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From the W. M. Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-enolase for
plasminogen1-3
and uPAR for uPA.4
These
functions are supported by in vitro studies that have
identified uPA and uPAR at the leading migratory edges of monocytes and
smooth muscle cells.5,6
In addition to the involvement of
components of the fibrinolytic system in facilitating cell migration
through matrix-degrading processes,7-9
these agents have
been shown to influence normal and pathological cell migratory events
by release and activation of a number of inflammatory
mediators,10-12
as well as by chemotactic
processes,13-15
integrin-mediated
signaling,16
and other potentially novel
mechanisms.17
Plasmin has also been shown to act directly
as a chemoattractant for human peripheral monocytes.18
Alternatively, PAI-1 has also been implicated in cell migration through
its ability to disrupt uPA/uPAR-matrix protein interactions, thus
facilitating cell detachment.19
Indeed, macrophage
colony-stimulating factor (or CSF-1) and granulocyte-macrophage
colony-stimulating factor have been shown to increase both PAI-1 and
PAI-2 expression in human monocytes,20
potentially
implicating these proteins in processes involved in inflammation and
tissue remodeling.21 Atherosclerosis is a chronic inflammatory disease in which the fibrinolytic system plays a major role. For example, several studies have indicated that high plasma levels of fibrinogen and decreased fibrinolytic activity, ie, increased PAI-1, lead to an increased risk for cardiovascular disease.22,23 Additionally, components of the fibrinolytic system have been identified in atherosclerotic lesion tissue.24,25 Other studies have indicated that insoluble fibrin may promote atherosclerotic lesion formation by affecting smooth muscle cell proliferation and migration, collagen deposition, and cholesterol accumulation.26
The generation of mice deficient for components of the fibrinolytic system has resulted in the development of valuable resources for directly assessing the physiological impact of an imbalanced fibrinolytic system on both early and late stages of a number of inflammation-based diseases. Diminished inflammatory responses have been identified in uPA-deficient (UPA-/-) and plasminogen-deficient (PG-/-) mice challenged with a number of different agents.27-29
Murine models for vascular injury/repair are extremely valuable for the study of early and late stage inflammatory disease because the role of genetic factors in inflammation can be investigated effectively using gene-targeted animals. In the current study, a copper-induced model of inflammation has been characterized in WT mice, and applied to mice deficient in the PAI-1 gene (PAI-1-/-). This model is based on the finding that increased plasma levels of copper have been associated with cardiovascular disease.30,31 The results of this study are presented herein.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Prosthetic silicone elastomer, MDX4-4210, (Factor II, Inc.,
Lakeside, AZ) and copper powder, spherical, -100 + 325 mesh, (Alfa
Aesar, Ward Hill, MA) were used to construct the cuffs, which have an
inside diameter of 0.028" and an outside diameter of 0.062". The
construction was a major modification of a similar cuff used in
rats.32
The two-part silicone product was combined with
the copper dust and then degassed under vacuum. Stainless steel molds,
which mimic the size of the diameter of a mouse carotid artery, were
used in the construction. The copper/silicone mixture was spread over
both halves of the mold, after which stainless steel rods (0.028"
outside diameter/22 gauge) were placed in each of the 15 slots of the
mold (0.042" outside diameter of the complete mold slot). The mold
halves were combined, pressed closed, and baked at 80°C for 
8
hours. The copper/silicone-coated rods were then inserted in one-half
of a larger mold (0.062" outside diameter of the complete mold slot),
coated with silicone alone, pressed closed with the other one-half of
the similarly coated mold, and then baked as described above.
Placement of Copper/Silicone Cuff around the Artery
Male and female C57 BL/6J wild-type (WT) mice (8 to12 weeks of age) and mice totally deficient for the PAI-1 gene (PAI-1-/-) were used in this study. All animals were maintained in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and experimental protocols were approved by the Institutional Animal Care and Use Committee.
The left carotid artery of mice anesthetized with an intraperitoneal injection of rodent cocktail (0.015 mg xylazine/0.075 mg ketamine/0.0025 mg aceprozamine/g weight of animal) was surgically exposed via a midline incision over an area from the chin to the sternum that had been sterilized with a 1% iodine solution. The salivary gland was separated and the artery dissected proximal to the bifurcation. A copper/silicone cuff, 1 to 1.5 mm in length, was placed around the periphery of the artery proximal to the bifurcation. The surgical site was then closed with a 6-0 nylon suture and the mice allowed to recover. At 7- and 21-days after implantation, the mice were again anesthetized and the left carotid artery re-exposed to remove the cuffed artery. The contralateral right artery served as a negative control.
Histochemistry
Arteries were either fixed in 10% neutral-buffered formalin for processing and paraffin embedding or immersed in 20% sucrose and then frozen in Tissue-Tek OCT (Sakura Fine Tek Co., Torrance, CA) compound for cryosectioning. Paraffin-embedded arteries were sectioned between 3 µm and 4 µm. Hematoxylin 2 and eosin Y (H&E; Richard Allen Scientific, Kalamazoo, MI) stains were performed to assess cellular morphology. Masson’s trichrome stain33 was used to identify collagen in the arterial wall and Verhoeff’s Van Gieson staining34 was used to identify elastica laminae and to perform morphometric measurements. Cryotomy sections (8 µm) were used for Oil Red O staining to identify fat deposits in the injured arteries.35
Immunohistochemistry
A polyclonal goat anti-mouse fibrin(ogen) antibody (Accurate Chemicals, Westbury, NY) was used for immunohistochemical identification of fibrin. The slides were incubated with rabbit serum and then with the anti-fibrin antibody, followed by secondary rabbit anti-goat IgG (DAKO, Carpinteria, CA) and goat peroxidase anti-peroxidase (DAKO). Peroxidase activity was detected with the substrate, 3-amino,9-ethylcarbazole (AEC) (Biomeda, Foster City, CA). A hematoxylin counterstain (Biomeda) was used for all immunohistochemistry. Antigen retrieval was performed under high temperature and pressure with citrate buffer, pH 6.0 (Zymed, South San Francisco, CA), followed by endogenous peroxidase blocking with Peroxoblock (Zymed).
CD45 rat anti-mouse monoclonal antibody (Pharmingen, San Diego, CA) was
used to identify leukocytes. The secondary antibody consisted of a
biotin-conjugated goat anti-rat antibody (DAKO), which was followed by
a solution of streptavidin-conjugated horseradish peroxidase
(Biogenex). Detection with AEC, antigen retrieval with citrate
buffer, and blocking of endogenous peroxidase were as above. A similar
procedure was used for detection of smooth muscle cells with an
anti--actin monoclonal antibody (Sigma Chemical Co., St. Louis, MO),
except that antigen retrieval was accomplished with a limited trypsin
treatment.
Immunohistochemical identification of von Willebrand factor (vWF)-positive cell types (endothelial cells, megakaryocytes, and platelets) was accomplished using an EPOS anti-human vWF antibody conjugated to peroxidase (DAKO). Development was accomplished with AEC. Antigen retrieval was performed with limited trypsin digestion. Blocking of endogenous peroxidase was as above.
PAI-1 expression in the vessel wall was evaluated by immunohistochemistry using a rabbit anti-murine PAI-1 polyclonal antibody (Molecular Innovations, Inc., Royal Oak, MI). The second antibody was biotin-conjugated porcine anti-rabbit IgG (DAKO), after which streptavidin-conjugated horseradish peroxidase (Biogenex) was added. Antigen retrieval with citrate buffer, detection with AEC, and blocking of endogenous peroxidase were as above.
Cell Proliferation
Mice were injected intraperitoneally with 50 mg/kg
bromodeoxyuridine (BrdU) in physiological saline at times of 24, 16,
and 1 hour before sacrificing. A mouse monoclonal anti-human antibody
to BrdU was used to identify proliferating cells in the vascular wall.
The secondary antibody consisted of a biotin-conjugated rabbit
anti-mouse IgG antibody (DAKO), after which was added
streptavidin-conjugated horseradish peroxidase, followed by development
with AEC. Antigen retrieval was accomplished by incubation in 1 mol/L
HCl at 37°C for 10 minutes followed by limited trypsin digestion.
Endogenous peroxidase activity was blocked with Peroxoblock. Total
cells in the vascular wall compartments were counted and the percentage
of BrdU-positive cells was determined for equally spaced sections
within the cuffed area of the artery. Five sections per artery,
separated by 50 µm/section, of 200 to 300 µm length of injured
artery were analyzed. The average values per artery for each genotype
were used to determine the mean ±SEM.
Morphometric Analyses
Morphometric measurements of cross-sectional areas were performed on transverse sections of the artery using a computer-assisted image analysis system (Bioquant True Color Windows software; Biometrics, Nashville, TN) on equally spaced sections within the cuffed area of the artery. The number of sections and length of injured artery analyzed were similar to that described for cell proliferation analyses. The average values per artery for each genotype were used to determine the mean ±SEM.
Neovascularization
Neovascularization was determined by counting the number of vWF-positive vessels in the adventitial compartment of injured arteries and expressed as the number of vessels per mm2 area. Counts were made over equally spaced sections (4 to 5 fields/vessel) within the cuffed area of the artery and average values per artery for each genotype were used to determine the mean ±SEM.
Electron Microscopy
Ultrastructural analyses were performed on 3-day injured arteries. The arteries were perfused and fixed with Karnovsky solution36 and postfixed in 1% osmium tetroxide, dehydrated in a graded series of ethanol solutions, and embedded in epoxy resins (Polysciences, Warrington, PA). Ultrathin sections (90 nm) were cut and stained in 2% uranyl acetate and Reynolds lead stain.37 Sections were viewed and photographed using a transmission electron microscope (Hitachi H 600; Hitachi, Tokyo, Japan) at 75 kV accelerating voltage.
Statistical Analysis
Where appropriate, values were expressed as mean ±SEM. Comparisons were made using Student’s t-test and P values <0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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H&E stains of WT carotid arteries 7 days after injury demonstrated
an increase in cellularity and reactivity in medial and adventitial
compartments relative to uninjured arteries, with evidence of a small
neointima (Figure 1A)
. Intimal, medial,
and adventitial compartments were significantly increased in size in
arteries from WT mice relative to arteries from
PAI-1-/- mice (0.011 ± 0.001
mm2
versus 0.004 ± 0.0004
mm2, P < 0.001, respectively,
for the intimal compartment; 0.046 ± 0.004
mm2
versus 0.020 ± 0.001
mm2, P = 0.003, respectively, for
the medial compartment; and 0.108 ± 0.009
mm2
versus 0.075 ± 0.008
mm2, P = 0.021, respectively, for
the adventitial compartment; Table 1
).
Despite the smaller adventitia in arteries from
PAI-1-/- mice relative to WT mice, the
proliferative index, as measured by BrdU uptake, was significantly
increased in the adventitia in arteries from
PAI-1-/- mice compared to arteries from WT mice
(16.7 ± 3.3% versus 3.5 ± 1.9%,
P = 0.0269, respectively; Table 2
). Medial compartments in arteries from
both WT and PAI-1-/- mice exhibited a smooth
muscle cell-enriched region (Figure 1, C and D)
. The neointima in
WT-injured arteries consisted primarily of leukocytes (Figure 1, E and F)
. Additionally, fibrin deposits were significantly enhanced in
the medial and adventitial compartments (Figure 1G)
. This is in sharp
contrast to that observed in injured arteries from
PAI-1-/- mice, wherein no fibrin was observed
in the vessel wall (Figure 1H)
.
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H&E stains of carotid arteries from WT mice 21 days after injury
revealed an enlarged multilayered neointima (0.036 ± 0.005
mm2
for day 21 versus 0.011 ±
0.001 mm2
for day 7, P = 0.0003;
Figure 2A
and Table 1
), consisting of
smooth muscle cells that appeared to be primarily confined to the
luminal edges of the neointima (Figure 2C)
. These arteries also
presented enhanced collagen deposition (Figure 2E)
. WT neointima was
also significantly larger than PAI-1-/-
neointima at day 21 (0.036 ± 0.005 mm2
versus 0.007 ± 0.002 mm 2,
P < 0.0001, respectively; Table 1
). Cell proliferation
in the medial compartment of arteries from WT mice compared to
PAI-1-/- arteries were also enhanced (10.1
± 3.9% versus 2.3 ± 0.3%, P =
0.1168, respectively; Table 2
). This is consistent with a lack of
neointima formation in arteries from PAI-1-/-
mice, which is derived primarily from proliferating smooth muscle cells
from the medial compartment (Figure 2, B, D, and F)
. Although there did
not seem to be any degradation of the elastica laminae in injured
arteries from WT mice, as visualized by Verhoeff’s Van Gieson
staining, stretching and thinning were evident (Figure 3A)
. In contrast, the elastica laminae
appeared unaffected in injured arteries from
PAI-1-/- mice (Figure 3B)
. Immunostaining of
vWF in carotid arteries from both WT and
PAI-1-/- mice indicated the presence of a
normal intact contiguous single-layer intima of endothelial cells
adjacent to the lumen of the vessel (Figure 3, C and D)
. Fibrin
deposits in the injured WT arteries remained unresolved, primarily in
the adventitial compartment (Figure 4A)
,
most likely because of continued injury to the vessel wall by copper.
Injured arteries from PAI-1-/- mice
demonstrated little, if any, fibrin in the vessel wall (Figure 4B)
.
Enhanced PAI-1 expression was also evident in carotid arteries from WT
mice (Figure 4C)
in the same vascular compartments that fibrin deposits
were found, but not in the uninjured contralateral artery (Figure 4D)
.
Fat deposition in the arterial wall, most likely because of copper
ion-induced oxidation of low-density lipoprotein (LDL), was evident in
arteries from WT mice, primarily confined to the medial layer adjacent
to the elastic lamina (Figure 4E)
, but not in arteries from
PAI-1-/- mice (Figure 4F)
. At day 21,
neovascularization in the adventitia was more evident in injured
arteries from WT mice than in PAI-1-/- mice
(159 ± 6/mm2
versus 105 ±
8/mm2
vessels, P = 0.0057; Figure 5
). Neovascularization of the adventitial
compartment in PAI-1-/- arteries was relatively
unchanged in day 21 arteries compared to those analyzed at day 7
(105 ± 8/mm2
versus 106 ±
5/mm2, respectively).
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To investigate the effects of a perivascular source of injury on
the luminal side of the vessel, electron microscopic analyses were
performed 3 days after cuff placement. Although injury was induced from
the adventitial side of the vessel, inflammatory cell adhesion and
transendothelial migration from the lumen were already evident 3 days
after injury (Figure 6, A and B)
. Similar
changes were observed in injured arteries from
PAI-1-/- mice (Figure 6, C and D)
. This
indicates that the response to injury was also occurring from the
luminal side of the vessel as early as a few days after perivascular
cuff placement.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A number of animal models have evolved that attempt to differentiate among specific mechanisms involved in atherosclerotic lesion development.48 Transgenic mice have been developed in which genes that regulate the atherosclerotic process have been altered, ie, apo E and LDL receptor (LDLR).49,50 However, because of the complexity of human atherosclerotic development, the relevance of the mouse model has been questioned. Despite this, the mouse has become increasingly useful for studying atherosclerosis and its risk factors. For example, this animal presents a classic model for genetic studies because inbred strains and complete linkage maps are available. Additionally, a number of strains exhibiting genetic variations relevant to atherosclerosis have been identified and have provided an opportunity to examine the involvement of candidate genes. Finally, techniquesfor genetic manipulation in vivo are more advanced in the mouse than in other animals.
In the current study, copper-induced oxidative damage to the vascular wall resulted in accelerated neointima formation, matrix protein and lipid deposition, and neovascularization; all clinical features of atherosclerosis. It has been indicated that neovascularization of the vessel wall may be an important feature of early atherosclerosis development and could potentially serve as an alternative means for transport of leukocytes and lipid into the vessel wall.51 Interestingly, in this study fibrin deposits persisted throughout the progression of lesion formation and were major components of the diseased artery. Indeed, fibrin and fibrin degradation products have been shown to stimulate the migration of smooth muscle cells and, therefore, may contribute directly to neointima formation.26,52 Advanced human atherosclerotic lesions also contain significant amounts of fibrin and, therefore, this model is ideal for studying the thrombotic response associated with the progression of this disease.53
Because clinical studies have shown that increased plasma PAI-1 levels are conducive to the development of cardiovascular disease,22,23 a number of in vivo investigations have been undertaken to assess the effects of PAI-1 on vascular repair processes. A murine model of pulmonary embolism showed an accelerated clot lysis response to a preformed thrombus in PAI-1-/- mice.54 Additionally, these mice demonstrated delayed effects on the development of occlusive arterial and venous thrombosis after photochemical injury.55 Together, these studies indicate that an imbalance in the expression of fibrinolytic components dictate the extent and severity of vascular thrombosis.
Although alterations in plasma PAI-1 levels could have a profound effect on the extent of luminal thrombosis, localized arterial wall responses to thrombosis could influence PAI-1 expression in endothelial and vascular smooth muscle cells56 and lead to an antifibrinolytic environment with resultant arterial wall fibrin deposition and eventual neointima formation. Indeed, PAI-1 levels were enhanced in the vessel wall of WT animals. However, the effect of PAI-1 on neointima thickening remains controversial. A study using transfected smooth muscle cells that overexpress PAI-1 seeded on denuded rat carotid arteries led to enhanced neointimal thrombosis, but reduced neointima thickening.57 Additionally, in an electrical injury model, PAI-1 inhibited arterial neointima formation.58 Another investigation using mice either deficient in, or overexpressing, PAI-1, with a combined deficiency of apoE or LDLR, and challenged with a high-fat diet, concluded that PAI-1 did not influence the development or characteristics of atherosclerotic lesions in the dietary-challenged apoE-/- or LDLR-/- mice.59 This latter study, although differing from the results reported herein, relies on a simple pathophysiological effect, namely, lipid deposition, to drive this disease. On the other hand, the copper cuff model detailed herein relies on oxidative injury events that result in fatty streak formation as well as deposition of fibrin in the vascular wall. These features are apparent in advanced complex lesions observed in humans. Because of the thrombotic response to injury featured in this model, the effects of alterations in endogenous fibrinolysis on the progress of oxidative-induced lesion formation can be assessed.
In conclusion, the data obtained in this investigation show that enhanced fibrinolytic potential, because of the absence of PAI-1, results in attenuated thrombotic lesion development, with resultant lack of neointima formation. We suggest that a lack of vascular wall fatty streak formation in PAI-1-/- mice is a consequence of limited leukocyte accumulation in the vessel wall possibly due in part to diminished neovascularization and that an imbalance in the spatial expressions of components of the fibrinolytic system, within the vascular wall compartments, could have a profound effect on the progression and persistence of vascular lesions. Thus, the expression of fibrin-containing lesions within the vessel wall of challenged WT animals, which result from a prothrombotic environment driven by increased expression of plasminogen activator inhibitors and procoagulant factors, culminates in the development of occlusive vascular lesions. This study clearly demonstrates that deficiencies in PAI-1 expression alter the development and progression of vascular lesions by affecting the local hemostatic environment of the vessel wall.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health grants HL-13423 (to F. J. C.) and HL-63682 (to V. A. P.), a National Scientist Development Award (9630009N) from the American Heart Association (to V. A. P.), a grant from the W.M. Keck Foundation (to F. J. C.), and by the Kleiderer/Pezold Family Endowed Professorship (to F. J. C.).
Accepted for publication September 26, 2000.
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References |
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-enolase as a candidate plasminogen receptor. Biochemistry 1991, 30:1682-1691[Medline]
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