cell-associated plasmin mediates the migration of smooth muscle and inflammatory cells within the blood vessel wall.3 4 Plasmin also degrades fibrin-platelet thrombi, which can be incorporated into atherosclerotic lesions and contribute to their growth.5 Plasminogen activator inhibitor type 1 (PAI-1), the primary inhibitor of tissue plasminogen activator and urokinase, is a key regulator of the plasminogen activation system. PAI-1 is present in plasma and platelets, and it is synthesized by vascular endothelial and smooth muscle cells.6 In humans, PAI-1 deficiency is associated with abnormal bleeding, and elevated plasma and vascular wall PAI-1 levels are associated with atherosclerosis and myocardial infarction.7 8 9 Vascular cell migration after injury is inhibited by PAI-1.10 This effect appears to be mediated by inhibition of plasmin formation and possibly by PAI-1 binding to vitronectin, thereby preventing its interaction with vitronectin receptors present on vascular smooth muscle cells.11
The effects of PAI-1 on arterial remodeling after injury have been studied in animals with normal lipid metabolism.10 12 Hyperlipidemia modulates the expression of multiple genes that regulate the arterial response to injury, however, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and monocyte chemoattractant protein 1.13 The effects of PAI-1 on the arterial response to injury under hyperlipidemic conditions are unknown. The purpose of this study was to examine the impact of PAI-1 deficiency on intimal hyperplasia and other vascular wall changes that develop after arterial injury in apolipoprotein E–deficient (apoE-/-) mice. Our results suggest that PAI-1 contributes to neointima formation under these experimental conditions and support the hypothesis that disordered lipid metabolism plays an important role in modulating the effect of PAI-1 on the arterial response to injury.
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Methods |
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Animals
ApoE-/- mice were purchased from Jackson Laboratories. PAI-1–deficient (PAI-1-/-) mice were a gift from Dr Peter Carmeliet, University of Leuven, Leuven, Belgium.14 All mice were backcrossed
8 generations into the C57BL/6J genetic background.
PAI-1–deficient mice and apolipoprotein E–deficient mice were crossed
to generate apoE-/-,
PAI-1-/- mice. Genotyping of mice was
performed by polymerase chain reaction analysis of tail DNA.
All animal care and experimental procedures complied with the
"Principles of Laboratory Animal Care" established by the National
Society for Medical Research and were approved by the University of
Michigan Committee on Use and Care of Animals.
Carotid Injury Protocol
Ferric chloride injury of the carotid artery was
performed on 6- to 10-week-old mice as reported
previously.15 Vascular
injury and thrombosis were induced by placing filter paper saturated
with 10% ferric chloride on the adventitia of the midportion of the
artery for 3 minutes. After the filter paper had been removed, the
incision was sutured closed. Mice subsequently were fed either
high-cholesterol chow (TD 88137, Harlan Teklad) or normal
chow (Rodent Diet 5001, LabDiet). Four to 8 weeks after carotid injury,
the inferior vena cava was exposed, and a blood sample was
collected for subsequent determination of plasma total
cholesterol, HDL cholesterol, and
triglycerides with colorimetric assay kits
(Sigma). The arterial vasculature
was perfusion-fixed,16 and
both carotid arteries were excised and processed for
histological analyses. Mice were injected with
bromodeoxyuridine (BrdU) 18 hours (100 mg/kg IP) and 1 hour (25 mg/kg
by tail vein injection) before they were euthanized. Selected mice were
sedated 1 to 4 days after the surgical procedure, and the injured
carotid artery was interrogated with a 20-MHz Doppler flow probe
(provided by Dr Craig Hartley, Baylor College of Medicine, Houston,
Tex) or perfusion-fixed and excised for histological
analysis.
Measurements of Carotid Artery Occlusion Time
and Platelet Aggregation
ApoE-/- mice (6 to 8
weeks old) were fed normal chow or high-cholesterol chow
for 4 weeks, then subjected to ferric chloride carotid injury. Time
required to form an occlusive thrombus was determined as
described.15 In vitro
platelet aggregation was studied as
described.17
Histological
Analyses
Four evenly spaced cross sections were prepared from
the midportion of each carotid artery and subjected to
hematoxylin-eosin staining. Intima and media areas of each cross
section were determined by computer-assisted planimetry
(Image-Pro Plus, Media Cybernetics), and the
mean intima and media cross-sectional area was calculated for each
artery. Intima was defined as the area bounded by the
endothelium and the internal elastic lamina. Media was
defined as the area bounded by the internal and external elastic
laminae. The operator was blinded to specimen genotype when
performing all analyses. Oil red O staining was performed as
described previously.18
Elastic stain (HT25-A, Sigma) was used to identify the elastic laminae.
Anti-BrdU staining was performed with a BrdU staining kit
(Zymed Laboratories). Tissue factor expression
was detected by digoxigenin-labeled human factor VIIa
staining.19 The chromogen
for tissue factor staining was nitro blue tetrazolium
chloride/X-phosphate (Digoxigenin Detection Kit, Boehringer
Mannheim), and counterstaining was performed with nuclear fast red
solution (Poly Scientific R&D Corp). Macrophages were
identified by a rat monoclonal antibody to Mac-3 (Pharmingen). Smooth
muscle 
-actin staining was performed with anti-human smooth muscle
-actin monoclonal antibody (clone 1A4, Dako). Fibrin was detected
with a goat anti-mouse fibrinogen antibody (Accurate). von
Willebrand factor (vWF) was detected with rabbit anti-human vWF
antibody (Dako). All cross sections were 5 µm thick. Frozen sections
were used for oil red O staining. All other sections were
paraffin-embedded.
Statistical Analyses
Data are presented as mean±SEM. An unpaired
Student’s t test was used to
compare groups.
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Results |
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Characterization of the Arterial Response to Ferric Chloride Injury in ApoE-/- Mice
Application of ferric chloride to the adventitial surface of arteries induces full-thickness injury, endothelial denudation, and platelet-rich thrombus formation.15 20 Carotid artery blood flow was monitored with a transcutaneous 20-MHz Doppler flow probe in 6 apoE-/- mice (3 female) at 24 and 48 hours after ferric chloride injury. At 24 hours, 4 of 6 arteries were patent; at 48 hours, 6 of 6 arteries were patent. Another 4 apoE-/- mice (2 female) were subjected to ferric chloride carotid artery injury. Four days later, mice were euthanized, and the injured carotid artery was excised, sectioned, and subjected to hematoxylin-eosin staining. All 4 injured arteries were patent, although residual mural thrombus was present in 2 arteries. These studies in 10 mice indicated that 10% ferric chloride carotid artery injury produced thrombi that only transiently occluded blood flow.
ApoE-/- mice were euthanized
4 weeks (n=12) or 8 weeks (n=10) after carotid injury. Of mice that
were studied at 4 weeks after injury, 5 animals (3 female) received
normal chow and 7 animals (4 female) received
high-cholesterol chow. Of mice that were euthanized 8 weeks
after injury, 5 animals (2 female) received normal chow and 5 animals
(2 female) received high-cholesterol chow. Marked intimal
hyperplasia was observed in all injured arteries, regardless of diet,
whereas no intimal hyperplasia was observed in the contralateral (ie,
noninjured) carotid arteries
(Figure 1
). Intima and media cross-sectional areas and
intima/media ratios are shown in
Table 1. Mean intima area 4 weeks after injury was
greater in mice fed high-cholesterol chow than in those fed
normal chow. As controls, 5 apoE+/+ mice
were subjected to ferric chloride injury, then fed a
high-cholesterol chow for 8 weeks. No or only minimal
neointima formation was observed
(Figure 1D). These results indicated that both abnormal lipid
metabolism and arterial injury were necessary
to induce significant intimal hyperplasia within the midportion of the
murine carotid artery.
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We performed detailed histological
analyses of arteries retrieved 8 weeks after injury.
Immunohistochemistry confirmed the presence of smooth muscle
-actin–positive cells in neointima
(Figure 2E). Anti-BrdU staining demonstrated ongoing cell
proliferation within the intima and media
(Figure 2B). Cholesterol clefts
(Figure 1B
) and numerous foam cells
(Figure 1C) were observed. Oil red O staining demonstrated
neutral lipid deposition within the intima and media
(Figure 2A). Immunostaining confirmed the
presence of macrophages in neointimal lesions
(Figure 2F). Tissue factor expression, which is restricted
almost entirely to the adventitia of normal
arteries,19 21
was detected in the intima, media, and adventitia of injured arteries
(Figure 2C and 2D). Fibrin deposition was detectable in the
intima of 2 of 6 apoE-/-,
PAI-1+/+ mice
(Figure 2H) and in 0 of 3
apoE-/-,
PAI-1-/- mice. Diffuse
neointimal (ie, not restricted to
endothelial cells) vWF staining was observed in 5 of 5
arteries studied
(Figure 2G).
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Effect of High-Cholesterol Diet on
the Rate of Occlusive Thrombus Formation
To explore potential interactions between diet and
thrombosis, 6-week-old apoE-/- mice were
fed normal chow (n=7, 4 female) or high-cholesterol chow
(n=7, 3 female) for 4 weeks, then subjected to carotid artery injury.
The mean time necessary to form an occlusive thrombus was shorter in
mice fed a high-cholesterol diet (12.7±2.8 minutes) than
in those fed normal chow (22.3±1.7 minutes;
P<0.02). Platelet-rich
plasma was prepared from apoE-/- mice
after 4 weeks of a normal chow diet (n=8, 4 female) or a
high-cholesterol diet (n=8, 4 female). Mean maximal percent
aggregation after ADP stimulation (20 µmol/L) was 80±3% for mice
fed high-cholesterol chow versus 64±6% for mice fed
normal chow
(P<0.05).
Effect of PAI-1 Deficiency on Remodeling After
Carotid Artery Injury in ApoE-/-
Mice
We tested the hypothesis that PAI-1 enhances
neointima formation after vascular injury in
apoE-/- mice.
ApoE-/-,
PAI-1+/+ mice (n=12, 6 female) and
apoE-/-,
PAI-1-/- mice (n=12, 6 female) were
subjected to ferric chloride carotid injury, then fed a
high-cholesterol diet for 8 weeks. The gross appearance of
arteries at the time of harvest differed significantly between the 2
groups
(Figure 3A and 3B). Histological
analyses confirmed that neointima formation was
significantly greater in apoE-/-,
PAI-1+/+ mice than in
apoE-/-,
PAI-1-/- mice
(Figure 3C and 3D). Mean intima and media cross-sectional
areas were 
10-fold and 2-fold greater, respectively, for
apoE-/-,
PAI-1+/+ mice (intima 0.143± 0.05
mm2; media 0.025±0.0035
mm2) than for
apoE-/-,
PAI-1-/- mice (intima 0.014±0.0049
mm2; media 0.015±0.0028
mm2). These differences were statistically
significant
(Figure 4). Intima/media ratios of
apoE-/-,
PAI-1+/+ mice were 5.6±1.8, compared with
1.2±0.55 for apoE-/-,
PAI-1-/- mice
(P<0.03). Mean intima and
media cell proliferation indices, determined by anti-BrdU staining,
were significantly greater for apoE-/-,
PAI-1+/+ mice than for
apoE-/-,
PAI-1-/- mice
(Table 2). Four sets of adjacent cross sections obtained
from 4 different arteries were immunostained with
anti-smooth muscle -actin and anti-BrdU antibodies. This
analysis revealed that 96% of BrdU-positive cells (ie, 48 of
50 counted cells) were also smooth muscle -actin–positive. To
determine whether the amount of thrombus present in arteries early
after ferric chloride injury differed between
apoE-/-,
PAI-1-/- mice and
apoE-/-,
PAI-1+/+ mice, transcutaneous Doppler
analysis was performed in 5
apoE-/-,
PAI-1-/- animals. Carotid arteries were
patent in 5 of 5 apoE-/-,
PAI-1-/- mice 24 hours after injury.
Histological analysis of multiple
hematoxylin-eosin–stained cross sections from 4
apoE-/-,
PAI-1-/- mice (different animals than
the 5 apoE-/-,
PAI-1-/- mice studied with
transcutaneous Doppler ultrasound) 4 days after injury revealed no
detectable thrombus. These results contrasted with those of similar
experiments (described above) performed with
apoE-/-,
PAI-1+/+ mice. Plasma total
cholesterol, HDL cholesterol, and
triglyceride levels were measured in
apoE-/-,
PAI-1+/+ mice and
apoE-/-,
PAI-1-/- mice. Total
cholesterol and triglycerides were higher in
mice lacking PAI-1, whereas HDL cholesterol levels did not
differ between groups
(Table 3). These results indicated that the enhanced
neointima formation observed in mice with normal PAI-1
expression could not be explained by higher plasma lipid concentrations
than in mice lacking PAI-1.
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Discussion |
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We examined the arterial response to injury in atherosclerosis-prone mice. We found that topical application of ferric chloride to the murine carotid artery resulted in endothelial cell denudation, medial cell necrosis, and formation of transiently occlusive, platelet-rich thrombi. This acute response was followed by intimal and medial hyperplasia and deposition of foam cells, neutral lipid, tissue factor, vWF, and fibrin within the blood vessel wall. We examined the impact of PAI-1 on the arterial response to injury by performing morphometric analyses of apoE-/-, PAI-1+/+ mice and apoE-/-, PAI-1-/- mice 8 weeks after injury. We found that PAI-1 deficiency resulted in a marked reduction in the hyperplastic response to injury. Carmeliet et al10 found greater neointima formation in PAI-1-/- mice than PAI-1+/+ mice after mechanical carotid artery injury or electrical femoral artery injury. In contrast, in our experiments, PAI-1 deficiency was protective against neointima formation. Although our results and those of Carmeliet et al are potentially contradictory, the factors regulating cell migration and proliferation in the hyperlipidemic environment caused by apoE deficiency (as in our experiments) most likely differ considerably from those that control posttraumatic neointima formation in the absence of hyperlipidemia (as in the experiments of Carmeliet et al). Hyperlipidemia alters the expression of multiple genes that regulate the arterial response to injury, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1.13 The effects of mouse strain could also have contributed to the differential effects of PAI-1 in the 2 studies. The mice used in our experiments were extensively backcrossed (n
8) to the C57BL6 genetic background,
whereas Carmeliet et al used mice that were 75% C57BL6/25% 129.
Alternatively, the method of injury may have contributed to the
differences between studies. Carmeliet et al predominantly used
perivascular electric injury, whereas we used chemical injury. Electric
current and ferric chloride both induce cell necrosis within the
intima, media, and adventitia, and both forms of injury cause
thrombosis.16 Ferric
chloride induces the formation of highly reactive oxygen species, such
as hydroxyl radical, that injure cells by causing lipid
peroxidation.20 Oxidative
stress and lipid peroxidation play major roles in a variety of
arterial disorders, such as
atherosclerosis.13
In a copper-induced arterial injury model, Ploplis et
al12 observed decreased
neointima formation in
PAI-1-/- mice compared with
PAI-1+/+ mice. These results are
consistent with ours and support the hypothesis that PAI-1
contributes to neointima formation after oxidative vascular
injury.
The function of PAI-1 in vascular diseases has been
considered paradoxical.22
Vascular smooth muscle cell migration is a major determinant of the
pathological neointima that develops after
arterial injury. Inhibition of cell migration by PAI-1
might be expected to exert a "good" effect by limiting the size of
arterial lesions. Inhibition of cell migration, however,
could help to produce hypocellular lesions that are prone to rupture
and trigger thrombosis. Such a "bad" effect of PAI-1 might be
highly dependent on hypercholesterolemia,
because it is lipid-rich atheroma that typically rupture.
Our studies yield important data regarding the "PAI-1
paradox."22 We have shown
that PAI-1 deficiency protects against lesion growth after oxidative
injury in hyperlipidemic mice. Several mechanisms could
account for this effect. The impact of PAI-1 on the extent and duration
of mural thrombosis after injury could be involved. Platelet
thrombi are a source of growth factors that can stimulate vascular cell
proliferation.1 Our current
and previously published data show that thrombi are cleared from
injured arteries more rapidly in
PAI-1-/- mice than
PAI-1+/+
mice.15 17 We
hypothesize that enhanced stimulation of cell proliferation by
thrombus-associated growth factors may have accounted for the increased
intimal and medial hyperplasia observed in
apoE-/-,
PAI-1+/+ mice compared with
apoE-/-,
PAI-1-/- mice. We observed fibrin in
some arteries of apoE-/-,
PAI-1+/+ mice 8 weeks after injury,
suggesting that organization and incorporation of thrombus into
developing lesions may have contributed to their growth.
Consistent with this hypothesis, the pattern of vWF staining in
the neointima was diffuse—ie, not restricted to the
endothelial cell monolayer
(Figure 2G). Such a pattern, which has been observed in
injured arteries of other
species,23 could occur if
platelet-rich thrombi were incorporated into developing lesions.
Although Carmeliet et al16
also observed transient thrombosis after arterial injury,
it is possible that the thrombus-dependent effects of PAI-1 on
neointima formation after injury could be significantly
greater in hyperlipidemic mice. We found that the
marked hypercholesterolemia induced in
apoE-/- mice by
high-cholesterol feeding resulted in enhanced
platelet-dependent thrombosis compared with
apoE-/- mice fed a normal chow diet,
results consistent with those of Eitzman et
al.24
Hypercholesterolemia is associated with
enhanced tissue factor expression, which may help to explain this
observation.21 We also
observed enhanced ADP-induced platelet aggregation in vitro after
high-cholesterol feeding, however, suggesting a direct
effect of hyperlipidemia on platelet
reactivity.
A direct effect of PAI-1 on the blood vessel wall must also
be considered a possible mechanism underlying our results. PAI-1
regulates processes important in cell migration, including plasmin
formation and the interactions of cell-surface receptors, such as the
uPA receptor and the integrin
vß3, with
vitronectin.11 25
PAI-1 deficiency, however, would be expected to enhance cell migration
mediated by plasmin digestion of extracellular matrix or by interaction
of vitronectin with cell-surface receptors. PAI-1 could
inhibit the activation of transforming growth factor-ß (TGF-ß) by
plasmin. The preponderance of published studies suggest that
activated TGF-ß inhibits vascular smooth muscle cell
proliferation.26 Our results
are consistent with the hypothesis that PAI-1 can promote cell
proliferation by inhibiting TGF-ß activation. Because
hyperlipidemia enhances TGF-ß expression in
macrophages and vascular smooth muscle
cells,27 28 the
magnitude of a potential effect of PAI-1 on TGF-ß expression might be
expected to differ between mice with normal versus abnormal lipid
metabolism. Finally, recent studies suggest that PAI-1
inhibits apoptosis in a variety of cultured cell lines,
including umbilical vein endothelial
cells.29 Vascular cell
apoptosis is observed after arterial injury in
hyperlipidemic
rabbits.30 An
antiapoptotic effect of PAI-1 would be consistent with
the increased intimal hyperplasia that we observed in
apoE-/-,
PAI-1+/+ mice compared with
apoE-/-,
PAI-1-/- mice. Additional studies are
needed to explore these hypotheses.
Our study is relevant to the potential role of PAI-1 in atherosclerosis development.9 When apoE-/-, PAI-1+/+ mice and apoE-/-, PAI-1-/- mice are compared, atherosclerosis within the aortic root does not differ,31 whereas atherosclerosis at the carotid artery bifurcation is reduced in mice lacking PAI-1.32 It is likely that the impact of PAI-1 on atherosclerosis development depends on the degree to which vascular injury (eg, from turbulent flow at arterial branch points) is present, because injury triggers activation of pathways that are regulated by PAI-1. Our model adds a component of injury at a readily retrievable vascular site to a widely used model of atherosclerosis (ie, apoE-/- mice). Therefore, it may prove useful in studying the roles of other genetic loci that modulate atherosclerosis development after arterial injury.
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Acknowledgments |
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This work was supported by NIH grant HL-57346 (Dr Fay) and a Postdoctoral Fellowship award from the American Heart Association, Midwest Affiliate (Dr Zhu).
Received December 14, 2000; revision received February 23, 2001; accepted March 1, 2001.
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