(Circulation. 2000;102:2861.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Remodeling of Carotid Artery Is Associated With Increased Expression of Matrix Metalloproteinases in Mouse Blood Flow Cessation Model
From the Department of Medicine, Emory University (D.G., E.I., Z.S.G.), and the Georgia Tech/Emory Department of Biomedical Engineering (C.J., R.M., Z.S.G.), Atlanta, Ga.
Correspondence to Zorina S. Galis, PhD, Division of Cardiology, Department of Medicine, Emory University School of Medicine, 1639 Pierce Dr, WMB #319, Atlanta, GA 30322. E-mail zgalis{at}emory.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—The matrix-degrading activity of matrix metalloproteinases (MMPs), required for cell migration and general tissue reshaping, is thought essential for pathological arterial remodeling in atherosclerosis and restenosis.
Methods and Results—We triggered remodeling of the carotid artery in C57BL/6 mice by blood flow cessation to study the relationship with gelatinases MMP-9 and MMP-2. Ligated and contralateral carotid arteries from ligated and sham-operated mice were harvested fresh, for biochemical analyses, or were perfusion-fixed, for histological studies, at 0, 1, 3, 7, 14, and 28 days after ligation. An early statistically significant (P<0.01) 4- to 5-fold increase in MMP-9 expression detected by SDS-PAGE zymography and Western blotting in tissue homogenates of ligated carotid arteries 1 day after flow cessation was maintained through day 7, after which expression gradually fell. Maximal MMP-9 levels were higher than MMP-2 levels, which became significantly increased 7 days after ligation. Proliferating cells, identified by bromodeoxyuridine incorporation, were detectable at day 1 in the adventitia and subsequently throughout the wall. Neointima was visible in 3-day specimens of ligated arteries. Suggested by morphology and predicted by theoretical considerations, maximal MMP-9 expression coincided with cell migration into the neointima, supporting its enabling role. Morphological measurements also demonstrated positive lumen remodeling up to 7 days after ligation.
Conclusions—MMP-9 induction is associated with the formation of intimal hyperplasia and does not require frank mechanical injury. Our data also show that a significant increase in MMP-9 expression preceded the positive geometrical remodeling of arteries, suggesting a potentially beneficial role for this matrix-degrading enzyme.
Key Words: metalloproteinases • carotid arteries • remodeling
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Besides direct mechanical injury by surgical vascular interventions,1 pathological vascular remodeling can occur naturally in response to immunologic, biochemical, or hemodynamic stimuli. Artery reaction to vascular injury has become the object of intense research, because of potential clues for human atherosclerotic lesion etiology and because restenosis is a major cause of morbidity in humans. However, remodeling of human vessels can only be captured as snapshots. Longitudinal observations in a variety of experimental models have provided much insight into the evolution of vascular lesions. Observations made in rat and rabbit balloon injury models of arterial remodeling2 3 support the importance of the matrix-degrading action of matrix metalloproteinases (MMPs), especially the gelatinases MMP-2 and MMP-9. These are necessary for general reshaping of the extracellular matrix scaffold of the arterial wall and likely enable migration of vascular smooth muscle cells (SMCs) and adventitial fibroblasts.4 Recently, murine models of vascular remodeling have attracted great interest because of their potential for genetic manipulation. Remodeling of murine arteries has been induced by the insertion of a thin wire,5 electric burning,6 and flow cessation.7 To study gelatinases MMP-9 and MMP-2 in relation to mouse carotid artery remodeling, we chose the flow-cessation model, characterized by rapid and reproducible remodeling with the development of significant intimal thickening.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Model
Male C57BL/6J mice (2 months old, 20 to 28 g, Jackson Laboratory, Bar Harbor, Me) were anesthetized by intraperitoneal injection of xylazine (Rompun, Bayer Corp) and ketamine HCl (Abbott Laboratories) (13 mg/kg and 87 mg/kg body weight, respectively). The left common carotid artery was ligated near bifurcation with the use of 5-0 silk (Ethicon).7 In sham-operated animals, the suture was passed under the exposed left carotid artery but not tightened. The wound was sutured, and the animals were allowed to recover on a warming blanket. Two groups of injured or sham-operated animals were processed for morphological and biochemical studies at 1, 3, 7, 14, and 28 days after the procedure. Before they were euthanized (at 12 and 4 hours), the animals from the first group received 2 subcutaneous 2.5-mg injections of the thymidine analogue bromodeoxyuridine (BrdU, Sigma). Animal survival was >95%. A total of 110 mice were used in the final analysis, with 4 or 5 animals per each time point. The Emory University Committee on Institutional Animal Care and Use approved the protocol. For morphological analysis, animals were perfused with normal saline and fixed with 10% phosphate-buffered formalin at physiological pressure for 3 minutes. Left and right carotid arteries were removed in block, further fixed for 16 hours, and paraffin-embedded without further dissection. Because lesion thickness varies longitudinally,7 the entire length of the left and right carotid arteries was sectioned and examined for identification of the apex of the lesion, which displays the smallest lumen. Groups of 5 sections (5 µm) were collected at equally spaced intervals (measured by discarding 15x10-µm-thick slices). The first section in each group was counterstained with hematoxylin-eosin. Within the group selected as the apex for each carotid, the subsequent 4 sections were processed for detection of specific histological features.
Immunostaining
MMP-9 was detected with the use of rabbit anti-mouse MMP-9
polyclonal antibody (generously provided by Drs Senior and Shipley,
Washington University, St. Louis, Mo), followed by biotinylated
goat anti-rabbit IgG (Fisher Biotech), streptavidin–horseradish
peroxidase (Dako), and diaminobenzidine (DAB kit, Vector Laboratories),
and counterstained with Gill’s hematoxylin (Fisher Scientific)
and Scott’s solution. For negative controls, primary antibody was
replaced with nonimmune rabbit serum. Cellular proliferation was
detected as nuclear incorporation of BrdU with use of a monoclonal
antibody (Cappel), in combination with the M.O.M. kit (Vector),
followed by horseradish peroxidase or Texas red–conjugated donkey
anti-mouse (Jackson); counterstaining was achieved with 0.5 mg/mL
Hoechst (bis-benzimide, Sigma). Images were collected by use of a Zeiss
Axioscope microscope.
Morphometric Analysis
Perimeters of the lumen, internal elastic lamina (IEL), and
external elastic lamina (EEL) were obtained by tracing the contours on
digitized images. Intimal thickness (distance between lumen and IEL),
medial thickness (distance between IEL and EEL), and adventitial
thickness (distance between EEL and the outer edge between tightly
packed and surrounding loose tissue) were automatically calculated by
ImagePro Plus 3.0 software (Media Cybernetics) as the mean
perpendicular distance between 2 bordering tracings. All the areas were
back-calculated with the assumption of circular structures.
Proliferation indices were calculated as a percentage of BrdU-positive
cells (pink nuclei) of the total number of cells (blue-counterstained
nuclei) per arterial cross section.
Biochemical Analyses
Fresh carotid arteries were collected separately, pulverized
under liquid nitrogen, and extracted with the use of ice-cold lysis
buffer (10 mmol/L sodium phosphate, pH 7.2, containing 150
mmol/L NaCl [PBS], and 1% Triton X-100, 0.1% SDS, 0.5% sodium
deoxycholate, and 0.2% sodium azide) for 1 hour at 4°C;
centrifugation was at 10 000g for 5
minutes. For detection of MMP-2 and MMP-9, equal amounts of tissue
extract protein (20 µg), assayed by using the DC protein assay
(Bio-Rad), were loaded on each lane and run in parallel with prestained
molecular weight markers (Bio-Rad) in 10% SDS-PAGE gels containing 1%
gelatin, as described in detail previously.8 The
optical volume-density product of individual lytic bands in
Coomassie blue–stained gels was quantified by use of the Molecular
Analyst (Bio-Rad). A single value was derived for MMP-9 and for MMP-2
by adding the bands associated with both pro and activated
forms.
For Western blotting, samples (20 µg protein) were loaded on 10% SDS-PAGE mini gels and transferred onto nitrocellulose with use of a SemiDry system (Bio-Rad). MMP-9 was detected with rabbit anti-mouse MMP-9 polyclonal antibodies, followed by enhanced chemiluminescence (ECL kit, Amersham). Signals on x-ray films were quantified by use of the Multi-Analyst (BioRad).
Data Analysis
Average values were obtained per time point from image
analysis of the apex section of each of the 4 or 5 carotid
arteries. Densitometric data from Western blotting and SDS-PAGE
zymography were generated through analysis of 4 or 5 individual
carotid arteries per each time point. Comparisons were made by ANOVA
followed by the Tukey protected t test to compare the means
of multiple groups. Means were considered significantly different at
P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
General Features of Vascular Remodeling in Flow Cessation Murine Model
The ligated carotid artery underwent rapid remodeling, as previously reported.7 A neointima was visible at day 3 and was well developed by 7 days. By 28 days, neointima accounted for >30% of the total wall thickness. Morphometric analysis (Figure 1
)
showed that compared with the sham-operated artery, the ligated carotid
artery lumen initially undergoes a statistically significant
enlargement, followed later by a significant decrease. Measurement of
individual layer and total wall thickness showed both
neointima development and overall wall shrinkage. The
neointimal layer steadily increased throughout 28 days
(Figure 2). Medial and adventitial layer
thickness increased until day 14 but decreased thereafter. Cell number
over time paralleled the layer thickness, suggesting that cell
dynamics, the net result of cell turnover and migration between layers,
is a major determinant of vascular remodeling in this model.
|
|
Expression of Gelatinases During Mouse Carotid Artery
Remodeling
MMP gelatinolytic activity in the carotid
artery was increased after ligation (Figure 3). At day 1, MMP-9 activity had already
increased 4- to 5-fold (P<0.01) in the ligated arteries.
MMP-9 activity was detected also in sham-operated arteries at day 1
(this activity was likely stimulated by the surgical injury) and then
returned to baseline levels but remained significantly elevated in
ligated arteries through day 7. In contrast, activity corresponding to
MMP-2 apparent molecular weight became significantly increased only
after 7 days and remained lower than absolute MMP-9 levels. Pro-MMP-2
activation was detectable in 14- and 28-day specimens.
Immunoblotting confirmed significant MMP-9 protein
upregulation in ligated arteries up to 7 days after ligation (Figure 4). By immunocytochemistry, MMP-9 was not
detectable in normal mouse carotid arteries and had very low levels in
sham-operated arteries at all time points. In contrast, MMP-9
expression was clearly detectable by day 3 in many adventitial and
medial cells of ligated arteries. MMP-9–positive cells appeared to be
engaged in migration (Figure 5, inset). Scattered MMP-9–positive cells were detected in contralateral
arteries as well. By day 7, intense MMP-9 staining was visible in the
well-developed neointima of ligated arteries.
Neointimal cells remained highly positive for MMP-9 in the
ligated arteries harvested at day 28. Adventitial MMP-9 expression was
also maintained.
|
|
|
We analyzed the dynamics of cell accumulation and proliferation
within the 3 layers of the ligated artery. BrdU-positive cells were
detected throughout the wall (Figure 5
). For each time point,
average individual layer proliferation indices (intimal, medial, and
adventitial) and the average overall arterial wall index
were calculated (Figure 6). The
proliferation index was maximal at day 1 in the adventitia, where it
subsequently decreased sharply. Up to 14 days, proliferation slowly
increased in both intimal and medial layers and then decreased in the
medial layer, while being sustained in the intimal layer. Comparison of
total cell counts (Figure 2) and proliferation index data
(Figure 6) produces a picture of cell dynamics within different
layers. In the intima, the total cell count continued to increase
throughout day 28, consistent with the increased proliferation
index. In contrast, the total medial cell number initially modestly
increased and then tapered off, in spite of sustained proliferation.
Similarly, the adventitial cell number initially increased and then
decreased after 14 days. The decrease observed in the outer 2 layers is
compatible with cells migrating into the intimal layer.
|
The murine carotid artery does not contain intimal SMCs under normal
conditions; thus, cell migration is an absolute requirement for
neointimal development. MMP-9–positive cells appeared to
be engaged in migration, which is thought to require MMP activity.
However, such an in situ association remains circumstantial, inasmuch
as to date there are no definitive markers of cell migration. The
number of neointimal cells is also influenced by the rate
of cell proliferation and cell loss. To gain further insight regarding
the specific contribution of migration to neointimal
formation, we made some theoretical considerations. With the use of
data recorded from cell proliferation analysis, for the
intimal layer these data were fit to a log curve (Figure 6) with
the following equation: r=-0.015+0.032 ln(t), where
r is the proliferation rate, and t is daysxdoublings per
day. The cell number, plotted with use of actual neointimal
proliferation rates (Figure 6), and doubling times reported for
mouse cells9 were compared with the actual
neointimal cell numbers counted in the specimens (Figure 2). Because of the simplicity of our model, we limited
calculations to early proliferation rates (up to 7 days). We confirmed
that the actual cell number detected in the neointima up to
day 7 was higher than what was possible solely through proliferation,
indicating that additional cells had to have migrated from other wall
layers. The time course obtained is similar to that of MMP-9, which is
consistent with MMP-9 contribution to cell migration.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
On the basis of the requirement that cells have a matrix-degrading capacity to free themselves from the matrix cage to move and proliferate and to reshape the tissues, we and others have hypothesized that MMPs play a key role in tissue remodeling associated with vascular lesion progression. After activation by soluble mediators, SMCs increase their secretion of matrix-degrading enzymes, including MMP-9.8 Previous studies support the role of MMP-9 in SMC migration and proliferation in vitro10 11 and in situ after carotid balloon angioplasty injury in rat and rabbit models.2 3 Data available for the mouse from studies of remodeling after perivascular femoral artery electric burning, another type of frank injury, also show increased MMP-9 expression.12 In the present study, we investigated the expression of gelatinases during vascular remodeling of the murine carotid artery induced by flow cessation.7 Low flow is thought to contribute to the development of human vascular lesions and was previously reported to upregulate MMP expression in a rabbit model of carotid artery remodeling.13 Like other experimental models, the murine flow cessation model is an obvious departure from the human situation. However, through emphasizing in vivo formation of intimal hyperplasia, a major contributor to pathological vascular remodeling of injured human arteries, this murine model has become the preferred choice for studying different aspects of vascular remodeling in wild-type mice14 and several transgenic mice.15 16 We also favored flow-induced remodeling because of its practical advantages, namely, producing a reproducible injury through a relatively easy surgical procedure and allowing us to obtain a fair amount of arterial tissue for biochemical analysis.
As in the case of healthy human carotid and coronary arteries,17 we found in normal murine carotid arteries that the gelatinolytic activity likely associated with MMP-2 was constitutively expressed, whereas MMP-9–associated activity was undetectable in uninjured vessels. However, both activities were significantly upregulated during injury-induced remodeling. Levels of MMP-9, quickly induced by flow cessation, were higher than levels of MMP-2, as revealed by gelatin zymography. This detected difference is likely underestimated, inasmuch as MMP-2 digests gelatin twice as fast as does MMP-9.18 As expected, we found that flow cessation rapidly induced the formation of a neointima. Maximal upregulation of MMP-9 preceded and then occurred along with cell migration and positive arterial remodeling. Similarly, although not examined in detail, the late increase in MMP-2 activity may be associated with carotid artery shrinkage.
Interestingly, our analysis revealed that the ligated mouse carotid artery undergoes initially positive and then late negative remodeling, another nice feature of this model, reminiscent of the evolution of the human restenotic artery. Arterial lumen stenosis after mechanical injury was shown to be a combination of intimal thickening and a reduction in the total wall circumference. Expression of matrix components and integrins characteristic of wound healing suggests that tissue contraction contributes to lumen constriction at sites of arterial reconstruction.19 Recent reexamination of angiographic studies of human lesions20 and of deep vascular injury in animal models21 suggests that negative geometrical remodeling may be of greater importance in arterial lumen narrowing than the development of intimal mass.
The potential implications of the obvious adventitial upregulation of MMP-9 expression during mouse carotid artery remodeling are several. Recent observations support the participation of differentiated adventitial myofibroblasts to the formation of intimal thickening through migration across the wall,22 23 especially in vessels in which the EEL has been compromised24 or is lacking.25 MMP-9 could provide the elastolytic activity26 necessary for the migration of cells through the elastic laminae. Whether adventitial cells actually migrate into the developing neointima in the flow cessation model, in which carotid artery integrity is not compromised, has yet to be determined, along with such adventitial contribution to the formation of intimal hyperplasia in human arteries. The extensive perivascular fibrosis leading to wall shrinkage during pathological vascular remodeling may also be related to the regulation of adventitial MMP-9. Recently reported actions of MMP-9 include proteolytic modification of biological activity of important nonmatrix substrates, such as interleukin-1ß and several inhibitors of serine proteases,27 which in turn modulate vascular cells, suggesting that MMP-9 may influence vascular remodeling beyond matrix degradation.
Our present study of murine carotid artery remodeling suggests that MMP-9 participates in positive remodeling, an initial beneficial phase after vascular injury. Additionally supporting this finding was the result of analysis of contralateral carotid arteries, which experience increased blood flow after ligation. We found that MMP-9 gelatinolytic activity was also doubled in contralateral arteries 1 day after ligation (not shown). After 7 days, the lumen of arteries contralateral to ligated arteries had increased on average by 30% (P<0.01), and the total wall areas increased >50% (P<0.05) compared with arteries contralateral to sham-operated carotid arteries. The potential role of MMP-9 in positive remodeling is of great interest, inasmuch as therapeutic inhibition of vascular MMPs is currently contemplated in restenosis. Currently available strategies, including the administration of chemical or biological MMP inhibitors28 and the overexpression of TIMPs,29 suffer from inescapable limitations, such as poor efficiency or tissue access, and also from nonspecific effects. A definitive confirmation of the role of MMP-9 in vascular remodeling proposed by the present and previous studies awaits the development and utilization of better experimental tools, including the recent availability of MMP-deficient animals.
|
Acknowledgments |
|---|
Funding for these studies was provided through an American Heart Association Grant-in-Aid (No. 9650798). Dr Galis is an Established Investigator of the American Heart Association (award No. 0040087N). Dr Ivan was supported through a National Research Service Award training grant (No. T32 HL-07745-06). C. Johnson was supported through a National Science Foundation grant (No. EEC-9731643). The advice of Dr Volkard Lindner was invaluable in establishing the murine flow cessation model in our laboratory. The authors wish to acknowledge the excellent and enthusiastic assistance of Lisa Thacher, supported by a National Science Foundation Research Experience for Undergraduates summer scholarship (award No. EEC-9731643).
Received April 7, 2000; revision received June 12, 2000; accepted June 30, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Gibbons GH, Dzau VJ. The emerging concept of
vascular remodeling. N Engl J Med. 1994;330:1431–1438.
[Free Full Text]
-
Bendeck MP, Zempo N, Clowes AW, et al. Smooth muscle
cell migration and matrix metalloproteinase expression after
arterial injury in the rat. Circ Res. 1994;75:539–545.
[Abstract/Free Full Text]
-
Aoyagi M, Yamamoto M, Azuma H, et al.
Immunolocalization of matrix metalloproteinases in rabbit carotid
arteries after balloon denudation. Histochem Cell Biol. 1998;109:97–102.[Medline]
[Order article via Infotrieve]
-
Shi Y, Patel S, Niculescu R, et al. Role of matrix
metalloproteinases and their tissue inhibitors in the
regulation of coronary cell migration. Arterioscler
Thromb Vasc Biol. 1999;19:1150–1155.
[Abstract/Free Full Text]
-
Lindner V, Fingerle J, Reidy MA. Mouse model of
arterial injury. Circ Res. 1993;73:792–796.
[Abstract/Free Full Text]
-
Carmeliet P, Moons L, Herbert JM, et al. Urokinase but
not tissue plasminogen activator mediates
arterial neointima formation in mice.
Circ Res. 1997;81:829–839.
[Abstract/Free Full Text]
-
Kumar A, Lindner V. Remodeling with
neointima formation in the mouse carotid artery after
cessation of blood flow. Arterioscler Thromb Vasc Biol. 1997;17:2238–2244.
[Abstract/Free Full Text]
-
Galis ZS, Muszynski M, Sukhova GK, et al.
Cytokine-stimulated human vascular smooth muscle cells
synthesize a complement of enzymes required for extracellular matrix
digestion. Circ Res. 1994;75:181–189.
[Abstract/Free Full Text]
-
Orecchia R, Infusini E, Sciutto A, et al. Ki-ras
activation in vitro affects G1 and G2 M cell-cycle transit times and
apoptosis. J Pathol. 2000;190:423–429.[Medline]
[Order article via Infotrieve]
-
Southgate KM, Davies M, Booth RF, et al. Involvement of
extracellular-matrix-degrading metalloproteinases in rabbit aortic
smooth-muscle cell proliferation. Biochem J. 1992;288:93–99.
-
Kenagy RD, Clowes AW. A possible role for MMP-2 and
MMP-9 in the migration of primate arterial smooth muscle
cells through native matrix. Ann N Y Acad Sci. 1994;732:462–465.[Medline]
[Order article via Infotrieve]
-
Lijnen HR, Van Hoef B, Lupu F, et al. Function of the
plasminogen/plasmin and matrix metalloproteinase systems
after vascular injury in mice with targeted inactivation of
fibrinolytic system genes. Arterioscler Thromb Vasc Biol. 1998;18:1035–1045.
[Abstract/Free Full Text]
-
Bassiouny HS, Song RH, Hong XF, et al. Flow regulation
of 72-kD collagenase IV (MMP-2) after experimental
arterial injury. Circulation. 1998;98:157–163.
[Abstract/Free Full Text]
-
Bryant SR, Bjercke RJ, Erichsen DA, et al. Vascular
remodeling in response to altered blood flow is mediated by fibroblast
growth factor-2. Circ Res. 1999;84:323–328.
[Abstract/Free Full Text]
-
Kumar A, Hoover JL, Simmons CA, et al. Remodeling and
neointimal formation in the carotid artery of normal and
P-selectin-deficient mice [see comments]. Circulation. 1997;96:4333–4342.
[Abstract/Free Full Text]
-
Harada K, Komuro I, Sugaya T, et al. Vascular injury
causes neointimal formation in angiotensin II
type 1a receptor knockout mice. Circ Res. 1999;84:179–185.
[Abstract/Free Full Text]
-
Galis ZS, Sukhova GK, Lark MW, et al. Increased
expression of matrix metalloproteinases and matrix degrading activity
in vulnerable regions of human atherosclerotic plaques. J
Clin Invest. 1994;94:2493–2503.
-
Xia T, Akers K, Eisen AZ, et al. Comparison of cleavage
site specificity of gelatinases A and B using collagenous peptides.
Biochim Biophys Acta. 1996;1293:259–266.[Medline]
[Order article via Infotrieve]
-
Geary RL, Nikkari ST, Wagner WD, et al. Wound healing:
a paradigm for lumen narrowing after arterial
reconstruction. J Vasc Surg. 1998;27:96–106.[Medline]
[Order article via Infotrieve]
-
Mintz GS, Popma JJ, Pichard AD, et al.
Arterial remodeling after coronary angioplasty: a
serial intravascular ultrasound study. Circulation. 1996;94:35–43.
[Abstract/Free Full Text]
-
Andersen HR, Maeng M, Thorwest M, et al. Remodeling
rather than neointimal formation explains luminal narrowing
after deep vessel wall injury: insights from a porcine coronary
(re)stenosis model [see comments]. Circulation. 1996;93:1716–1724.
[Abstract/Free Full Text]
-
De Leon H, Scott NA, Martin F, et al. Expression of
nonmuscle myosin heavy chain-B isoform in the vessel wall of porcine
coronary arteries after balloon angioplasty. Circ
Res. 1997;80:514–519.
[Abstract/Free Full Text]
-
Zalewski A, Shi Y. Vascular myofibroblasts: lessons
from coronary repair and remodeling. Arterioscler Thromb
Vasc Biol. 1997;17:417–422.
[Free Full Text]
-
Wilcox JN, Cipolla GD, Martin FH, et al. Contribution
of adventitial myofibroblasts to vascular remodeling and lesion
formation after experimental angioplasty in pig coronary
arteries. Ann N Y Acad Sci. 1997;811:437–447.
[Free Full Text]
-
Shi Y, O’Brien JE Jr, Ala-Kokko L, et al. Origin of
extracellular matrix synthesis during coronary repair.
Circulation. 1997;95:997–1006.
[Abstract/Free Full Text]
-
Senior RM, Griffin GL, Fliszar CJ, et al. Human 92- and
72-kilodalton type IV collagenases are elastases.
J Biol Chem. 1991;266:7870–7875.
[Abstract/Free Full Text]
-
Vu TH, Werb Z. Gelatinase B: structure, regulation, and
function. In: Parks WC, Mecham RP, eds. Matrix
Metalloproteinases. 1st ed. San Diego, Calif: Academic Press;
1998:115–149.
-
Brown PD. Synthetic inhibitors of matrix
metalloproteinases. In: Parks WC, Mecham RP, eds. Matrix
Metalloproteinases. 1st ed. San Diego, Calif: Academic Press;
1998:243–261.
-
Baker AH, Zaltsman AB, George SJ, et al. Divergent
effects of tissue inhibitor of metalloproteinase-1, -2, or
-3 overexpression on rat vascular smooth muscle cell invasion,
proliferation, and death in vitro: TIMP-3 promotes apoptosis.
J Clin Invest. 1998;101:1478–1487.[Medline]
[Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  L. Paczek, W. Michalska, and I. Bartlomiejczyk Trypsin, elastase, plasmin and MMP-9 activity in the serum during the human ageing process Age Ageing, May 1, 2008; 37(3): 318 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Adya, B. K. Tan, A. Punn, J. Chen, and H. S. Randeva Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis Cardiovasc Res, May 1, 2008; 78(2): 356 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 H.-J. Sung, A. Yee, S. G. Eskin, and L. V. McIntire Cyclic strain and motion control produce opposite oxidative responses in two human endothelial cell types Am J Physiol Cell Physiol, July 1, 2007; 293(1): C87 - C94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. S. Chatzizisis, A. U. Coskun, M. Jonas, E. R. Edelman, C. L. Feldman, and P. H. Stone Role of Endothelial Shear Stress in the Natural History of Coronary Atherosclerosis and Vascular Remodeling: Molecular, Cellular, and Vascular Behavior J. Am. Coll. Cardiol., June 26, 2007; 49(25): 2379 - 2393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Newby Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates Cardiovasc Res, February 15, 2006; 69(3): 614 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. D. Defawe, R. D. Kenagy, C. Choi, S. Y.C. Wan, C. Deroanne, B. Nusgens, N. Sakalihasan, A. Colige, and A. W. Clowes MMP-9 regulates both positively and negatively collagen gel contraction: A nonproteolytic function of MMP-9 Cardiovasc Res, May 1, 2005; 66(2): 402 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Arno, J C Kaski, D A Smith, J P Akiyu, S E Hughes, and C Baboonian Matrix metalloproteinase-9 expression is associated with the presence of Chlamydia pneumoniae in human coronary atherosclerotic plaques Heart, April 1, 2005; 91(4): 521 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bouvet, L.-A. Gilbert, D. Girardot, D. deBlois, and P. Moreau Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition Hypertension, March 1, 2005; 45(3): 432 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 Yasmin, S. Wallace, C. M. McEniery, Z. Dakham, P. Pusalkar, K. Maki-Petaja, M. J. Ashby, J. R. Cockcroft, and I. B. Wilkinson Matrix Metalloproteinase-9 (MMP-9), MMP-2, and Serum Elastase Activity Are Associated With Systolic Hypertension and Arterial Stiffness Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 372 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
A.-C. Jonsson-Rylander, T. Nilsson, R. Fritsche-Danielson, A. Hammarstrom, M. Behrendt, J.-O. Andersson, K. Lindgren, A.-K. Andersson, P. Wallbrandt, B. Rosengren, et al. Role of ADAMTS-1 in Atherosclerosis: Remodeling of Carotid Artery, Immunohistochemistry, and Proteolysis of Versican Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 180 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tazaki, K. Minoguchi, T. Yokoe, K. T. R. Samson, H. Minoguchi, A. Tanaka, Y. Watanabe, and M. Adachi Increased Levels and Activity of Matrix Metalloproteinase-9 in Obstructive Sleep Apnea Syndrome Am. J. Respir. Crit. Care Med., December 15, 2004; 170(12): 1354 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Lessner, D. E. Martinson, and Z. S. Galis Compensatory Vascular Remodeling During Atherosclerotic Lesion Growth Depends on Matrix Metalloproteinase-9 Activity Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2123 - 2129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. von Offenberg Sweeney, P. M Cummins, Y. A Birney, J. P Cullen, E. M Redmond, and P. A Cahill Cyclic strain-mediated regulation of endothelial matrix metalloproteinase-2 expression and activity Cardiovasc Res, September 1, 2004; 63(4): 625 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Kim, S. M. Lessner, Y. Sakurai, and Z. S. Galis Cyclophilin A as a Novel Biphasic Mediator of Endothelial Activation and Dysfunction Am. J. Pathol., May 1, 2004; 164(5): 1567 - 1574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ferri, N. O. Carragher, and E. W. Raines Role of Discoidin Domain Receptors 1 and 2 in Human Smooth Muscle Cell-Mediated Collagen Remodeling: Potential Implications in Atherosclerosis and Lymphangioleiomyomatosis Am. J. Pathol., May 1, 2004; 164(5): 1575 - 1585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Johnson, H.-J. Sung, S. M. Lessner, M. E. Fini, and Z. S. Galis Matrix Metalloproteinase-9 Is Required for Adequate Angiogenic Revascularization of Ischemic Tissues: Potential Role in Capillary Branching Circ. Res., February 6, 2004; 94(2): 262 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Khatri, C. Johnson, R. Magid, S. M. Lessner, K. M. Laude, S. I. Dikalov, D. G. Harrison, H.-J. Sung, Y. Rong, and Z. S. Galis Vascular Oxidant Stress Enhances Progression and Angiogenesis of Experimental Atheroma Circulation, February 3, 2004; 109(4): 520 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Johnson and Z. S. Galis Matrix Metalloproteinase-2 and -9 Differentially Regulate Smooth Muscle Cell Migration and Cell-Mediated Collagen Organization Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 54 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 M. Potier, M. Karl, S. J. Elliot, G. E. Striker, and L. J. Striker Response to sex hormones differs in atherosclerosis-susceptible and -resistant mice Am J Physiol Endocrinol Metab, December 1, 2003; 285(6): E1237 - E1245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Perree, T. G. van Leeuwen, R. Kerindongo, J. A. E. Spaan, and E. VanBavel Function and Structure of Pressurized and Perfused Porcine Carotid Arteries: Effects of in Vitro Balloon Angioplasty Am. J. Pathol., November 1, 2003; 163(5): 1743 - 1750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|