© 1999 American Heart Association, Inc.
Integrative Physiology |
Tissue Inhibitor of Matrix Metalloproteinases-1 Impairs Arterial Neointima Formation After Vascular Injury in Mice
From the Center for Molecular and Vascular Biology (H.R.L., D.C.), University of Leuven, Belgium, and Roswell Park Cancer Institute (P.S.), Buffalo, NY.
Correspondence to H.R. Lijnen, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O & N, Herestraat 49, B-3000 Leuven, Belgium. E-mail roger.lijnen{at}med.kuleuven.ac.be
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Abstract |
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Abstract—The hypothesis that tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a role in neointima formation was tested with the use of a vascular injury model in wild-type (TIMP-1+/+) and TIMP-1–deficient (TIMP-1-/-) mice. The neointimal area at 1 to 3 weeks after electric injury of the femoral artery was significantly higher in TIMP-1-/- as compared with TIMP-1+/+ mice (0.012±0.0015 versus 0.0033±0.0008 mm2 at 1 week, P<0.005). The medial areas were comparable, resulting in intima/media ratios that were significantly larger in TIMP-1-/- as compared with TIMP-1+/+ arteries (1.2±0.22 versus 0.39±0.08 at 1 week, P<0.005). Nuclear cell counts in cross-sectional areas of the intima of the injured region were higher in TIMP-1-/- as compared with TIMP-1+/+ arteries (138±15 versus 69±8 at 1 week, P<0.005). Immunocytochemical analysis revealed that
-actin–positive smooth muscle cells (SMCs) at 2 weeks after
injury were more abundant in the intima of TIMP-1-/-
arteries than in that of TIMP-1+/+ arteries, whereas after
3 weeks the intimal cell population consisted mainly of SMCs in both
genotypes. In in vitro scrape-wounding assays, SMCs of
TIMP-1-/- mice migrated faster than those of
TIMP-1+/+ mice. Zymography of arterial extracts
revealed a higher active matrix metalloproteinase (MMP)–2 level at 1
to 3 weeks after injury in TIMP-1-/- arteries, whereas
active MMP-9 was only detected in TIMP-1-/- arteries at 1
week after injury. These data are compatible with a role of TIMP-1 in
the impairment of SMC migration and neointima formation
after vascular injury, as a result of inhibition of MMP activity.
Key Words: matrix metalloproteinase • TIMP • vascular injury • restenosis • gene-deficient mice
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Introduction |
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Neointima formation plays a role in the pathogenesis of atherosclerosis, restenosis after angioplasty, and late vein graft failure.1 It involves degradation of extracellular matrix with migration of smooth muscle cells (SMCs) from the media to the intima.2 3 Matrix metalloproteinases (MMPs) contribute to matrix remodeling and play an essential role in SMC migration.4 5 6 7 This is supported by the findings that MMP-2 (gelatinase A) and MMP-9 (gelatinase B) levels are elevated after arterial injury in nonhuman primates,8 in rat4 5 and pig9 balloon injury models, in a vascular injury model in mice,10 in a human saphenous vein organ culture model,11 and in porcine saphenous vein to carotid interposition vein grafts.12 In baboon aortic explants, SMC migration requires plasminogen activators and both MMP-2 and MMP-9.7 8 Expression of MMPs was also observed in models of atherosclerotic aneurysm formation13 and transplant atherosclerosis.14 Furthermore, inhibition of MMPs by synthetic inhibitors impairs SMC migration in isolated rat SMCs and in the rat in vivo,15 16 in rabbit aortic explants,17 in human saphenous vein organ culture,18 and in primate arterial explants.8
In vivo, MMPs are inhibited by endogenous tissue inhibitors of metalloproteinases (TIMPs), of which 4 different types have been identified.19 20 21 TIMP-1, TIMP-2, and TIMP-3 are equipotent in inhibiting active MMPs, although their capacity to bind to the proenzymes differs.22 TIMP-1, which is synthesized by most types of connective tissue cells as well as by macrophages, acts against all members of the collagenase, stromelysin, and gelatinase classes.19
In the present study, we have evaluated the role of TIMP-1 in neointima formation with the use of a vascular injury model in mice with TIMP-1 gene inactivation.
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Materials and Methods |
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Animals
TIMP-1–deficient (TIMP-1-/-) and wild-type (TIMP-1+/+) mice were obtained and characterized as described.23 24 They were maintained as outcrossed animals arising from F1 (C57BL/6x129 SvJae) founders. Because of the X-linked inheritance pattern, female homozygous deficient mice are TIMP-1-/-, whereas males are TIMP-1-/0 (hemizygous; for convenience we will always refer to TIMP-1-/- mice as homozygotes). Homozygosity of offspring was confirmed by genotyping of tail-tip DNA using Southern blotting (data not shown). Mice were kept in microisolation cages on a 12-hour day-night cycle and fed a regular chow. The animals were anesthetized by intraperitoneal injection of 60 mg/kg pentobarbital (Nembutal; Abbott Laboratories), and all experiments were performed in accordance with the guiding principles for care and use of animals of the American Physiological Society and the International Society on Thrombosis and Hemostasis.25 Perivascular electric injury to the femoral artery was performed essentially as described elsewhere.26 Adult mice (males and females) were used with body weight (mean±SEM) 26±0.7 g (n= 30) or 24±0.8 g (n= 29) for TIMP-1+/+ or TIMP-1-/- mice. Statistical analysis of the data obtained for both genotypes was performed by t test. With some animals, the injury model was applied separately to the left and right femoral artery. Statistical analysis did not reveal differences between the groups comprising only left or only right arteries, and the variability between experiments with left and right artery of the same animal was comparable with the variability between experiments in different animals (data not shown). Data obtained with left and right arteries were therefore pooled for further analysis.
In TIMP-1+/+ animals, 6 arteries (from 3 mice) were studied as controls, and 10 arteries (from 5 mice) at 1, 2, and 3 weeks after injury each. In TIMP-1-/- animals, 6 arteries (from 6 mice) were used as controls, and 6 arteries (from 5 mice) were studied at 1 week after injury, 11 arteries (from 7 mice) at 2 weeks, and 8 arteries (from 6 mice) at 3 weeks.
Histology, Immunocytochemistry, and Zymographic Analysis
Morphometric measurements of cross-sectional areas and cell
counts were performed in a blinded manner on transverse
arterial sections (stained with hematoxylin and eosin)
using a computer-assisted image analysis system as described
elsewhere.26 Measurements were performed at equally spaced
positions (140 µm apart) along the artery. The areas in the
injured region of the artery (positions 2 to 4) were then averaged per
artery (between 6±1 and 12±1 sections per artery in the different
groups). Data are reported as mean±SEM of these average values
obtained in all arteries analyzed.
Immunostaining of SMCs was performed using biotinylated
mouse anti-human smooth muscle -actin.26 Proliferating
cells in the intima were identified by immunostaining
of unfixed arterial sections with the monoclonal
anti–proliferating cell nuclear antigen (PCNA; clone PC10, Sigma) as
recommended by the manufacturer and were counted microscopically. The
number of proliferating cells was expressed as a percentage of the
total nuclear cell count. For each artery, 4 to 9 sections were
analyzed and averaged per artery.
Zymographic analysis of gelatinase activity in arterial extracts or in conditioned cell culture media was performed as described.27 28
In Vitro SMC Migration Assay
To compare SMC migration rates, cultured SMCs from
TIMP-1+/+ and TIMP-1-/-
mice were wounded by scraping them from 1 part of the culture dish and
quantifying their accumulation into the denuded area.29
Cells that had migrated from the edge of the wound into the denuded
area were counted microscopically in 5 successive 100-µm
compartments. In each compartment, 5 to 7 sections were counted and
were then averaged per compartment. Data are reported as mean±SD of
the values obtained in 6 dishes.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Histology and Immunocytochemistry
Hematoxylin and eosin staining of femoral arterial sections taken from noninjured arteries (control animals) did not show a detectable neointima (Table 1
). Staining of sections taken 1 to 3
weeks after injury at equally spaced locations (positions 2 to 4)
throughout the damaged artery showed the formation of a
neointima in both TIMP-1+/+ and
TIMP-1-/- mice (Figure 1a and 1b). In
TIMP-1-/- mice, the intimal area was always
larger than that at corresponding time points in
TIMP-1+/+ mice, whereas the medial areas were
comparable, resulting in significantly higher intima/media ratios in
TIMP-1-/- mice (Table 1). The
adventitial areas in the injured sections (positions 2 to 4) increased
(as compared with noninjured sections in the same artery; positions 1
and 5) by a factor of 2.8±0.23, 6.0±1.2, and 4.4±1.0 at 1, 2, and 3
weeks after injury in TIMP-1+/+ arteries, with
corresponding values of 3.8±0.45 (P<0.05), 3.4±0.35
(P<0.05), and 2.7±0.26 (P=NS) in
TIMP-1-/- arteries.
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Nuclear cell counts revealed a comparable cell population in media of
control noninjured arteries of TIMP-1+/+ and
TIMP-1-/- mice (62±3 versus 71±10,
respectively), whereas the numbers of cells associated with the
internal elastic lamina (mainly endothelial cells) were
also comparable (19±1, mean±SEM, n= 6, in both genotypes). At
1 to 3 weeks after injury, cell counts in the injured area (positions 2
to 4) were higher in the intima of TIMP-1-/-
than in TIMP-1+/+ arteries (Table 2). Cell counts in media and intima of
TIMP-1+/+ arteries increased between 1 and 2
weeks and then decreased, whereas such an effect was less apparent in
TIMP-1-/- arteries. This may be to some extent
correlated with the observed changes in intimal and medial areas,
whereas differences in extracellular matrix can also not be excluded.
The intimal nuclear density was 
2-fold higher at 1 week after injury
in TIMP-1+/+ as compared with
TIMP-1-/- arteries (25 600±4600 versus
11 100±740 cells/mm2; mean±SEM,
P=0.008), whereas there was no significant difference at 2
weeks (17 400±2550 versus 10 500±740; P=0.07) or at 3
weeks (12 000±2400 versus 8900±690; P=0.63).
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PCNA staining did not reveal significant differences in cell proliferation in injured sections of the intima of TIMP-1+/+ and TIMP-1-/- arteries at 1 or 2 weeks after injury. The percentage of proliferating cells at 1 week (mean±SEM of n arteries) was 1.9±0.7 (n= 5) in TIMP-1+/+ arteries and 2.3±1.0 (n= 6) in TIMP-1-/- arteries, with corresponding values of 1.8±0.1 and 1.8±0.7 at 2 weeks after injury.
Immunostaining for -actin revealed the absence
of positively stained cells at 1 week after injury in the intima of
both genotypes, whereas they represented 10% to
20% of the cell population in the media (not shown). At 2 weeks after
injury, -actin–positive SMCs were much more abundant in the intima
of TIMP-1-/- arteries (>75% of the total cell
population) than in that of TIMP-1+/+ arteries
(10% of the total cell population) (Figure 1c
and 1d),
whereas after 3 weeks the intimal cell population consisted mainly of
SMCs in both genotypes (75% to 100%). Occasionally,
penetration of -actin–positive cells in the adventitia through
cracks in the elastica lamina was observed in
TIMP-1-/- arteries (Figure 1d).
Gelatinase Activities
Gelatin zymography of femoral arterial extracts after
injury revealed enhanced levels of MMP-2 and MMP-9 in both
genotypes (Figure 2). The
identity of MMP-2 and MMP-9 was confirmed by immunoprecipitation with
specific antisera, as described previously27 (not shown).
Quantitative analysis of the different molecular forms of MMP-2
indicated that total MMP-2 levels (active plus latent) were comparable
in TIMP-1+/+ and
TIMP-1-/- groups, whereas latent MMP-2 (70-kDa
plus 65-kDa proMMP-2) represented >80% of the total level
in all groups. Active 58-kDa MMP-2 levels were higher in
TIMP-1-/- than in
TIMP-1+/+ arteries at 1 to 3 weeks after injury
(Table 3). ProMMP-9 (94 kDa) was detected
only after injury in both genotypes (at higher levels in
TIMP-1-/- arteries at 1 week after injury, but
at comparable levels at 2 and 3 weeks), whereas active 83-kDa MMP-9 was
only detected in TIMP-1-/- arteries at 1 week
after injury (Table 3).
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In serum-free conditioned medium from cultured SMCs, at 24 hours, the contribution of active and latent molecular forms of MMP-2 to the total level was comparable for TIMP-1+/+ and TIMP-1-/- SMCs (18±3% versus 14±2% for 70-kDa proMMP-2, 69±4% versus 68±1% for 65-kDa proMMP-2, and 19±1% versus 18±1% for 58-kDa MMP-2). The contribution of active MMP-9 to the total MMP-9 level was also comparable for TIMP-1+/+ and TIMP-1-/- SMCs at 24 hours (13±1% versus 14±0%). Total levels of gelatinase (active plus latent forms) were comparable in culture medium of SMCs derived from TIMP-1+/+ or TIMP-1-/- arteries (in arbitrary units per 106 cells per mL, 1380±130 versus 1160±76 for MMP-2, and 94±15 versus 76±29 for MMP-9).
In Vitro SMC Migration Assay
At 30 hours after scrape wounding, the number of SMCs accumulated
into the denuded area was significantly higher (P<0.005) in
5 consecutive 100-µm compartments of the dishes with
TIMP-1-/- SMCs as compared with
TIMP-1+/+ SMCs (44±5, 40±6, 36±4, 31±5, and
27±2 versus 26±4, 23±3, 20±3, 17±2, and 13±4; mean±SD, n=6). The
total number of SMCs in the area was 178±20 for
TIMP-1-/- and 99±12 for
TIMP-1+/+ cells (P=0.002). Control
dishes cultured in the same way but without scrape wounding contained
comparable numbers of TIMP-1+/+ or
TIMP-1-/- SMCs at the time of analysis
(1.8 to 2.2x106).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MMPs play an important role in vascular remodeling by degrading extracellular matrix and thereby allowing SMC migration.4 5 6 7 Inhibition of MMPs by synthetic inhibitors15 16 17 18 or by overexpression of TIMP-130 results in impaired SMC migration in several in vitro and in vivo models. Furthermore, it was shown that adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits SMC migration and neointimal formation in human saphenous vein,31 and retrovirally induced local overexpression of TIMP-1 prevents aortic aneurysmal degeneration and rupture in a rat model.32 To assess a potential role of TIMP-1 in neointima formation, a perivascular electric injury model was used in mice with targeted inactivation of TIMP-1. In this model, wound healing initiates from the adjacent uninjured borders and progresses into the necrotic center and is associated with migration of SMCs.26
This study demonstrates that deficiency of TIMP-1 significantly
enhances neointima formation, confirming that MMP-mediated
proteolysis promotes SMC migration and vascular wound healing after
injury. Because SMCs are surrounded by an encaging extracellular
matrix, they can only migrate into the wound by degrading this matrix.
At 1 to 3 weeks after injury, the total nuclear cell count in the
injured region of the femoral arteries was indeed higher in
TIMP-1-/- than in
TIMP-1+/+ mice. However, the intimal nuclear
density at 1 week after injury was 2-fold higher in
TIMP-1+/+ than in
TIMP-1-/- arteries. It thus appears that part
of the early increase (1 week) in intimal area in
TIMP-1-/- arteries results from changes in
matrix volume. Immunostaining for -actin revealed
that at 1 week after injury very few SMCs are present in the
intima, whereas they make up 20% of the medial cell population in
both genotypes. The total cell count is, however, 2-fold
higher in the TIMP-1-/- arteries. It should
also be kept in mind that staining of proliferating/migrating SMCs (at
1 week) for -actin may be deficient.26 Furthermore, in
this model, the intimal cell population at 1 to 2 weeks after injury is
heterogeneous, consisting not only of -actin–positive
SMCs, but also of leukocytes and, occasionally,
macrophages.10 26 Therefore, it cannot be excluded
that a different contribution of other cell types contributes to the
early differences in matrix volume between both genotypes. At 2
weeks after injury, SMCs were more abundant in the injured arteries of
TIMP-1-/- mice, whereas at 3 weeks most of the
cells in the intima were SMCs for both genotypes. In vitro SMC
migration assays after wounding confirmed a faster migration of
TIMP-1-/- SMCs. This assay primarily monitors
SMC migration and not proliferation.29 PCNA staining of
arterial sections, furthermore, did not reveal significant
differences in intimal cell proliferation of
TIMP-1-/- or TIMP-1+/+
arteries at 1 to 2 weeks after injury. This does not, however, exclude
differences in proliferation earlier after injury.
Vascular injury in mice results in significantly enhanced expression of
MMP-2 and MMP-9, with a higher contribution of active enzyme to the
total gelatinase level after injury.10 Within 1 to 3 weeks
after injury, the active MMP-2 levels were higher in extracts of
TIMP-1-/- than of
TIMP-1+/+ arteries. However, most of the MMP-2
remained in the latent form in both genotypes (Table 3).
Active MMP-9 could only be detected in
TIMP-1-/- arteries at 1 week after injury,
which is compatible with the temporal expression pattern of MMP-9 in
this model.10 These data thus indicate that TIMP-1 may
impair gelatinase activity after injury of the femoral artery. In
cultured SMCs derived from the aorta of TIMP-1+/+
or TIMP-1-/- mice, total levels of gelatinase
were comparable and the contribution of active MMP-2 and MMP-9 to their
total levels was similar. This may be due to the fact that the levels
of active MMPs exceed TIMP-1 activity in the cultured medium.
Furthermore, it cannot be excluded that in the tissue, other cells
besides SMCs contribute to the observed gelatinase activity.
In this model, significant differences in neointima formation have been observed in mice with different genetic background.29 33 34 Pronounced differences between genetic backgrounds in mice have also been reported in other biological processes, including atherosclerotic lesion formation.35 36 37 Therefore, quantitative comparison of the data of this study with data obtained in other genetic backgrounds may not be justified.
In summary, the present data indicate that TIMP-1 may impair SMC migration and neointima formation as a result of inhibition of MMP activity.
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Acknowledgments |
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This study was supported by grants from the Flemish Fund for Scientific Research (FWO, contract G.0293.98) and from the Interuniversitaire Attractiepolen (contract P4/34). Skillful technical assistance by A. De Wolf, L. Frederix, G. Lemmens, B. Van Hoef, I. Vanlinthout, and M. Verstreken is gratefully acknowledged.
Received March 1, 1999; accepted September 15, 1999.
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S. Janssens and H. R. Lijnen What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models? Cardiovasc Res, February 15, 2006; 69(3): 585 - 594. [Abstract] [Full Text] [PDF]
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 K. Kobayashi, K. Yokote, M. Fujimoto, K. Yamashita, A. Sakamoto, M. Kitahara, H. Kawamura, Y. Maezawa, S. Asaumi, T. Tokuhisa, et al. Targeted Disruption of TGF-{beta}-Smad3 Signaling Leads to Enhanced Neointimal Hyperplasia With Diminished Matrix Deposition in Response to Vascular Injury Circ. Res., April 29, 2005; 96(8): 904 - 912. [Abstract] [Full Text] [PDF]
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 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
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 P. Zahradka, G. Harding, B. Litchie, S. Thomas, J. P. Werner, D. P. Wilson, and N. Yurkova Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent expression of MT1-MMP Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2861 - H2870. [Abstract] [Full Text] [PDF]
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 P. C. Saunders, G. Pintucci, C. S. Bizekis, R. Sharony, K. M. Hyman, F. Saponara, F. G. Baumann, E. A. Grossi, S. B. Colvin, P. Mignatti, et al. Vein graft arterialization causes differential activation of mitogen-activated protein kinases J. Thorac. Cardiovasc. Surg., May 1, 2004; 127(5): 1276 - 1284. [Abstract] [Full Text] [PDF]
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 J. S. Forrester Prevention of Plaque Rupture: A New Paradigm of Therapy Ann Intern Med, November 19, 2002; 137(10): 823 - 833. [Abstract] [Full Text] [PDF]
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A. Cho and M. A. Reidy Matrix Metalloproteinase-9 Is Necessary for the Regulation of Smooth Muscle Cell Replication and Migration After Arterial Injury Circ. Res., November 1, 2002; 91(9): 845 - 851. [Abstract] [Full Text] [PDF]
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J. Silence, D. Collen, and H.R. Lijnen Reduced Atherosclerotic Plaque but Enhanced Aneurysm Formation in Mice With Inactivation of the Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Gene Circ. Res., May 3, 2002; 90(8): 897 - 903. [Abstract] [Full Text] [PDF]
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 I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
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 L. J. Feldman, M. Mazighi, A. Scheuble, J.-F. Deux, E. De Benedetti, C. Badier-Commander, E. Brambilla, D. Henin, P. G. Steg, and M.-P. Jacob Differential Expression of Matrix Metalloproteinases After Stent Implantation and Balloon Angioplasty in the Hypercholesterolemic Rabbit Circulation, June 26, 2001; 103(25): 3117 - 3122. [Abstract] [Full Text] [PDF]
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A. Vieillard-Baron, E. Frisdal, S. Eddahibi, I. Deprez, A. H. Baker, A. C. Newby, P. Berger, M. Levame, B. Raffestin, S. Adnot, et al. Inhibition of Matrix Metalloproteinases by Lung TIMP-1 Gene Transfer or Doxycycline Aggravates Pulmonary Hypertension in Rats Circ. Res., September 1, 2000; 87(5): 418 - 425. [Abstract] [Full Text] [PDF]
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J. Silence, D. Collen, and H.R. Lijnen Reduced Atherosclerotic Plaque but Enhanced Aneurysm Formation in Mice With Inactivation of the Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Gene Circ. Res., May 3, 2002; 90(8): 897 - 903. [Abstract] [Full Text] [PDF]
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