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Circulation Research. 2002;90:251-262

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(Circulation Research. 2002;90:251.)
© 2002 American Heart Association, Inc.


Review

Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis

The Good, the Bad, and the Ugly

Zorina S. Galis, Jaikirshan J. Khatri

From the Division of Cardiology, Departments of Medicine (Z.S.G., J.J.K.) and Biomedical Engineering (Z.S.G.), Emory University School of Medicine, Atlanta, Ga.

Correspondence to Zorina S. Galis, PhD, 1639 Pierce Dr, WMB 319, Atlanta, GA 30322. E-mail zgalis{at}emory.edu


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMMPs: Agents of Change
down arrowMajor Stimuli of Vascular...
down arrowMMPs and Vascular Remodeling...
down arrowOutward Geometrical Remodeling:...
down arrowPlaque Instability
down arrowArterial Stenosis
down arrowMMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
Vascular remodeling, defined as any enduring change in the size and/or composition of an adult blood vessel, allows adaptation and repair. On the other hand, inappropriate remodeling, including its absence, underlies the pathogenesis of major cardiovascular diseases, such as atherosclerosis and restenosis. Since degradation of the extracellular matrix scaffold enables reshaping of tissue, participation of specialized enzymes called matrix metalloproteinases (MMPs) has become the object of intense recent interest in relation to physiological ("good") and pathological ("bad") vascular remodeling. Experimental evidence acquired in vitro and in vivo suggests that the major drivers of vascular remodeling, hemodynamics, injury, inflammation, and oxidative stress, regulate MMP expression and activity. Alternatively, nonspecific MMP inhibition seems to oppose remodeling, as suggested by the inhibition of intimal thickening and outward arterial remodeling. An emerging concept is that MMP-related genetic variations may contribute to heterogeneity in the presentation and natural history of atherosclerosis. The hypothesis that MMPs contribute to weakening of atherosclerotic plaques is especially attractive for the potential development of therapeutic interventions aimed at preventing plaque disruption ("the ugly"), a major cause of acute cardiovascular events. However, the current lack of appropriate experimental tools, including availability of specific MMP inhibitors and pertinent animal models, still limits our understanding of the many actions and relative contributions of specific MMPs. Our future potential ability to control vascular remodeling via regulation of MMPs will also depend on reaching a consensus of what is indeed "good" or "bad" vascular remodeling, concepts that have continued to evolve and change.


Key Words: atherosclerosis • extracellular matrix • metalloproteinases • arterial remodeling


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMMPs: Agents of Change
down arrowMajor Stimuli of Vascular...
down arrowMMPs and Vascular Remodeling...
down arrowOutward Geometrical Remodeling:...
down arrowPlaque Instability
down arrowArterial Stenosis
down arrowMMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
Vascular remodeling, used in the present discussion to represent any enduring change in the size and/or composition of an adult blood vessel, not only allows blood vessels to adapt and heal but also underlines the pathogenesis of major cardiovascular diseases, including atherosclerosis and restenosis.1 Physiological and pathological vascular remodeling entails degradation and reorganization of the extracellular matrix (ECM) scaffold of the vessel wall, explaining the recent interest in the potential participation of specialized enzymes, called matrix metalloproteinases (MMPs). The current discussion, which is part of a series of reviews examining various aspects of MMP participation in cardiovascular development, function, and pathology,2 will focus on what we perceive to be currently available pertinent information, specific challenges, and yet unanswered questions that still limit our knowledge and thus the potential ability to use MMPs to control remodeling of blood vessels.


*    MMPs: Agents of Change
up arrowTop
up arrowAbstract
up arrowIntroduction
*MMPs: Agents of Change
down arrowMajor Stimuli of Vascular...
down arrowMMPs and Vascular Remodeling...
down arrowOutward Geometrical Remodeling:...
down arrowPlaque Instability
down arrowArterial Stenosis
down arrowMMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
MMPs are an ever-expanding family of endopeptidases with common functional domains and mechanisms of action discovered because of their ability to degrade ECM components. MMP actions have been implicated in both physiological and pathological tissue reshaping, including organ development, wound healing, inflammation, and cancer.3 MMP activity is regulated at multiple levels: gene transcription and synthesis of inactive zymogens, posttranslational activation of zymogens, and interactions of secreted MMPs with tissue inhibitors of metalloproteinases (TIMPs).4 Enzymatic activation requires removal of their prodomain, which can occur through degradation by other proteases, such as plasmin, or cell-associated membrane-type MMPs (MT-MMPs). Alternatively, fully activated MMPs can arise through prodomain autolysis secondary to conformational changes that reveal the catalytic site. Such conformational changes also allow substrate lysis by pro-MMPs and are the basis for detection of both latent and activated MMPs in the presence of sodium dodecyl sulfate by zymography. Once activated, MMPs participate in a broad spectrum of physiological and pathological processes including, but not limited to, degradation of ECM components. Other important nonmatrix MMP substrates include molecules whose biological activity is regulated by MMP processing, such as TNF-{alpha},5 growth factors and their receptors,6 plasminogen and its activators,7,8 and endothelin.9

Because any lasting change in blood vessel structure entails remodeling of its matrix scaffold, MMP contribution has recently been questioned in relation to the main pathological vascular conditions characterized by wall remodeling, including atherosclerosis, development of restenotic lesions, arterial aneurysmal dilation, failure of vein grafts, and atherosclerotic plaque disruption. In vitro studies with cultured cells and histological observations of normal and diseased human and experimental blood vessels indicate that both vascular and inflammatory cells produce MMPs, although the spectra of MMPs secreted basally or in response to stimuli are distinctive. The major cellular constituents of normal blood vessels, human endothelial cells (ECs) and smooth muscle cells (SMCs), produce constitutively in vitro MMP-2, TIMP-1, and TIMP-2.10,11

Immunocytochemical studies suggest that nondiseased human arteries and experimental animal arteries uniformly express, across the wall, MMP-2 and the inhibitory TIMP-1 and TIMP-2; however, no in situ enzymatic activity is detectable,12,13 suggesting tight control of MMP activity in the face of zymogen abundance. On the other hand, focally increased expression of several MMPs and presence of MMP activity were observed in diseased human arteries,12,1416 and in association with arterial morphological changes in experimental models of atherosclerosis and restenosis,1719 suggesting that MMPs enable blood vessel reshaping, including that associated with pathological conditions. Further evidence was obtained from in vitro studies of cultured vascular and inflammatory cells, which have tested the effect of stimuli characteristic for the environment of diseased vessels (Table).


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Table 1. Vascular MMPs


*    Major Stimuli of Vascular MMP Expression and Activity
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMMPs: Agents of Change
*Major Stimuli of Vascular...
down arrowMMPs and Vascular Remodeling...
down arrowOutward Geometrical Remodeling:...
down arrowPlaque Instability
down arrowArterial Stenosis
down arrowMMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
All acquired evidence indicates that the major drivers of vascular remodeling, hemodynamics, injury, inflammation, and oxidative stress, regulate MMP expression and activation. Although not clearly addressed in many studies that have investigated participation of MMPs in vascular remodeling, it is important to emphasize the distinction between regulation of MMP gene expression and that of their enzymatic activity, since the latter is likely to unleash the biological effects of MMPs.

By combining a low-flow state and balloon injury in rabbit carotid arteries, Bassiouny et al33 suggested that blood flow might be a more important regulator of arterial pro–MMP-2 expression than injury. Carotid artery flow cessation in a murine model resulted in an early significant upregulation of MMP-9 expression and expansive remodeling.41 Conversely, a nonselective MMP inhibitor inhibited the expansive remodeling at the site of rat arteriovenous fistulae.46 Elevation of transmural pressure in porcine arteries ex vivo induced the matrix-degrading activity of MMP-2 and MMP-9,31 suggesting that MMPs may also be involved in the early vascular remodeling associated with hypertension. Changes in the hemodynamic environment are thought to be of major importance in the failure of saphenous vein grafts. Investigation of potential MMP involvement has shown upregulation of MMP-2 and MMP-9 production after transposition of porcine saphenous veins in the carotid artery position.30 Ex vivo comparison of human saphenous vein grafts in simulated arterial versus venous conditions indicated that arterial conditions stimulate MMP expression and activation, likely via control of the vessel wall’s redox state.47

Several other recent studies suggest that MMP-mediated vascular remodeling in response to hemodynamic conditions could be modulated by the interplay between reactive nitrogen and oxygen species, which can lead to local oxidative stress. The role of nitric oxide (NO) in the shear-induced remodeling response was indicated by the lack of compensatory arterial remodeling in response to increased flow in endothelial nitric oxide synthase (ecNOS)-null mice.48 NO breakdown, together with accumulation of collagen, was considered responsible for constrictive remodeling of rabbit femoral arteries after balloon injury.49 Studies of flow-induced remodeling of rabbit arteriovenous fistulae suggested that the effect of NO might be exerted via modulation of MMP expression.50 In vitro ecNOS gene transfer to SMCs was shown to reduce MMP-2 and MMP-9 expression and impair their migration. However, it has become apparent that the biological effects of NO are modified in the presence of other reactive species generated in diseased vessels by activated vascular cells and infiltrating inflammatory cells.51 For instance, simultaneous production of NO and superoxide, generates peroxynitrite, found to activate latent MMPs,32 and degrade TIMP-1.52 Therefore, whereas under normal conditions NO production in healthy vessels may help keep MMP expression in check, in diseased vessels, products of NO secondary reactions may tip the MMP/TIMP balance in favor of matrix degradation. Other reactive species such as hydrogen peroxide, which can be generated from superoxide through the action of dismutases, can also modulate the activity of MMPs.32

Inflammatory cells are an important source of MMPs and other proteases, such as cathepsins, which degrade vascular matrix. In addition, activated macrophages secrete cytokines that upregulate MMP gene expression in vascular cells.11,53 Intracellular accumulation of lipid, characteristic of macrophages residing in atherosclerotic plaques, or in vitro incubation with oxidized lipoproteins, increases MMP expression in macrophages,17,38 as well as vascular cells.22,44 Presence of foam cell macrophages further enhances the oxidative stress through increased production of reactive oxygen species (ROS), which among other actions can trigger the activation of latent MMP zymogens stored in the vessel wall.32 Thus, macrophage foam cells resident in atheroma have the complete arsenal required to degrade matrix. All these actions facilitate the proteolytic degradation of matrix and may be related to the weakening of plaques with high content of foam cell macrophages.54 Focal degradation of the fibrous cap collagen by MMPs produced by foam cell macrophages was demonstrated ex vivo in human atheroma20 and was associated with in vivo rupture of an experimental model of atherosclerotic lesions developed in rabbit.25 Similar ROS-dependent activation of MMPs has been reported in connection with degranulation of mast cells in the shoulder region of atherosclerotic plaques23 and would occur in other circumstances leading to release of ROS within the vessel wall, thus enabling degradation of matrix and consequently vascular remodeling. Oxidative stress-driven remodeling may also explain the correlation between hypercholesterolemia and expansive remodeling of coronary arteries in patients with myocardial ischemia55 and the prevalence of coronary ectasia in the setting of heterozygous familial hypercholesterolemia.56 On the other hand, scavenging of ROS40 and lipid lowering24 have decreased MMP expression in experimental atheroma. Interestingly, HMG-CoA reductase inhibitors, a widely prescribed class of lipid-lowering agents, decrease MMP expression in macrophages57 as well as vascular cells.58


*    MMPs and Vascular Remodeling in Atherosclerosis
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMMPs: Agents of Change
up arrowMajor Stimuli of Vascular...
*MMPs and Vascular Remodeling...
down arrowOutward Geometrical Remodeling:...
down arrowPlaque Instability
down arrowArterial Stenosis
down arrowMMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
The growth of atherosclerotic plaque occurs through structural changes that lead to accumulation of cells, ECM, and lipids within the intimal layer of the diseased artery. Although the exact mechanisms that lead to an increased number of intimal SMCs in atherosclerotic lesions remain largely unknown, the contribution of early migration and proliferation of medial SMCs has been suggested.59 Increased MMP expression and activity were associated with development of neointimal arterial lesions and SMC migration after arterial balloon injury in experimental models, whereas MMP inhibition decreases SMC migration in vitro and in situ.34,35,60,61

Another major contributor to the growth of atherosclerotic lesions is through the recruitment of circulating inflammatory cells,62 mediated via interactions with adhesion molecules expressed by the activated endothelium.63 The mechanisms allowing for the subsequent infiltration of leukocytes through the endothelial layer and its associated basement membrane after the adhesion event remain largely unknown. Recent experiments suggest that MMP action may facilitate this step. Direct interaction of monocytic cells with a paraformaldehyde-fixed monolayer of human ECs was shown to increase monocyte MMP-9 production severalfold,64 but the mechanism was not explored. Cellular interaction in vitro between T lymphocytes and EC monolayers was shown to trigger T-cell secretion of MMP-2, the other basement membrane-degrading MMP.65 Release was dependent on the expression of VCAM-1 by the ECs. Surprisingly, the effect of cell-cell interaction on endothelial MMPs was not assessed in either study. MMP degradation of EC basement membrane during diapedesis of inflammatory cells could contribute to a decreased endothelial barrier function66 with increased influx of plasma proteins, including lipoproteins. Once inside the vessel wall, infiltrating cells interact with ECM, oxidized lipids, and with each other. All of these interactions have been shown to increase production of MMPs in macrophages.38,67,68 As mentioned, macrophages also provide stimuli for MMP production in neighboring cells and mechanisms for activation of secreted MMP zymogens.69 This increased MMP activity in developing atherosclerotic lesions may facilitate further structural changes and enable their growth (Figure 1).



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Figure 1. Cells within the vessel wall produce and secrete MMPs. Expression of various latent (pro-) MMPs is increased in atherosclerotic lesions. The spectrum of MMPs is diversified through the presence of inflammatory cells, stimulation by soluble factors, cell-cell, and cell-matrix interactions. Degradation of matrix by activated MMPs, detectable in vessels undergoing remodeling, is thought to facilitate cell migration and general reorganization of vascular tissue. Ultimately, MMPs are thought to weaken the arterial wall, thus contributing to destabilization and rupture of atherosclerotic plaques.

Clinically significant atherosclerosis has been associated with obvious morphological changes of diseased arteries. Interestingly, these changes span the whole spectrum to include progressive flow-limiting stenosis, resulting in claudication or stable angina, as well as aneurysmal dilation, resulting in dissection or rupture. Recent basic research and advances in clinical imaging have underscored the realization that while atheroma develops within the intimal layer, the whole arterial wall undergoes major reshaping. The lumen size, which is the major functional parameter, is ultimately determined not only by the magnitude of the intimal lesion but also by the overall size change of the remodeling arterial wall. Geometrical vascular remodeling can be expansive, also known as outward or positive remodeling, or constrictive, also known as inward or negative remodeling. These later considerations shifted the classic emphasis away from the burden of the intimal lesion, consequently changing our current appreciation of pathological determinants of vascular remodeling in general and of atherosclerosis in particular. The current concept of atherosclerosis, which places emphasis on the remodeling of the arterial wall, provides a framework for understanding how, through weakening and destabilization, angiographically undetectable moderate lesions could become culprits for acute coronary syndromes. It is our belief that acute cardiovascular events in fact represent a late stage of vascular remodeling.54 The action of MMPs has been studied in relation to formation of intimal lesion and overall geometrical remodeling, as these both require sustained changes in the structure and dimensions of the arterial wall (Figure 2).



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Figure 2. MMPs and arterial remodeling. There are two major directions in which arterial remodeling may progress. Expansive remodeling of the wall tends to preserve the lumen in the face of increased lesion burden. Pathological observations and experimental studies indicate that MMP expression is increased in such arteries. At the same time, plaque rupture occurs in arteries that have undergone outward remodeling, suggesting that degradation of matrix by MMPs may eventually lead to weakening and destabilization. Aneurysmal dilation may be considered an extreme case of expansive remodeling. Changes that decrease the lumen of a remodeling artery include intimal thickening and constrictive geometric remodeling of the wall. Increased MMP expression and activation have been associated with neointimal growth after balloon angioplasty of experimental arteries. Use of nonspecific inhibitors decreases intimal thickening and seems to limit outward remodeling. Arteries with an increased SMC and collagen content are considered stable but tend to become stenotic.


*    Outward Geometrical Remodeling: Too Much of a Good Thing May Be Bad
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMMPs: Agents of Change
up arrowMajor Stimuli of Vascular...
up arrowMMPs and Vascular Remodeling...
*Outward Geometrical Remodeling:...
down arrowPlaque Instability
down arrowArterial Stenosis
down arrowMMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
Outward remodeling delays the development of flow-limiting stenosis by preserving the lumen.70,71 The trigger for outward remodeling is thought to be the physiological tendency of blood vessels to optimize shear stress and wall tension.72 Because such expansive remodeling of the arterial wall likely requires releasing the constraints imposed by the structural scaffold of ECM, it is plausible to suspect that the action of MMPs is involved. Pasterkamp et al73 observed more immunopositive MMP-2 and MMP-9 and more MMP-2 activity in plaques of expansively remodeled segments compared with constrictively remodeled segments of human coronary arteries. Experimental overexpression of MMP-9 in rat SMCs enlarged the circumference of arteries seeded with such cells.74 On the other hand, nonselective MMP inhibition was found to diminish expansive arterial remodeling of rat arteriovenous fistulae.46 Treatment of LDL receptor–null mice with another nonspecific MMP inhibitor has been shown to retard expansive aortic remodeling.75

Although outward remodeling is initially beneficial by preserving the lumen, recent evidence suggests it may ultimately increase the propensity for plaque destabilization and rupture. Angioscopic and intravascular ultrasound (IVUS) studies of coronary artery lesions associated with unstable angina were associated with larger lesions and outward remodeling compared with those of stable angina, which were more fibrous and calcified.76,77 Previously identified markers of plaque instability, rich inflammatory infiltrate and decreased collagen and SMCs in the caps and shoulders of atheroma,7880 have been more recently also associated with outward vessel remodeling.81 The postmortem examination of human coronary arteries revealed increased immunostaining of MMP-2 and MMP-9, but not MMP-1, and elevated MMP-2 activity in the plaques of expansively remodeled segments.73 Thus, the increased matrix degradation that enables outward remodeling may eventually result in the weakening of the vessel wall.

Aneurysmal arterial dilation may represent an extreme form of outward remodeling. Increased MMP-2 and MMP-9 expression was detected in human abdominal aortic aneurysms (AAAs).82,83 Medial SMCs isolated from AAA tissue seem to produce significantly higher levels of MMP-2 and MMP-9 in vitro than cells obtained from control arterial tissues.27 However, the histological feature most clearly associated with enlarging human AAA diameter is a higher density of mural inflammation, composed primarily of macrophages.84 Increased MMP-9 expression may account for the propensity of AAAs to continue to expand.85 Local TIMP-1 overexpression prevented aneurysmal degeneration and rupture in a rat model of aneurysm.86 Experimental models of aneurysmal destruction of arteries in genetically deficient mice showed protection in MMP-9–null animals,87 confirming an important role for MMP-9. These experiments also suggested that the protective effect of urokinase-plasminogen activator (u-PA) deficiency against medial destruction and aneurysm formation is exerted indirectly by means of reduced activation of pro-MMPs by plasmin.36

The outward or positive remodeling preserves the lumen, however, in the process may decrease the mechanical strength of the arterial wall and thus may not be very positive after all.


*    Plaque Instability
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMMPs: Agents of Change
up arrowMajor Stimuli of Vascular...
up arrowMMPs and Vascular Remodeling...
up arrowOutward Geometrical Remodeling:...
*Plaque Instability
down arrowArterial Stenosis
down arrowMMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
The demise of atherosclerotic plaque occurs through structural disruption of the arterial wall, which triggers thrombosis, the cause of occlusion and the majority of acute vascular events.88 Plaque disruption takes one of two forms, frank rupture and superficial erosion.80,89 Rupture is associated with fracture of the fibrous cap with exposure of the prothrombotic core.90 The discovery of strong local MMP overexpression and in situ matrix-degrading activity in the vulnerable shoulders of human atheroma,12 seemingly overcoming inhibition by ubiquitously expressed TIMPs, later found to coincide with areas subjected to the highest mechanical stress,91 has provided a potential mechanistic insight into the process of plaque destabilization through matrix weakening by MMPs, especially in the vulnerable shoulders.54 Analysis of human coronary atherectomy specimens revealed uniformly active synthesis of MMP-9 by macrophages and SMCs in lesions of patients with unstable versus stable angina,14 suggesting the role of this specific MMP in acute syndromes. Peripheral blood levels of MMP-2 and MMP-926 may be increased in patients with acute coronary syndrome, raising the interesting question of the possibility to develop noninvasive tests for detection of plaque vulnerability.

Resident macrophage-derived foam cells, characteristic of unstable plaques, have been identified as a major source of MMPs, including MMP-1, MMP-2, MMP-3, MMP-7, and MMP-associated activity in human and experimental atherosclerotic lesions.12,17,40 The mechanism responsible for focally increased expression and activation of macrophage-derived MMPs, which may enable arterial remodeling and precipitate plaque destabilization, is likely related to oxidative stress.32 The capacity of human monocyte-derived macrophages to induce collagen breakdown in the fibrous caps of atheromas via release of MMPs was demonstrated ex vivo.20 Using a cleavage-specific antibody, in situ–degraded collagen was found to colocalize with MMP-1– and MMP-13–positive macrophages in atheromatous human carotid arteries.21

Alternative or complementary systems for activation of latent MMPs in atherosclerotic plaques have been suggested. Thrombin has been shown to proteolytically activate purified pro–MMP-2 in vitro and thus could provide cell-independent MMP activation at sites of vascular injury.92 In complicated atherosclerotic plaques, thrombin could promote plaque instability in episodes of intraplaque hemorrhage or superimposed plaque thrombosis by increasing the local matrix-degrading activity of MMPs. The mutually activating MMP/thrombin system may serve as an important positive-feedback loop in acute coronary syndrome.54 As acute plaque disruption leads to local thrombin production at the site of vascular injury, this may facilitate proteolytic activation of MMP-2, shown to be able to mediate platelet aggregation,93 thus further generation of thrombin and, respectively, more MMP-2 activation. Pericellular activation of pro–MMP-2 can be achieved by MT-MMPs, expressed by vascular ECs and SMCs in response to cytokines and oxidized lipoproteins.94 The plasminogen cascade represents another proteolytic-activating mechanism of MMP zymogens. Its contribution to the development of experimental neointimal lesions after injury and to aortic medial destruction was demonstrated in u-PA and plasminogen activator inhibitor (PAI)-1–null mice95 and apolipoprotein E (ApoE)–null mice, respectively.36


*    Arterial Stenosis
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMMPs: Agents of Change
up arrowMajor Stimuli of Vascular...
up arrowMMPs and Vascular Remodeling...
up arrowOutward Geometrical Remodeling:...
up arrowPlaque Instability
*Arterial Stenosis
down arrowMMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
A common occurrence after the treatment of coronary and peripheral atherosclerosis by balloon angioplasty, restenosis is a result of the concomitant contribution of intimal hyperplasia as well as constrictive remodeling. Histological and IVUS studies have suggested that the degree of luminal narrowing is more dependent on the direction of geometrical remodeling.9698 In addition, serial IVUS studies revealed that constrictive remodeling of human coronary arteries after angioplasty and atherectomy was the most important determinant of restenosis99101 and of posttransplant vasculopathy.102

The reaction of various components of the vessel wall to direct vascular injury by balloon angioplasty has been investigated in many experimental models, including the rat,35 rabbit,103 pig,129 primates,104 and mouse105 arteries. This shares major features with the process of wound healing, including deposition of collagen and tissue contraction.106 The remodeling of matrix is a result of the interplay between increased degradation early after injury and subsequent matrix accumulation and contraction. Such a temporal sequence was suggested by studies of arterial remodeling after balloon injury in the rabbit, which showed a delay between the immediate increase in procollagen mRNA expression and a detectable increase in vessel mural collagen content.107 This pattern may be due to a post–balloon injury peak in MMP expression and activity, reported in numerous studies.34,35 Studying the effects of angioplasty in rabbits with previously developed atherosclerotic lesions, Coats et al108 reported that an increase in gelatinase activity, concurrent with decreased collagen content, was associated with restenosis, further supporting a role for gelatinases in intimal thickening.

The contribution of SMC migration and thus the need for degradation of the internal elastic lamina remain to be demonstrated in pathogenesis of human lesions.59 This is likely necessary in experimental models whose normal arteries do not initially contain intimal SMCs, such as the rat and mouse carotid arteries. Administration of a nonselective MMP inhibitor reduced SMC migration and neointimal thickening in the rat carotid injury model,35,109 supporting MMP participation in the breakdown of vascular matrix and especially of the internal elastic lamina allowing migration of SMCs from outer layers. Similarly, synthetic MMP inhibitors and antibodies raised against MMPs dramatically reduce in vitro migration of rat SMCs through a reconstituted basement membrane.110 Conversely, overexpression of MMP-9 has been shown to enhance migration of rat SMCs in a collagen invasion assay.74 Proteolytic activators of latent MMPs, plasmin and thrombin, may cooperate to enhance SMC migration. Inactivation of these proteases through use of specific antibodies inhibited in vitro migration of primate aortic SMCs,111 whereas genetic deficiency inhibited in vivo SMC migration and neointima formation in mice.95 The discovery that use of either MMP or serine elastase inhibitors reverses the progressive thickening of rat pulmonary artery in organ culture112 also supports cooperation between MMPs and serine proteases in processes associated with vascular remodeling.

The migratory advantage of adventitial fibroblasts compared with medial SMCs of porcine coronary artery has been attributed to characteristic transmural variations in the balance between MMPs and TIMPs.113 MMPs may also play a role in SMC proliferation, as suggested by experiments where MMP inhibitors diminished rabbit vascular SMC proliferation in vitro.114 The overexpression of various TIMPs in rat SMCs has been shown to result in multiple divergent effects including inhibition of SMC proliferation and migration, induction of SMC apoptosis, decreased intimal hyperplasia, and increased accumulation of matrix after arterial balloon injury.60,115,116


*    MMPs and Heterogeneity of the Remodeling Response
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMMPs: Agents of Change
up arrowMajor Stimuli of Vascular...
up arrowMMPs and Vascular Remodeling...
up arrowOutward Geometrical Remodeling:...
up arrowPlaque Instability
up arrowArterial Stenosis
*MMPs and Heterogeneity of...
down arrowWhy Didn’t We Figure...
down arrowReferences
 
The remodeling response of blood vessels has been previously shown to depend on a variety of endogenous and environmental factors. These can vary for instance from vessel to vessel, as constrictive or inadequate expansive remodeling seems common in iliofemoral arteries, but not in renal arteries,97 varies with age and gender,117,118 and is modulated by known cardiovascular risk factors. Angiographic as well as IVUS data have suggested that negative and inadequate positive coronary artery remodeling are more common in individuals who smoke and in individuals with insulin-dependent diabetes compared with non–insulin-dependent diabetes but less frequent in individuals with hypercholesterolemia.55,119

Recent advances in comparative genetic analyses of normal and diseased tissue can detect the presence of unique genes or variations of common ones. As these become more reproducible and widely available, such techniques are expected to add new dimensions to the classical pathological investigative characterization of features associated with the vulnerable or ruptured plaque phenotypes.120 Identified potential molecular targets that will be further validated by other techniques may become useful markers for early diagnostics or targets for tailored treatment of plaque vulnerability.

An emerging concept is that variations in MMP expression and activity contribute to the heterogeneity in the presentation and natural history of atherosclerosis. Recent observations suggest genetic diversity that affects expression of various members of the MMP family may contribute to progression of cardiovascular disease.121 A common polymorphism in the promoter region of the human MMP-3 gene causing reduced enzyme expression has been associated with a more rapid progression of angiographically detectable lesions in patients with documented coronary artery disease who were homozygous for the allele.122 In a more recent study, carriers of this genotype were found to have increased common carotid wall thickness, enlarged lumen, and local reduction of wall shear stress, which could predispose to formation of atherosclerotic plaques.123 Interestingly, these observations suggest that decreased expression of MMP-3 makes matters worse, whereas postmortem observations of advanced human lesions suggest that increased focal expression and activity of MMP-3,12 and of MMPs in general, increase plaque vulnerability21,91 and contribute to acute events,14 underscoring the complexity of MMP actions. In accord with these observations, heterozygosity or homozygosity for a common polymorphism in the MMP-9 promoter, which leads to increased MMP-9 transcription, has been associated with an increased likelihood of detecting triple-vessel disease on angiography in patients with known coronary artery disease.124 Further complexity arises through the presence of other risk factors that can add to, or even exacerbate, effects of some of the MMP genetic polymorphisms on remodeling before, or in response to interventions. For instance, a common functional polymorphism within the MMP-12 promoter was associated with smaller luminal diameter coronary artery disease in patients with diabetes.125


*    Why Didn’t We Figure It Out Yet? Are They Good, Are They Bad, and Are They Responsible for the Ugly?
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMMPs: Agents of Change
up arrowMajor Stimuli of Vascular...
up arrowMMPs and Vascular Remodeling...
up arrowOutward Geometrical Remodeling:...
up arrowPlaque Instability
up arrowArterial Stenosis
up arrowMMPs and Heterogeneity of...
*Why Didn’t We Figure...
down arrowReferences
 
The physiological activity of MMPs must be tightly regulated in normal arteries considering that the MMP family is capable of degrading all the individual components of blood vessel ECM. An ever-increasing fund of experimental as well as clinical data illustrates the key role of MMPs in many of the processes that control vascular remodeling and especially formation and progression of atherosclerotic plaques. The net effect of the various triggers shown to increase MMP activity in the setting of atherosclerosis and vascular remodeling is an imbalance of the MMP:TIMP ratio in favor of ECM degradation. Therefore, it is conceivable that modulation of MMP activity or the MMP:TIMP balance may be useful in the management and prevention of atherosclerosis. Such approaches may hold great promise for the therapeutic management of clinical cardiovascular conditions, including acute coronary syndrome.

Recent efforts focused on finding ways to control the action of vascular MMPs through the use of nonspecific synthetic inhibitors34,40,126 or of natural inhibitors.86,115,116 The use of various nonselective MMP inhibitors to modify the natural progression of arterial restenosis after experimental balloon injury has produced mixed results. In the rat carotid artery, administration of an MMP inhibitor resulted in a 97% reduction in the number of SMCs migrating into the intima after balloon angioplasty; however, medial SMCs in treated animals reportedly underwent increased replication and eventually caught up with the untreated control lesion.109 Yet others have found that administration of a nonselective MMP inhibitor decreased constrictive arterial remodeling without reduction of neointimal formation in a porcine balloon injury model.127 Treatment of LDL receptor–null mice with yet another nonselective MMP inhibitor has been shown to retard expansive aortic remodeling.75 Thus, decreased arterial remodeling through MMP inhibition could be interpreted as beneficial in the setting of aneurysmal dilation, however equivocal in restenosis where little impact on lumen preservation was noted due to persistent neointimal reaction despite inhibition of constrictive remodeling.

Unfortunately, because of the current absence of selective MMP inhibitors, experiments have provided little insight into the role of individual MMPs, which may prove essential especially in the complicated local milieu of atherosclerotic lesions, which contains many potential substrates whose biological activity can be modified by MMPs. Experimental genetic manipulation of expression of individual MMPs or TIMPs may represent a more promising way to understand the specific activities of selective members of the large family of MMPs in isolation. Several recent studies using genetically modified animals, tissues, and cells have provided support for participation of MMP in vascular remodeling. For instance, it has been reported that MMP-9–deficient mice are resistant to experimentally induced abdominal aortic aneurysmal dilation.87 Recently, transgenic mice modified to express human MMP-1 in macrophages were crossed into the ApoE-null background and fed an atherogenic diet. Interestingly, the transgenic mice demonstrated markedly diminished lesion formation compared with controls.128 Effects of plasmin inactivation in genetically deficient mice have been correlated to decreased expression and activation of several MMPs.129 Adenoviral transfection of human saphenous vein organ culture with TMP-1 and TIMP-2130 has been shown to inhibit MMP-2 and MMP-9 gelatinolytic activity and reduce neointimal thickening without inhibiting MMP-2 and MMP-9 production or SMC proliferation. Overexpression of TIMPs in rat vascular SMCs has resulted in a variety of divergent MMP-dependent and -independent effects.122

MMPs govern processes essential for the remodeling of blood vessels. Soluble factors, cell-cell, and cell-matrix interactions finely tune MMP expression and activation spatially and temporally. Although essential for the development and normal turnover of blood vessels, and beneficial for their adaptation and repair, the action of MMPs can evade normal control and thus push remodeling over the edge. A thorough understanding of the control and consequences of MMP actions may provide new ways to manipulate vascular remodeling. To complicate matters further, new insights obtained from recent studies with MMP inhibitors and genetic manipulation suggest that depending on the setting and timing, modulation of specific MMP activities may be considered beneficial or detrimental for vascular remodeling.

The burden of proof in demonstrating a direct relationship between the action of MMPs and various aspects of vascular remodeling relies on development of specific inhibitors, appropriate animal models, and diagnostic tools. Especially attractive is the hypothesis that control of MMPs could allow the stabilization of atherosclerotic plaques, thus preventing the occurrence of their clinical consequences. However, the proof of a causal connection between plaque rupture and matrix weakening by MMPs, or of other destabilizing mechanisms for that matter, remains elusive.131 Appropriate experimental models that could test mechanisms of plaque rupture are still lacking, in spite of recent reports of occurrence of spontaneous plaque rupture in mice.132 New technologies that may identify genes uniquely associated with various types of pathological remodeling still present challenges, but also a lot of promise.120 The advent of better clinical imaging should be able to soon create pictures detailed enough to identify all parameters currently thought to define vascular remodeling and indicate potential changes with treatment. Then, the day when all the tools will be in place, we should be able to shift vascular remodeling one way or the other. We better be ready to decide when and what is good or bad in order to avoid the ugly.


*    Acknowledgments
 
Dr Zorina Galis is an Established Investigator of the American Heart Association, Award No. 0040087N. Dr Jaikirshan Khatri is supported through a National Research Service Award Training in Cardiology No. T32HL07745-06.

Received November 15, 2001; revision received January 10, 2002; accepted January 10, 2002.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMMPs: Agents of Change
up arrowMajor Stimuli of Vascular...
up arrowMMPs and Vascular Remodeling...
up arrowOutward Geometrical Remodeling:...
up arrowPlaque Instability
up arrowArterial Stenosis
up arrowMMPs and Heterogeneity of...
up arrowWhy Didn’t We Figure...
*References
 
1. Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med. 1994; 330: 1431–1438.[Free Full Text]

2. Creemers EE, Cleutjens JP, Smits JF, Daemen MJ. Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ Res. 2001; 89: 201–210.[Abstract/Free Full Text]

3. Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995; 7: 728–735.[CrossRef][Medline] [Order article via Infotrieve]

4. Brew K, Dinakarpandian D, Nagase HU. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta. 2000; 1477: 267–283.[CrossRef][Medline] [Order article via Infotrieve]

5. Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon JL. Processing of tumour necrosis factor-{alpha} precursor by metalloproteinases. Nature. 1994; 370: 555–557.[CrossRef][Medline] [Order article via Infotrieve]

6. Levi E, Fridman R, Miao HQ, Ma YS, Yayon A, Vlodavsky I. Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc Natl Acad Sci U S A. 1996; 93: 7069–7074.[Abstract/Free Full Text]

7. Lijnen HR, Ugwu F, Bini A, Collen D. Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3). Biochemistry. 1998; 37: 4699–5702.[CrossRef][Medline] [Order article via Infotrieve]

8. Ugwu F, Van Hoef B, Bini A, Collen D, Lijnen HR. Proteolytic cleavage of urokinase-type plasminogen activator by stromelysin-1 (MMP-3). Biochemistry. 1998; 37: 7231–7236.[CrossRef][Medline] [Order article via Infotrieve]

9. Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res. 1999; 85: 906–911.[Abstract/Free Full Text]

10. Hanemaaijer R, Koolwijk P, le Clercq L, de Vree WJ, van Hinsbergh VW. Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells: effects of tumor necrosis factor {alpha}, interleukin 1 and phorbol ester. Biochem J. 1993; 296: 803–809.[Medline] [Order article via Infotrieve]

11. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Unemori EN, Lark MW, Amento E, Libby P. 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]

12. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994; 94: 2493–2503.[Medline] [Order article via Infotrieve]

13. Galis Z, Sukhova G, Libby P. Microscopic localization of active proteases by in situ zymography: detection of matrix metalloproteinase activity in vascular tissue. FASEB J. 1995; 9: 974–980.[Abstract]

14. Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM. Identification of 92-kD gelatinase in human coronary atherosclerotic lesions: association of active enzyme synthesis with unstable angina. Circulation. 1995; 91: 2125–2131.[Abstract/Free Full Text]

15. Nikkari ST, O’Brien KD, Ferguson M, Hatsukami T, Welgus HG, Alpers CE, Clowes AW. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation. 1995; 92: 1393–1398.[Abstract/Free Full Text]

16. Li Z, Li L, Zielke HR, Cheng L, Xiao R, Crow MT, Stetler-Stevenson WG, Froehlich J, Lakatta EG. Increased expression of 72-kd type IV collagenase (MMP-2) in human aortic atherosclerotic lesions. Am J Pathol. 1996; 148: 121–128.[Abstract]

17. Galis ZS, Sukhova GK, Kranzhöfer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci U S A. 1995; 92: 402–406.[Abstract/Free Full Text]

18. Zaltsman AB, Newby AC. Increased secretion of gelatinases A and B from the aortas of cholesterol fed rabbits: relationship to lesion severity. Atherosclerosis. 1997; 130: 61–70.[CrossRef][Medline] [Order article via Infotrieve]

19. Jeng AY, Chou M, Sawyer WK, Caplan SL, Von Linden-Reed J, Jeune M, Prescott MF. Enhanced expression of matrix metalloproteinase-3, -12, and -13 mRNAs in the aortas of apolipoprotein E-deficient mice with advanced atherosclerosis. Ann N Y Acad Sci. 1999; 878: 555–558.[CrossRef][Medline] [Order article via Infotrieve]

20. Shah PK, Falk E, Badimon JJ, Fernandez-Ortiz A, Mailhac A, Villareal-Levy G, Fallon JT, Regnstrom J, Fuster V. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques: potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995; 92: 1565–1569.[Medline] [Order article via Infotrieve]

21. Sukhova GK, Schonbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC, Libby P. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation. 1999; 99: 2503–2509.[Abstract/Free Full Text]

22. Huang Y, Mironova M, Lopes-Virella MF. Oxidized LDL stimulates matrix metalloproteinase-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol. 1999; 19: 2640–2647.[Abstract/Free Full Text]

23. Johnson JL, Jackson CL, Angelini GD, George SJ. Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 1998; 18: 1707–1715.[Abstract/Free Full Text]

24. Aikawa M, Rabkin E, Okada Y, Voglic SJ, Clinton SK, Brinckerhoff CE, Sukhova GK, Libby P. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation. 1998; 97: 2433–2444.[Abstract/Free Full Text]

25. Rekhter MD, Hicks GW, Brammer DW, Hallak H, Kindt E, Chen J, Rosebury WS, Anderson MK, Kuipers PJ, Ryan MJ. Hypercholesterolemia causes mechanical weakening of rabbit atheroma: local collagen loss as a prerequisite of plaque rupture. Circ Res. 2000; 86: 101–108.[Abstract/Free Full Text]

26. Kai H, Ikeda H, Yasukawa H, Kai M, Seki Y, Kuwahara F, Ueno T, Sugi K, Imaizumi T. Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol. 1998; 32: 368–372.[Abstract/Free Full Text]

27. Patel MI, Melrose J, Ghosh P, Appleberg M. Increased synthesis of matrix metalloproteinases by aortic smooth muscle cells is implicated in the etiopathogenesis of abdominal aortic aneurysms. J Vasc Surg. 1996; 24: 82–92.[CrossRef][Medline] [Order article via Infotrieve]

28. Bruno G, Todor R, Lewis I, Chyatte D. Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg. 1998; 89: 431–440.[Medline] [Order article via Infotrieve]

29. Galis ZS, Kranzhöfer R, Fenton JW2nd, Libby P. Thrombin promotes activation of matrix metalloproteinase-2 produced by cultured smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997; 17: 483–489.[Abstract/Free Full Text]

30. Southgate KM, Mehta D, Izzat MB, Newby AC, Angelini GD. Increased secretion of basement membrane-degrading metalloproteinases in pig saphenous vein into carotid artery interposition grafts. Arterioscler Thromb Vasc Biol. 1999; 19: 1640–1649.[Abstract/Free Full Text]

31. Chesler N, Ku D, Galis ZS. Transmural pressure induces matrix-degrading activity in porcine arteries ex vivo. Am J Physiol. 1999; 277: H2002–H2009.[Medline] [Order article via Infotrieve]

32. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. J Clin Invest. 1996; 98: 2572–2579.[Medline] [Order article via Infotrieve]

33. Bassiouny HS, Song RH, Hong XF, Singh A, Kocharyan H, Glagov S. Flow regulation of 72-kD collagenase IV (MMP-2) after experimental arterial injury. Circulation. 1998; 98: 157–163.[Abstract/Free Full Text]

34. Zempo N, Kenagy RD, Au YPT, Bendeck M, Clowes MM, Reidy MA, Clowes AW. Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery. J Vasc Surg. 1994; 20: 209–217.[Medline] [Order article via Infotrieve]

35. Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res. 1994; 75: 539–545.[Abstract/Free Full Text]

36. Carmeliet P, Moons L, Lijnen R, Baes M, Lemaitre V, Tipping P, Drew A, Eeckhout Y, Shapiro S, Lupu F, Collen D. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet. 1997; 17: 439–444.[CrossRef][Medline] [Order article via Infotrieve]

37. Halpert I, Sires UI, Roby JD, Potter-Perigo S, Wight TN, Shapiro SD, Welgus HG, Wickline SA, Parks WC. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc Natl Acad Sci U S A. 1996; 93: 9748–9753.[Abstract/Free Full Text]

38. Xu XP, Meisel SR, Ong JM, Kaul S, Cercek B, Rajavashisth TB, Sharifi B, Shah PK. Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages. Circulation. 1999; 99: 993–998.[Abstract/Free Full Text]

39. Ganne F, Vasse M, Beaudeux JL, Peynet J, Francois A, Mishal Z, Chartier A, Tobelem G, Vannier JP, Soria J, Soria C. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits urokinase/urokinase-receptor expression and MMP-9 secretion by peripheral blood monocytes: a possible protective mechanism against atherothrombosis. Thromb Haemost. 2000; 84: 680–688.[Medline] [Order article via Infotrieve]

40. Galis ZS, Asanuma K, Godin D, Meng X. N-acetyl-cysteine decreases the matrix-degrading capacity of macrophage-derived foam cells: new target for antioxidant therapy? Circulation. 1998; 97: 2445–2453.[Abstract/Free Full Text]

41. Godin D, Ivan E, Johnson C, Magid R, Galis ZS. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation. 2000; 102: 2861–2866.[Abstract/Free Full Text]

42. Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM, Tanji N, Ferran LJ Jr, Kohl B, Rao V, Kisiel W, Stern DM, Schmidt AM. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001; 107: 675–683.[Medline] [Order article via Infotrieve]

43. Gronski TJ Jr, Martin RL, Kobayashi DK, Walsh BC, Holman MC, Huber M, Van Wart HE, Shapiro SD. Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. J Biol Chem. 1997; 272: 12189–12194.[Abstract/Free Full Text]

44. Rajavashisth TB, Xu X-P, Jovinge S, Meisel S, Xu X-O, Chai N-N, Fishbein MC, Kaul S, Cercek B, Sharifi B, Shah PK. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation. 1999; 99: 3103–3109.[Abstract/Free Full Text]

45. Rajavashisth T, Liao J, Galis Z, Tripathi S, Laufs U, Tripathi J, Chai N, Xu X, Jovinge S, Shah P, Libby P. Inflammatory cytokines and oxidized-low density lipoproteins increase endothelial cell expression of membrane type-matrix metalloproteinase -1. J Biol Chem. 1999; 274: 11924–11929.[Abstract/Free Full Text]

46. Abbruzzese TA, Guzman RJ, Martin RL, Yee C, Zarins CK, Dalman RL. Matrix metalloproteinase inhibition limits arterial enlargements in a rodent arteriovenous fistula model. Surgery. 1998; 124: 328–335.[Medline] [Order article via Infotrieve]

47. Mavromatis K, Fukai T, Tate M, Chesler N, Ku DN, Galis ZS. Early effects of arterial hemodynamic conditions on human saphenous veins perfused ex vivo. Arterioscler Thromb Vasc Biol. 2000; 20: 1889–1895.[Abstract/Free Full Text]

48. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest. 1998; 101: 731–736.[Medline] [Order article via Infotrieve]

49. Lafont A, Durand E, Samuel JL, Besse B, Addad F, Levy BI, Desnos M, Guerot C, Boulanger CM. Endothelial dysfunction and collagen accumulation: two independent factors for restenosis and constrictive remodeling after experimental angioplasty. Circulation. 1999; 100: 1109–1115.[Abstract/Free Full Text]

50. Tronc F, Mallat Z, Lehoux S, Wassef M, Esposito B, Tedgui A. Role of matrix metalloproteinases in blood flow-induced arterial enlargement: Interaction with NO. Arterioscler Thromb Vasc Biol. 2000; 20: e120–e126.

51. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000; 87: 840–844.[Abstract/Free Full Text]

52. Frears ER, Zhang Z, Blake DR, O’Connell JP, Winyard PG. Inactivation of tissue inhibitor of metalloproteinase-1 by peroxynitrite. FEBS Lett. 1996; 381: 21–24.[CrossRef][Medline] [Order article via Infotrieve]

53. Libby P, Galis ZS. Cytokines regulate genes involved in atherosclerosis. In: Numano F, Wissler RW, eds. Atherosclerosis III: Recent Advances in Atherosclerosis Research. New York, NY: The New York Academy of Sciences; 1995: 158–170.

54. Galis Z. Molecular mechanisms of plaque weakening and disruption. In: Brown D, ed. Cardiovascular Plaque Rupture. New York, NY: Marcel Dekker, Inc; 2002: 79–121.

55. Tauth J, Pinnow E, Sullebarger JT, Basta L, Gursoy S, Lindsay J Jr, Matar F. Predictors of coronary arterial remodeling patterns in patients with myocardial ischemia. Am J Cardiol. 1997; 80: 1352–1355.[CrossRef][Medline] [Order article via Infotrieve]

56. Sudhir K, Ports TA, Amidon TM, Goldberger JJ, Bhushan V, Kane JP, Yock P, Malloy MJ. Increased prevalence of coronary ectasia in heterozygous familial hypercholesterolemia. Circulation. 1995; 91: 1375–1380.[Abstract/Free Full Text]

57. Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti R, Bernini F. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol. 1998; 18: 1671–1678.[Abstract/Free Full Text]

58. Ikeda U, Shimpo M, Ohki R, Inaba H, Takahashi M, Yamamoto K, Shimada K. Fluvastatin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells. Hypertension. 2000; 36: 325–318.[Abstract/Free Full Text]

59. Schwartz SM. Perspectives series. Cell adhesion in vascular biology: smooth muscle migration in atherosclerosis and restenosis. J Clin Invest. 1997; 99: 2814–2816.[Medline] [Order article via Infotrieve]

60. Forough R, Koyama N, Hasenstab D, Lea H, Clowes M, Nikkari ST, Clowes AW. Overexpression of tissue inhibitor of matrix metalloproteinase-1 inhibits vascular smooth muscle cell functions in vitro and in vivo. Circ Res. 1996; 79: 812–820.[Abstract/Free Full Text]

61. Southgate KM, Fisher M, Banning AP, Thurston VJ, Baker AH, Fabunmi RP, Groves PH, Davies M, Newby AC. Upregulation of basement membrane-degrading metalloproteinase secretion after balloon injury of pig carotid arteries. Circ Res. 1996; 79: 1177–1187.[Abstract/Free Full Text]

62. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.[Free Full Text]

63. Gimbrone MA Jr. Endothelial dysfunction and the pathogenesis of atherosclerosis. In: Gotto A, Smith LC, Allen B, eds. Atherosclerosis V: Proceedings of the Fifth International Symposium on Atherosclerosis: Springer-Verlag, New York, NY: 1980: 415–425.

64. Amorino GP, Hoover RL. Interactions of monocytic cells with human endothelial cells stimulate monocytic metalloproteinase production. Am J Pathol. 1998; 152: 199–207.[Abstract]

65. Romanic AM, Madri JA. The induction of 72-kD gelatinase in T cells upon adhesion to endothelial cells is VCAM-1 dependent. J Cell Biol. 1994; 125: 1165–1178.[Abstract/Free Full Text]

66. Rosenberg GA, Estrada EY, Dencoff JE. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke. 1998; 29: 2189–2195.[Abstract/Free Full Text]

67. Wesley RB, Meng X, Godin D, Galis ZS. Extracellular matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro. Arterioscler Thromb Vasc Biol. 1998; 18: 432–440.[Abstract/Free Full Text]

68. Mach F, Schonbeck U, Bonnefoy JY, Pober JS, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation. 1997; 96: 396–399.[Abstract/Free Full Text]

69. Galis ZS. Metalloproteases in remodeling of vascular extracellular matrix. Fibrinolysis Proteolysis. 1999; 13: 54–63.[CrossRef]

70. Armstrong ML, Heistad DD, Marcus ML, Megan MB, Piegors DJ. Structural and hemodynamic response of peripheral arteries of macaque monkeys to atherogenic diet. Arteriosclerosis. 1985; 5: 336–346.[Abstract/Free Full Text]

71. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987; 316: 1371–1375.[Abstract]

72. Langille BL. Arterial remodeling: relation to hemodynamics. Can J Physiol Pharmacol. 1996; 74: 834–841.[CrossRef][Medline] [Order article via Infotrieve]

73. Pasterkamp G, Schoneveld AH, Hijnen DJ, de Kleijn DP, Teepen H, van der Wal AC, Borst C. Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery. Atherosclerosis. 2000; 150: 245–253.[CrossRef][Medline] [Order article via Infotrieve]

74. Mason DP, Kenagy RD, Hasenstab D, Bowen-Pope DF, Seifert RA, Coats S, Hawkins SM, Clowes AW. Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. Circ Res. 1999; 85: 1179–1185.[Abstract/Free Full Text]

75. Prescott MF, Sawyer WK, Von Linden-Reed J, Jeune M, Chou M, Caplan SL, Jeng AY. Effect of matrix metalloproteinase inhibition on progression of atherosclerosis and aneurysm in LDL receptor-deficient mice overexpressing MMP-3, MMP-12, and MMP-13 and on restenosis in rats after balloon injury. Ann N Y Acad Sci. 1999; 878: 179–190.[CrossRef][Medline] [Order article via Infotrieve]

76. Smits PC, Pasterkamp G, de Jaegere PP, de Feyter PJ, Borst C. Angioscopic complex lesions are predominantly compensatory enlarged: an angioscopy and intracoronary ultrasound study. Cardiovasc Res. 1999; 41: 458–464.[Abstract/Free Full Text]

77. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation. 2000; 101: 598–603.[Abstract/Free Full Text]

78. Lendon CL, Davies MJ, Born GV, Richardson PD. Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis. 1991; 87: 87–90.[CrossRef][Medline] [Order article via Infotrieve]

79. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation. 1994; 90: 775–778.[Abstract/Free Full Text]

80. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994; 89: 36–44.[Abstract/Free Full Text]

81. Pasterkamp G, Schoneveld AH, van der Wal AC, Haudenschild CC, Clarijs RJ, Becker AE, Hillen B, Borst C. Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox. J Am Coll Cardiol. 1998; 32: 655–662.[Abstract/Free Full Text]

82. Thompson RW, Parks WC. Role of matrix metalloproteinases in abdominal aortic aneurysms. Ann N Y Acad Sci. 1996; 800: 157–174.[Medline] [Order article via Infotrieve]

83. Knox JB, Sukhova GK, Whittemore AD, Libby P. Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Circulation. 1997; 95: 205–212.[Abstract/Free Full Text]

84. Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 1995; 15: 1145–1151.[Abstract/Free Full Text]

85. McMillan WD, Tamarina NA, Cipollone M, Johnson DA, Parker MA, Pearce WH. Size matters: the relationship between MMP-9 expression and aortic diameter. Circulation. 1997; 96: 2228–2232.[Abstract/Free Full Text]

86. Allaire E, Forough R, Clowes M, Starcher B, Clowes AW. Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest. 1998; 102: 1413–1420.[Medline] [Order article via Infotrieve]

87. Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, Ziporin SJ, Ennis TL, Shapiro SD, Senior RM, Thompson RW. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest. 2000; 105: 1641–1649.[Medline] [Order article via Infotrieve]

88. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995; 92: 657–671.[Free Full Text]

89. Burke A, Farb A, Malcom G, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997; 336: 1276–1282.[Abstract/Free Full Text]

90. Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden ischemic death. N Engl J Med. 1984; 310: 1137–1140.[Abstract]

91. Lee RT, Schoen FJ, Loree HM, Lark MW, Libby P. Circumferential stress and matrix metalloproteinase 1 in human coronary atherosclerosis: implications for plaque rupture. Arterioscler Thromb Vasc Biol. 1996; 16: 1070–1073.[Abstract/Free Full Text]

92. Galis ZS, Kranzhofer R, Fenton JW, Libby P. Thrombin promotes activation of matrix metalloproteinase-2 produced by cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997; 17: 483–489.[Abstract/Free Full Text]

93. Sawicki G, Salas E, Murat J, Miszta-Lane H, Radomski MW. Release of gelatinase A during platelet activation mediates aggregation. Nature. 1997; 386: 616–619.[CrossRef][Medline] [Order article via Infotrieve]

94. Rajavashisth TB, Liao JK, Galis ZS, Tripathi S, Laufs U, Tripathi J, Chai NN, Xu XP, Jovinge S, Shah PK, Libby P. Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type 1-matrix metalloproteinase. J Biol Chem. 1999; 274: 11924–11929.[Abstract/Free Full Text]

95. Carmeliet P, Moons L, Dewerchin M, Mackman N, Luther T, Breier G, Ploplis V, Muller M, Nagy A, Plow E, Gerard R, Edgington T, Risau W, Collen D. Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system. Ann N Y Acad Sci. 1997; 811: 191–206.[Medline] [Order article via Infotrieve]

96. Pasterkamp G, Wensing PJ, Post MJ, Hillen B, Mali WP, Borst C. Paradoxical arterial wall shrinkage may contribute to luminal narrowing of human atherosclerotic femoral arteries. Circulation. 1995; 91: 1444–1449.[Abstract/Free Full Text]

97. Pasterkamp G, Schoneveld AH, van Wolferen W, Hillen B, Clarijs RJ, Haudenschild CC, Borst C. The impact of atherosclerotic arterial remodeling on percentage of luminal stenosis varies widely within the arterial system: a postmortem study. Arterioscler Thromb Vasc Biol. 1997; 17: 3057–3063.[Abstract/Free Full Text]

98. Shiran A, Mintz GS, Leiboff B, Kent KM, Pichard AD, Satler LF, Kimura T, Nobuyoshi M, Leon MB. Serial volumetric intravascular ultrasound assessment of arterial remodeling in left main coronary artery disease. Am J Cardiol. 1999; 83: 1427–1432.[CrossRef][Medline] [Order article via Infotrieve]

99. Di Mario C, Gil R, Camenzind E, Ozaki Y, von Birgelen C, Umans V, de Jaegere P, de Feyter PJ, Roelandt JR, Serruys PW. Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional coronary atherectomy. Am J Cardiol. 1995; 75: 772–777.[CrossRef][Medline] [Order article via Infotrieve]

100. Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Wong C, Hong MK, Kovach JA, Leon MB. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation. 1996; 94: 35–43.[Abstract/Free Full Text]

101. Kimura T, Kaburagi S, Tamura T, Yokoi H, Nakagawa Y, Yokoi H, Hamasaki N, Nosaka H, Nobuyoshi M, Mintz GS, Popma JJ, Leon MB. Remodeling of human coronary arteries undergoing coronary angioplasty or atherectomy. Circulation. 1997; 96: 475–483.[Abstract/Free Full Text]

102. Lim TT, Liang DH, Botas J, Schroeder JS, Oesterle SN, Yeung AC. Role of compensatory enlargement and shrinkage in transplant coronary artery disease: serial intravascular ultrasound study. Circulation. 1997; 95: 855–1869.[Abstract/Free Full Text]

103. Kakuta T, Currier JW, Haudenschild CC, Ryan TJ, Faxon DP. Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model. Circulation. 1994; 89: 2809–2815.[Abstract/Free Full Text]

104. Geary RL, Koyama N, Wang TW, Vergel S, Clowes AW. Failure of heparin to inhibit intimal hyperplasia in injured baboon arteries. The role of heparin-sensitive and -insensitive pathways in the stimulation of smooth muscle cell migration and proliferation. Circulation. 1995; 91: 2972–2981.[Abstract/Free Full Text]

105. Lindner V, Fingerle J, Reidy MA. Mouse model of arterial injury. Circ Res. 1993; 73: 792–796.[Abstract/Free Full Text]

106. Geary RL, Nikkari ST, Wagner WD, Williams JK, Adams MR, Dean RH. Wound healing: a paradigm for lumen narrowing after arterial reconstruction. J Vasc Surg. 1998; 27: 96–106.[CrossRef][Medline] [Order article via Infotrieve]

107. Strauss BH, Chisholm RJ, Keeley FW, Gotlieb AI, Logan RA, Armstrong PW. Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis. Circ Res. 1994; 75: 650–658.[Abstract/Free Full Text]

108. Coats WD Jr, Whittaker P, Cheung DT, Currier JW, Han B, Faxon DP. Collagen content is significantly lower in restenotic versus nonrestenotic vessels after balloon angioplasty in the atherosclerotic rabbit model. Circulation. 1997; 95: 1293–1300.[Abstract/Free Full Text]

109. Bendeck MP, Irvin C, Reidy MA. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ Res. 1996; 78: 38–43.[Abstract/Free Full Text]

110. Pauly RR, Passaniti A, Bilato C, Monticone R, Cheng L, Papadopoulos N, Gluzband YA, Smith L, Weinstein C, Lakatta EG, Crow MT. Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation. Circ Res. 1994; 75: 41–54.[Abstract/Free Full Text]

111. Kenagy RD, Vergel S, Mattsson E, Bendeck M, Reidy MA, Clowes AW. The role of plasminogen, plasminogen activators, and matrix metalloproteinases in primate arterial smooth muscle cell migration. Arterioscler Thromb Vasc Biol. 1996; 16: 1373–1382.[Abstract/Free Full Text]

112. Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest. 2000; 105: 21–34.[Medline] [Order article via Infotrieve]

113. Shi Y, Patel S, Niculescu R, Chung W, Desrochers P, Zalewski A. 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]

114. Southgate KM, Davies M, Booth RF, Newby AC. Involvement of extracellular-matrix-degrading metalloproteinases in rabbit aortic smooth-muscle cell proliferation. Biochem J. 1992; 288: 93–99.[Medline] [Order article via Infotrieve]

115. Baker AH, Zaltsman AB, George SJ, Newby AC. 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]

116. Forough R, Lea H, Starcher B, Allaire E, Clowes M, Hasenstab D, Clowes AW. Metalloproteinase blockade by local overexpression of TIMP-1 increases elastin accumulation in rat carotid artery intima. Arterioscler Thromb Vasc Biol. 1998; 18: 803–807.[Abstract/Free Full Text]

117. Kornowski R, Lansky AJ, Mintz GS, Kent KM, Pichard AD, Satler LF, Bucher TA, Popma JJ, Leon MB. Comparison of men versus women in cross-sectional area luminal narrowing, quantity of plaque, presence of calcium in plaque, and lumen location in coronary arteries by intravascular ultrasound in patients with stable angina pectoris. Am J Cardiol. 1997; 79: 1601–1605.[CrossRef][Medline] [Order article via Infotrieve]

118. Zhang Y, Stewart KG, Davidge ST. Estrogen replacement reduces age-associated remodeling in rat mesenteric arteries. Hypertension. 2000; 36: 970–974.[Abstract/Free Full Text]

119. Kornowski R, Mintz GS, Lansky AJ, Hong MK, Kent KM, Pichard AD, Satler LF, Popma JJ, Bucher TA, Leon MB. Paradoxic decreases in atherosclerotic plaque mass in insulin-treated diabetic patients. Am J Cardiol. 1998; 81: 1298–1304.[CrossRef][Medline] [Order article via Infotrieve]

120. Schwartz SM, Hatsukami TS, Yuan C. Molecular markers, fibrous cap rupture, and the vulnerable plaque: new experimental opportunities. Circ Res. 2001; 89: 471–473.[Free Full Text]

121. Henney AM, Ye S, Zhang B, Jormsjo S, Whatling C, Eriksson P, Hamsten A. Genetic diversity in the matrix metalloproteinase family: effects on function and disease progression. Ann N Y Acad Sci. 2000; 902: 27–38.[Medline] [Order article via Infotrieve]

122. Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM. Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J. 1995; 73: 209–215.[Abstract/Free Full Text]

123. Gnasso A, Motti C, Irace C, Carallo C, Liberatoscioli L, Bernardini S, Massoud R, Mattioli PL, Federici G, Cortese C. Genetic variation in human stromelysin gene promoter and common carotid geometry in healthy male subjects. Arterioscler Thromb Vasc Biol. 2000; 20: 1600–1605.[Abstract/Free Full Text]

124. Zhang B, Ye S, Herrmann SM, Eriksson P, de Maat M, Evans A, Arveiler D, Luc G, Cambien F, Hamsten A, Watkins H, Henney AM. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999; 99: 1788–1794.[Abstract/Free Full Text]

125. Jormsjo S, Ye S, Moritz J, Walter DH, Dimmeler S, Zeiher AM, Henney A, Hamsten A, Eriksson P. Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease. Circ Res. 2000; 86: 998–1003.[Abstract/Free Full Text]

126. Sierevogel MJ, Pasterkamp G, Velema E, de Kleijn DP, de Smet BJ, Borst C. MMP inhibition following balloon angioplasty inhibits constrictive remodeling in favour of expansive enlargement: an intravascular ultrasound study. Eur Heart J. 1999; 20: (suppl): 412. Abstract.

127. de Smet BJ, de Kleijn D, Hanemaaijer R, Verheijen JH, Robertus L, van der Helm YJ, Borst C, Post MJ. Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan micropig. Circulation. 2000; 101: 2962–2967.[Abstract/Free Full Text]

128. Lemaitre V, O’Byrne TK, Borczuk AC, Okada Y, Tall AR, D’Armiento J. ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. J Clin Invest. 2001; 107: 1227–1234.[Medline] [Order article via Infotrieve]

129. Carmeliet P, Collen D. Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res. 1998; 91: 255–285.[CrossRef][Medline] [Order article via Infotrieve]

130. George SJ, Baker AH, Angelini GD, Newby AC. Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins. Gene Ther. 1998; 5: 1552–1560.[CrossRef][Medline] [Order article via Infotrieve]

131. Shah PK, Galis ZS. Matrix metalloproteinase hypothesis of plaque rupture: players keep piling up but questions remain. Circulation. 2001; 104: 1878–1880.[Free Full Text]

132. Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol. 2000; 20: 2587–2592.[Abstract/Free Full Text]




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Home page
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J. Thorac. Cardiovasc. Surg., November 1, 2008; 136(5): 1123 - 1130.
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Home page
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[Abstract] [Full Text] [PDF]


Home page
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Circ. Res., September 26, 2008; 103(7): 694 - 701.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
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J. Am. Coll. Cardiol., September 16, 2008; 52(12): 1024 - 1032.
[Abstract] [Full Text] [PDF]


Home page
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K. W. Lee, N. J. Kang, M.-H. Oak, M. K. Hwang, J. H. Kim, V. B. Schini-Kerth, and H. J. Lee
Cocoa procyanidins inhibit expression and activation of MMP-2 in vascular smooth muscle cells by direct inhibition of MEK and MT1-MMP activities
Cardiovasc Res, July 1, 2008; 79(1): 34 - 41.
[Abstract] [Full Text] [PDF]


Home page
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C.-H. Pan, C.-H. Wen, and C.-S. Lin
Interplay of angiotensin II and angiotensin(1-7) in the regulation of matrix metalloproteinases of human cardiocytes
Exp Physiol, May 1, 2008; 93(5): 599 - 612.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Pathol.Home page
S. Delbosc, M. Glorian, A.-S. Le Port, G. Bereziat, M. Andreani, and I. Limon
The Benefit of Docosahexanoic Acid on the Migration of Vascular Smooth Muscle Cells Is Partially Dependent on Notch Regulation of MMP-2/-9
Am. J. Pathol., May 1, 2008; 172(5): 1430 - 1440.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
G. Spinetti, N. Kraenkel, C. Emanueli, and P. Madeddu
Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies
Cardiovasc Res, May 1, 2008; 78(2): 265 - 273.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
E. N.T.P. Bakker, H. L. Matlung, P. Bonta, C. J. de Vries, N. van Rooijen, and E. VanBavel
Blood flow-dependent arterial remodelling is facilitated by inflammation but directed by vascular tone
Cardiovasc Res, May 1, 2008; 78(2): 341 - 348.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
S. H. Goldbarg, S. Elmariah, M. A. Miller, and V. Fuster
Reply
J. Am. Coll. Cardiol., April 8, 2008; 51(14): 1416 - 1416.
[Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
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Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 611 - 614.
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Home page
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J D Raffetto and R A Khalil
Mechanisms of varicose vein formation: valve dysfunction and wall dilation
Phlebology, April 1, 2008; 23(2): 85 - 98.
[Abstract] [Full Text] [PDF]


Home page
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A. Zernecke, J. Bernhagen, and C. Weber
Macrophage Migration Inhibitory Factor in Cardiovascular Disease
Circulation, March 25, 2008; 117(12): 1594 - 1602.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
E. Lancelot, V. Amirbekian, I. Brigger, J.-S. Raynaud, S. Ballet, C. David, O. Rousseaux, S. Le Greneur, M. Port, H. R. Lijnen, et al.
Evaluation of Matrix Metalloproteinases in Atherosclerosis Using a Novel Noninvasive Imaging Approach
Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 425 - 432.
[Abstract] [Full Text] [PDF]


Home page
ICVTSHome page
E. Wilton, M. Bland, M. Thompson, and M. Jahangiri
Matrix metalloproteinase expression in the ascending aorta and aortic valve
Interactive CardioVascular and Thoracic Surgery, February 1, 2008; 7(1): 37 - 40.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
A. Zernecke, I. Bot, Y. Djalali-Talab, E. Shagdarsuren, K. Bidzhekov, S. Meiler, R. Krohn, A. Schober, M. Sperandio, O. Soehnlein, et al.
Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis
Circ. Res., February 1, 2008; 102(2): 209 - 217.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
D. Fukuda, M. Sata, N. Ishizaka, and R. Nagai
Critical Role of Bone Marrow Angiotensin II Type 1 Receptor in the Pathogenesis of Atherosclerosis in Apolipoprotein E Deficient Mice
Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 90 - 96.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
Y. T.Y. Li, K. E. Swales, G. J. Thomas, T. D. Warner, and D. Bishop-Bailey
Farnesoid X Receptor Ligands Inhibit Vascular Smooth Muscle Cell Inflammation and Migration
Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2606 - 2611.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
H. Hlawaty, A. San Juan, M.-P. Jacob, R. Vranckx, D. Letourneur, and L. J. Feldman
Inhibition of MMP-2 gene expression with small interfering RNA in rabbit vascular smooth muscle cells
Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3593 - H3601.
[Abstract] [Full Text] [PDF]


Home page
J. Immunol.Home page
T. Baranek, R. Debret, F. Antonicelli, B. Lamkhioued, A. Belaaouaj, W. Hornebeck, P. Bernard, M. Guenounou, and R. Le Naour
Elastin Receptor (Spliced Galactosidase) Occupancy by Elastin Peptides Counteracts Proinflammatory Cytokine Expression in Lipopolysaccharide-Stimulated Human Monocytes through NF-{kappa}B Down-Regulation
J. Immunol., November 1, 2007; 179(9): 6184 - 6192.
[Abstract] [Full Text] [PDF]


Home page
StrokeHome page
C. Armstrong, S. Abilleira, M. Sitzer, H. S. Markus, and S. Bevan
Polymorphisms in MMP Family and TIMP Genes and Carotid Artery Intima-Media Thickness
Stroke, November 1, 2007; 38(11): 2895 - 2899.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
A. Niessner, M. S. Shin, O. Pryshchep, J. J. Goronzy, E. L. Chaikof, and C. M. Weyand
Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-{alpha} and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque
Circulation, October 30, 2007; 116(18): 2043 - 2052.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
S. H. Goldbarg, S. Elmariah, M. A. Miller, and V. Fuster
Insights Into Degenerative Aortic Valve Disease
J. Am. Coll. Cardiol., September 25, 2007; 50(13): 1205 - 1213.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
B. Gogly, A. Naveau, B. Fournier, N. Reinald, E. Durand, C. Brasselet, B. Coulomb, and A. Lafont
Preservation of Rabbit Aorta Elastin From Degradation by Gingival Fibroblasts in an Ex Vivo Model
Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1984 - 1990.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
M. Koide, P. L. Penar, B. I. Tranmer, and G. C. Wellman
Heparin-binding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes
Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1750 - H1759.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
R. C.M. Siow and A. T. Churchman
Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in
Cardiovasc Res, September 1, 2007; 75(4): 659 - 668.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
A. J. White, S. J. Duffy, A. S. Walton, J. F. Ng, G. E. Rice, S. Mukherjee, J. A. Shaw, G. L. Jennings, A. M. Dart, and B. A. Kingwell
Matrix metalloproteinase-3 and coronary remodelling: Implications for unstable coronary disease
Cardiovasc Res, September 1, 2007; 75(4): 813 - 820.
[Abstract] [Full Text] [PDF]


Home page
StrokeHome page
T. Aoki, H. Kataoka, T. Moriwaki, K. Nozaki, and N. Hashimoto
Role of TIMP-1 and TIMP-2 in the Progression of Cerebral Aneurysms
Stroke, August 1, 2007; 38(8): 2337 - 2345.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
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]


Home page
J. Pharmacol. Exp. Ther.Home page
B. J. Wu, N. Di Girolamo, K. Beck, C. G. Hanratty, K. Choy, J. Y. Hou, M. R. Ward, and R. Stocker
Probucol [4,4'-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice
J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 477 - 484.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
C. D. Overton, P. G. Yancey, A. S. Major, M. F. Linton, and S. Fazio
Deletion of Macrophage LDL Receptor-Related Protein Increases Atherogenesis in the Mouse
Circ. Res., March 16, 2007; 100(5): 670 - 677.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
G. Zalba, A. Fortuno, J. Orbe, G. San Jose, M. U. Moreno, M. Belzunce, J. A. Rodriguez, O. Beloqui, J. A. Paramo, and J. Diez
Phagocytic NADPH Oxidase-Dependent Superoxide Production Stimulates Matrix Metalloproteinase-9: Implications for Human Atherosclerosis
Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 587 - 593.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
D. Segers, F. Helderman, C. Cheng, L. C.A. van Damme, D. Tempel, E. Boersma, P. W. Serruys, R. de Crom, A. F.W. van der Steen, P. Holvoet, et al.
Gelatinolytic Activity in Atherosclerotic Plaques Is Highly Localized and Is Associated With Both Macrophages and Smooth Muscle Cells In Vivo
Circulation, February 6, 2007; 115(5): 609 - 616.
[Abstract] [Full Text] [PDF]


Home page
JNMHome page
Y.-W. Wu, H.-L. Kao, M.-F. Chen, B.-C. Lee, W.-Y. I. Tseng, J.-S. Jeng, K.-Y. Tzen, R.-F. Yen, P.-J. Huang, and W.-S. Yang
Characterization of Plaques Using 18F-FDG PET/CT in Patients with Carotid Atherosclerosis and Correlation with Matrix Metalloproteinase-1
J. Nucl. Med., February 1, 2007; 48(2): 227 - 233.
[Abstract] [Full Text] [PDF]


Home page
StrokeHome page
D. Saloner, G. Acevedo-Bolton, M. Wintermark, and J. H. Rapp
MRI of Geometric and Compositional Features of Vulnerable Carotid Plaque
Stroke, February 1, 2007; 38(2): 637 - 641.
[Abstract] [Full Text] [PDF]


Home page
Toxicol SciHome page
A. K. Lund, T. L. Knuckles, C. Obot Akata, R. Shohet, J. D. McDonald, A. Gigliotti, J. C. Seagrave, and M. J. Campen
Gasoline Exhaust Emissions Induce Vascular Remodeling Pathways Involved in Atherosclerosis
Toxicol. Sci., February 1, 2007; 95(2): 485 - 494.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
N. Fulop, R. B. Marchase, and J. C. Chatham
Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system
Cardiovasc Res, January 15, 2007; 73(2): 288 - 297.
[Abstract] [Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
J. D. Schmoker, K. J. McPartland, E. K. Fellinger, J. Boyum, L. Trombley, F. P. Ittleman, C. Terrien III, A. Stanley, and A. Howard
Matrix metalloproteinase and tissue inhibitor expression in atherosclerotic and nonatherosclerotic thoracic aortic aneurysms
J. Thorac. Cardiovasc. Surg., January 1, 2007; 133(1): 155 - 161.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
W. Koenig and N. Khuseyinova
Biomarkers of Atherosclerotic Plaque Instability and Rupture
Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 15 - 26.
[Abstract] [Full Text] [PDF]


Home page
J. Med. Genet.Home page
S. Abilleira, S. Bevan, and H. S Markus
The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis
J. Med. Genet., December 1, 2006; 43(12): 897 - 901.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Pathol.Home page
J. Cuenca, P. Martin-Sanz, A. M. Alvarez-Barrientos, L. Bosca, and N. Goren
Infiltration of Inflammatory Cells Plays an Important Role in Matrix Metalloproteinase Expression and Activation in the Heart during Sepsis
Am. J. Pathol., November 1, 2006; 169(5): 1567 - 1576.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
N. Eldrup, M.-L. M. Gronholdt, H. Sillesen, and B. G. Nordestgaard
Elevated Matrix Metalloproteinase-9 Associated With Stroke or Cardiovascular Death in Patients With Carotid Stenosis
Circulation, October 24, 2006; 114(17): 1847 - 1854.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
P. Secchiero, R. Candido, F. Corallini, S. Zacchigna, B. Toffoli, E. Rimondi, B. Fabris, M. Giacca, and G. Zauli
Systemic Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Delivery Shows Antiatherosclerotic Activity in Apolipoprotein E-Null Diabetic Mice
Circulation, October 3, 2006; 114(14): 1522 - 1530.
[Abstract] [Full Text] [PDF]


Home page
LupusHome page
K De Leeuw, B Freire, A J Smit, H Bootsma, C G Kallenberg, and M Bijl
Traditional and non-traditional risk factors contribute to the development of accelerated atherosclerosis in patients with systemic lupus erythematosus
Lupus, October 1, 2006; 15(10): 675 - 682.
[Abstract] [PDF]


Home page
Hum ReprodHome page
S. Malik, K. Day, I. Perrault, D.S. Charnock-Jones, and S. K. Smith
Reduced levels of VEGF-A and MMP-2 and MMP-9 activity and increased TNF-{alpha} in menstrual endometrium and effluent in women with menorrhagia
Hum. Reprod., August 1, 2006; 21(8): 2158 - 2166.
[Abstract] [Full Text] [PDF]


Home page
FASEB J.Home page
C. M. Mallawaarachchi, P. L. Weissberg, and R. C. M. Siow
Antagonism of platelet-derived growth factor by perivascular gene transfer attenuates adventitial cell migration after vascular injury: new tricks for old dogs?
FASEB J, August 1, 2006; 20(10): 1686 - 1688.
[Abstract] [Full Text] [PDF]


Home page
Clin. Chem.Home page
L. Nilsson, L. Jonasson, J. Nijm, A. Hamsten, and P. Eriksson
Increased Plasma Concentration of Matrix Metalloproteinase-7 in Patients with Coronary Artery Disease
Clin. Chem., August 1, 2006; 52(8): 1522 - 1527.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
X. Qin, M. A. Corriere, L. M. Matrisian, and R. J. Guzman
Matrix Metalloproteinase Inhibition Attenuates Aortic Calcification
Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1510 - 1516.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
C.-F. Lai, V. Seshadri, K. Huang, J.-S. Shao, J. Cai, R. Vattikuti, A. Schumacher, A. P. Loewy, D. T. Denhardt, S. R. Rittling, et al.
An Osteopontin-NADPH Oxidase Signaling Cascade Promotes Pro-Matrix Metalloproteinase 9 Activation in Aortic Mesenchymal Cells
Circ. Res., June 23, 2006; 98(12): 1479 - 1489.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
K. von Wnuck Lipinski, P. Keul, N. Ferri, S. Lucke, G. Heusch, J. W. Fischer, and B. Levkau
Integrin-Mediated Transcriptional Activation of Inhibitor of Apoptosis Proteins Protects Smooth Muscle Cells Against Apoptosis Induced by Degraded Collagen
Circ. Res., June 23, 2006; 98(12): 1490 - 1497.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
B. Chandrasekar, S. Mummidi, L. Mahimainathan, D. N. Patel, S. R. Bailey, S. Z. Imam, W. C. Greene, and A. J. Valente
Interleukin-18-induced Human Coronary Artery Smooth Muscle Cell Migration Is Dependent on NF-{kappa}B- and AP-1-mediated Matrix Metalloproteinase-9 Expression and Is Inhibited by Atorvastatin
J. Biol. Chem., June 2, 2006; 281(22): 15099 - 15109.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
N. Fiotti, N. Altamura, M. Fisicaro, N. Carraro, L. Uxa, G. Grassi, L. Torelli, R. Gobbato, G. Guarnieri, B. T. Baxter, et al.
MMP-9 Microsatellite Polymorphism and Susceptibility to Carotid Arteries Atherosclerosis
Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1330 - 1336.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
A.P.J.J. Bijnens, E. Lutgens, T. Ayoubi, J. Kuiper, A.J. Horrevoets, and M.J.A.P. Daemen
Genome-Wide Expression Studies of Atherosclerosis: Critical Issues in Methodology, Analysis, Interpretation of Transcriptomics Data
Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1226 - 1235.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
H. Bujo and Y. Saito
Modulation of Smooth Muscle Cell Migration by Members of the Low-Density Lipoprotein Receptor Family
Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1246 - 1252.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
J. L. Martin-Ventura, V. Nicolas, X. Houard, L. M. Blanco-Colio, A. Leclercq, J. Egido, R. Vranckx, J.-B. Michel, and O. Meilhac
Biological Significance of Decreased HSP27 in Human Atherosclerosis
Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1337 - 1343.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
A. Zernecke, E. A. Liehn, J.-L. Gao, W. A. Kuziel, P. M. Murphy, and C. Weber
Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10
Blood, June 1, 2006; 107(11): 4240 - 4243.
[Abstract] [Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
L. Chen, X. Wang, S. A. Carter, Y. H. Shen, H. R. Bartsch, R. W. Thompson, J. S. Coselli, D. L. Wilcken, X. L. Wang, and S. A. LeMaire
A single nucleotide polymorphism in the matrix metalloproteinase 9 gene (-8202A/G) is associated with thoracic aortic aneurysms and thoracic aortic dissection
J. Thorac. Cardiovasc. Surg., May 1, 2006; 131(5): 1045 - 1052.
[Abstract] [Full Text] [PDF]


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