Physiol Rev 85: 1–31, 2005;
doi:10.1152/physrev.00048.2003.
Dual Role of Matrix Metalloproteinases (Matrixins)
in Intimal Thickening and Atherosclerotic Plaque Rupture
ANDREW C. NEWBY
Bristol Heart Institute, University of Bristol, Bristol, United Kingdom
VII.
VIII.
IX.
X.
Introduction
Intimal Thickening: From Physiological Adaptation to Pathological Failure
Why Consider a Role for Matrix Metalloproteinases in Intimal Expansion and Plaque Rupture?
Matrix Metalloproteinase Expressed in the Mammalian Vasculature
Criteria for Matrix Metalloproteinase Involvement in Intimal Thickening and Plaque Rupture
Matrix Metalloproteinase and Tissue Inhibitor of Metalloproteinase Gene Transcription Is
Differentially Regulated in Isolated Vascular Cells in Culture: Matrix Metalloproteinase
Upregulation May Occur in Several Distinct Stages
A. VSMC
B. EC
C. Macrophages
D. T lymphocytes
E. Mast cells
F. Adventitial fibroblasts
G. Transcriptional control mechanisms
Participation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinase
in Intimal Thickening by Regulation of Cell Migration and Proliferation
A. Methodologies
B. Patterns of MMP expression and activity in humans and in animal models
of neointima formation
C. Effects of MMP overexpression and TIMP knockout
D. Effects of MMP inhibition and knockout
E. Putative mechanisms
F. Conclusions
Role of Matrix Metalloproteinases in Atherosclerotic Plaque Destabilization
A. Methodologies
B. Patterns of MMP expression and activity in human pathological tissues and experimental models
of atherosclerosis
C. Effects of MMP overexpression and TIMP knockout
D. Effects of MMP inhibition and knockout
E. Putative mechanisms
F. Conclusions
Pharmacotherapy
A. Direct inhibition by synthetic inhibitors and gene therapy with TIMPs
B. Inhibition of MMP production
Summary: What Mediates the Transition From Physiological Remodeling to Matrix Destruction?
2
2
4
4
7
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
I.
II.
III.
IV.
V.
VI.
7
7
8
8
9
9
9
9
10
10
11
12
12
13
15
15
15
17
18
19
20
20
21
21
21
22
Newby, Andrew C. Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic
Plaque Rupture. Physiol Rev 85: 1–31, 2005; doi:10.1152/physrev.00048.2003.—Intimal thickening, the accumulation of
cells and extracellular matrix within the inner vessel wall, is a physiological response to mechanical injury, increased wall
stress, or chemical insult (e.g., atherosclerosis). If excessive, it can lead to the obstruction of blood flow and tissue
ischemia. Together with expansive or constrictive remodeling, the extent of intimal expansion determines final lumen size
and vessel wall thickness. Plaque rupture represents a failure of intimal remodeling, where the fibrous cap overlying an
atheromatous core of lipid undergoes catastrophic mechanical breakdown. Plaque rupture promotes coronary thrombosis and myocardial infarction, the most prevalent cause of premature death in advanced societies. The matrix
metalloproteinases (MMPs) can act together to degrade the major components of the vascular extracellular matrix. All
cells present in the normal and diseased blood vessel wall upregulate and activate MMPs in a multistep fashion driven in
www.prv.org
0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society
1
2
ANDREW C. NEWBY
part by soluble cytokines and cell-cell interactions. Activation of MMP proforms requires other MMPs or other classes of
protease. MMP activation contributes to intimal growth and vessel wall remodeling in response to injury, most notably
by promoting migration of vascular smooth muscle cells. A broader spectrum and/or higher level of MMP activation,
especially associated with inflammation, could contribute to pathological matrix destruction and plaque rupture. Inhibiting the activity of specific MMPs or preventing their upregulation could ameliorate intimal thickening and prevent
myocardial infarction.
I. INTRODUCTION
Physiol Rev • VOL
II. INTIMAL THICKENING: FROM
PHYSIOLOGICAL ADAPTATION
TO PATHOLOGICAL FAILURE
The normal intima of large arteries has a continuous
endothelial monolayer seated on a basement membrane.
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Already in the middle of the 19th century, Virchow
(282) described the key histological feature of the thickened intima in atherosclerosis, namely, the presence of
cholesterol as extracellular crystals and in “foam cells.”
He formulated the “infiltration” hypothesis, which is still
current, stating that atherosclerosis results from the infiltration of lipids and inflammatory cells from the blood.
The characterization of intimal expansion at the molecular level has continued to the present day and is summarized as background in section II of this review.
Based on Nobel Prize winning work by Goldstein and
Brown into the mechanisms of cholesterol uptake into
cells, Steinberg et al. (263) formulated the “modified lowdensity lipoprotein” (LDL) hypothesis. According to this,
modifications, including importantly oxidation, increase
the uptake of plasma LDL into macrophages and give rise
to foam cells. In 1972 Ross and Glomset (229) initially
formulated the “response to injury” hypothesis, which
focused on the behavior of vascular smooth muscle
(VSMC) and endothelial cells (EC) and took into account
the recent discovery of peptide growth factors. According
to this proposal and subsequent modifications, the vessel
wall responded by endothelial dysfunction and VSMC
proliferation when injured mechanically, by abnormal
flow, or by other noxious agents, such as cigarette smoke
or glycated proteins produced in diabetic patients. Response to injury provided a satisfactory explanation for
fibrous cap formation, for the localization of atherosclerosis in areas of disturbed flow and many risk factors in
addition to hypercholesterolemia. The hypothesis also
offered an explanation for the iatrogenic intimal thickening that had begun to be recognized as a clinical problem
following the introduction of coronary bypass grafting,
coronary angioplasty, and heart transplantation. Another
consequence of all these perturbations is inflammation,
and Libby (157) championed the possible pathogenetic
role of inflammatory mediators. Hansson and Wick (reviewed in Ref. 107) formulated convincing cases for an
immune component of atherosclerosis. In his later reviews, Ross (228) largely succeeded in unifying these
various hypotheses by proposing oxidized lipids as one
important protagonist of chronic vascular inflammation
and hence response to injury.
By the beginning of the 1990s, a long list of inflammatory cytokines and growth factors that might mediate
the response to injury had been identified (198). When
examined in isolated tissue culture, many of these cytokines promoted the proliferation of VSMC, and a smaller
subset affected migration. However, when these observations were translated into animal models of neointima
formation by Reidy and Clowes’ groups (58) or human
organ culture models (our work) (259), it was apparent
that growth factors by themselves were insufficient and
that extracellular proteases might also be needed (58).
Parallels between invasion of VSMC in the neointima and
invasion of cancer cells and other a priori reasons itemized in section III of this review led us to consider a role
for matrix metalloproteinases (MMPs) (256). Section IV
provides a necessary introduction to the MMP family
members that have subsequently been discovered in the
vessel wall. Section V attempts to structure the wealth of
data regarding the physiological and pathological regulation of MMP activity in the vasculature. A comprehensive
and critical examination of the evidence for involvement
of MMPs in intimal thickening is one of the major tasks of
this review. Section VI lists the criteria, and section VII
details the evidence.
Thanks mainly to careful autopsy observations, particularly by Davies and Thomas (64, 65) and Falk et al.
(77), it has become accepted that myocardial infarction is
a distinct acute pathological event superimposed on the
chronic process of atherosclerosis. Two main mechanisms were identified, most often rupture of the fibrous
cap (“plaque rupture”) or alternatively disruption of the
surface endothelium (“plaque erosion”) (reviewed in Ref.
63). Plaque rupture was associated inter alia with a
greater degree of inflammation and destruction of the
extracellular matrix (152). This led Henney et al. (113)
and Libby and co-workers (90) independently to propose
a pathogenetic role for MMPs in plaque rupture. A detailed critical appraisal of this concept is presented in
section IX. Section X summarizes the dual role of MMPs in
intimal expansion and plaque rupture and asks how these
two roles, which appear to have opposite effects on
plaque stability, can be reconciled.
METALLOPROTEINASES IN BLOOD VESSELS
Physiol Rev • VOL
to have arisen by clonal expansion of one or a few cells
(26, 194). This could arise by selection of a subpopulation
of medial VSMC that express a proliferative phenotype
(108) or expansion from circulating VSMC precursors
(stem cells) that have invaded the plaque (44, 118, 235).
Alternatively, it has been suggested that some neointimal
VSMC may be transdifferentiated adventitial fibroblasts
(308). The atherosclerotic intima also contains capillaries,
formation of which contributes to plaque growth in animal models (193).
If intimal growth is such that the initial lumen is
narrowed by ⬎70%, distal blood flow is restricted and
chronic tissue ischemia results. This occurs in native
coronary arteries and during restenosis after coronary
angioplasty or failure of some coronary vein grafts: it then
results in stable angina pectoris. Constrictive vessel wall
remodeling (shrinking of the whole vessel wall), which
involves the fibroblast-rich adventitia as well as the media, may exacerbate the unwanted flow restriction caused
by intimal thickening (71, 188). Conversely, expansive
remodeling, i.e., enlargement of the total vessel wall
cross-sectional area, ameliorates these adverse hemodynamic consequences (97). On the other hand, pathological
outward expansion, for example, in aortic aneurysms, can
lead to catastrophic medial dissection and rupture. In
humans, aortic aneurysms are considered the consequence of invasion of atherosclerotic inflammation into
the media (45, 224). Recent histological and in vivo intravascular ultrasound studies showed that ruptured plaques
are more likely to have undergone outward remodeling
(209, 240). Moreover, apolipoproteinE (ApoE) knockout
mice show frequent aortic microaneurysms at the base of
atherosclerotic plaques (47). It is tempting, therefore, to
conclude, as Pasterkamp et al. did (209), that aneurysmal
dilatation, expansive remodeling, and plaque rupture actually have a common inflammatory origin and can be
regarded as aspects of the same phenomenon.
Catastrophic rupture or surface erosion of the fibrous cap underlies fatal coronary thrombosis and myocardial infarction (MI), which is the leading cause of
premature death in developed countries (see http://www.
who.int/whosis/). Plaque rupture, which accounts for
more than 80% of fatal MI in men, occurs in regions of
high tangential stress and where collagen is depleted (63).
The implication is that matrix destruction weakens the
plaque to the point where it can no longer resist the
cyclical strain caused by the cardiac cycle (158). Plaque
erosion accounts for as much as 50% of MI in young
women (63). It is apparently a distinct pathology triggered
by large-scale loss of the endothelium and exposure of the
thrombogenic underlying basement membrane. Because
much less is known about its underlying basis, it will not
be considered further in this review.
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
In humans, the intima is focally thickened by a hyaluronan-rich matrix with sparse VSMC (261). All basement
membranes contain type IV collagen, laminin, and heparan sulfate proteoglycans, such as perlecan (276) and
syndecans (298). The normal media contains contractile
VSMC surrounded by their own basement membrane
(275), a few resident macrophages, and possibly fibroblasts (308). The medial interstitial matrix contains types
I and III collagen, a variety of glycoproteins, including
fibronectin, vitronectin, tenascin, and thrombospondin,
together with chondroitin/dermatan sulfate proteoglycans, such as versican (197). There is also elastin arranged into distinct layers (lamellae). The adventitia contains fibroblasts, small blood vessels, and fat in a loose
interstitial matrix (293, 294).
Intimal growth is mediated by an increase in the
number and diversity of cells and is accompanied by
accumulation of new extracellular matrix (57). It is an
adaptive or repair response to a variety of adverse physical and biochemical stimuli acting on the vessel wall. For
example, when pulmonary hypertension occurs secondary to congenital or acquired abnormalities of the heart,
VSMC hyperplasia is a direct response to increased tangential wall stress (289). A similar response occurs also in
arteriovenous fistulas and surgical vein-grafts into the
systemic circulation (10, 70). Mechanical injury, particularly to the luminal surface of arteries during percutaneous transluminal angioplasty, also triggers VSMC hyperplasia as a repair response, at least in healthy animals’
arteries (27, 28). Intimal remodeling is almost always
accompanied by transient inflammation. For example, immunologically driven processes, such as transplant arteriosclerosis (232) and foreign body reaction to stent implantation after angioplasty (79, 138, 281), provoke intimal thickening.
The most common and arguably most complex
chemical insult that provokes intimal expansion is atherosclerosis. Deposition of LDL, which subsequently becomes oxidized, is the most likely initial event. This is
followed by infiltration of circulating monocytes, which
convert to macrophages and take up oxidized LDL to
become foam cells (228). Activated lymphocytes also occur in atherosclerotic plaques at all stages of its progression, and other inflammatory cells including mast cells are
also present (107). Formation of a distinct fibrous cap
over a large lipid core occurs only as a late consequence
of atherosclerosis (261). The lipid core arises because
macrophages die by apoptosis and spill their lipid contents. The plaque cap could form by migration of typical,
contractile VSMC from the media, which would account
for the frequent medial wasting observed at the base of
atherosclerotic plaques (66). However, this paradigm has
been challenged recently. First, many plaque caps appear
3
4
ANDREW C. NEWBY
The remainder of this review discusses the structure of
MMPs and the ways in which their activity is regulated and
critically appraises their physiological roles in blood vessels.
III. WHY CONSIDER A ROLE FOR MATRIX
METALLOPROTEINASES IN INTIMAL
EXPANSION AND PLAQUE RUPTURE?
IV. MATRIX METALLOPROTEINASE EXPRESSED
IN THE MAMMALIAN VASCULATURE
The mammalian MMPs (also known as matrixins) are
a family of at least 25 secreted or surface-bound proteases
(264, 283), of which 14 have been characterized in vascular cells (Fig. 2). They belong to the subfamily of metallopeptidases known as metzincins because their active
site contains an essential Zn2⫹. Their activity can be
regulated at four levels: induction of MMP genes, vesicle
trafficking and secretion, activation of latent proforms,
and complexing with specific tissue inhibitors of metalloproteinases (TIMPs).
Structurally, MMPs comprise a signal sequence, a
prodomain, a catalytic domain, and usually a hemopexinlike domain, although this is absent in MMPs-7 and -26
and replaced with an immunoglobulin-like domain in
MMP-23 (Fig. 2). Most MMPs are expressed as inactive,
latent proforms, although MMP-11, -21, -23, and -27 and
the membrane-type MMPs (MT-MMPs) are activated by
FIG. 1. Hypothesis: matrix metalloproteinases (MMPs) promote basement membrane degradation, phenotypic modulation, migration, and proliferation of vascular smooth muscle cells (VSMC). MMPs could catalyze removal of the basement membrane around VSMC, which normally comprises
polymerized type IV collagen, laminin, and heparan sulfate proteoglycans (HSPGs). Removal of basement membranes facilitates contacts with the
interstitial matrix, which comprises polymerized types I and III collagen, fibronectin, and glycoproteins such as osteopontin, vitronectin and tenascin C,
and dermatan sulfate proteoglycans (DSPG) such as versican. Together with new matrix components such as tropocollagens and fibronectin, existing
interstitial matrix components could promote change in the phenotype from quiescent contractile VSMC to cells capable of migrating and proliferating to
mediate repair. Migration could be enhanced by fibronectin polymerization providing a track way for migration. Freeing of sequestered growth factors (GF,
circled) could promote VSMC proliferation together with autocrine effects of production of newly produced, permissive matrix components such as
monomeric collagen.
Physiol Rev • VOL
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
The following four arguments represent the a priori
case for the involvement of MMPs in intimal thickening
and plaque rupture.
Intimal thickening constitutes the generation of new
tissue at least in part using VSMC derived from the media.
As illustrated in Figure 1, MMPs could catalyze removal of
the basement membrane around VSMC and facilitate contacts with the interstitial matrix. This could promote a
change from quiescent, contractile VSMC to cells capable
of migrating and proliferating to mediate repair. Freeing
of sequestered growth factors and production of new,
permissive matrix components could further promote
VSMC migration and proliferation.
Plaque rupture results from net destruction of the
intimal extracellular matrix (ECM), which must be driven
by proteases.
Remodeling of the vascular ECM occurs at neutral
pH, where MMPs are active.
The MMPs (also known as matrixins) are a large
family of proteases that each has at least one ECM component as a putative substrate.
METALLOPROTEINASES IN BLOOD VESSELS
5
removal of the prodomain by furins in the endosomal
pathway. Except in MMP-23, latency is maintained because a conserved cysteine residue in the prodomain
sequence PRCGXPD displaces the catalytic water molecule from the active site zinc ion (260). In the test tube
MMPs can be activated by physical (e.g., low pH, binding
of sodium dodecyl sulfate) or chemical (e.g., 4-aminophenylmercuric acid) modification, which provokes structural unwinding, autocatalytic cleavage of the NH2-termi-
nal prodomain and hence opens the so-called “cysteine
switch” (260). A physiological example of chemical activation may be the ability of nitric oxide to activate MMP-9
in the brain (102). Reactive oxygen species (ROS) potentially released from macrophages can also activate MMP-2
and -9 (220).
Most pro-MMPs are likely to be activated biologically
by tissue or plasma proteinases, including other MMPs
(Fig. 3). One well-established case is activation of MMP-2
FIG. 3. Hypothetical activation cascades for MMPs. Up to four levels of catalytic activation of MMPs may be responsible
for their ultimate proteolytic effect on matrix components. Lysosomal cathepsins
might provide a link between tissue injury
and increased proteolysis. Tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) as well as reactive
oxygen species (ROS) and nitric oxide (NO)
are also implicated.
Physiol Rev • VOL
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
FIG. 2. Structure of MMPs: variations on
a theme. The domain structure common to
MMPs and variations on this in individual
MMPs are shown. Tm represents the transmembrane domain, while hexagonP represents a glycosylphosphatidylinositol (GPI)anchor membrane anchor.
6
ANDREW C. NEWBY
Physiol Rev • VOL
COOH-terminal transmembrane domain while MMPs-17
and -25 have a glycophosphatidylinositol anchor.
A variety of protein inhibitors of MMP have been
described, among which the TIMPs are by far the most
potent and selective (15). There are at least four members
of the TIMP family that form tight inhibitory 1:1 complexes with MMPs. These interactions are generally rather
nonselective, although, exceptionally, TIMP-1 is a much
weaker inhibitor of MT-MMPs than other TIMPs (248,
295). TIMPs-1 to -4 are each made up of two domains
containing three disulfide bonds (195). The NH2-terminal
cysteine is particularly important in inhibition, since its
free ␣-amino group and carbonyl function displace the
catalytic water molecule from the essential zinc ion in the
MMP active site (99). The three COOH-terminal loops of
TIMPs mediate complex formation with the progelatinase
hemopexin domain and are largely responsible for the
unique matrix binding capacity of TIMP-3 (146). The importance of the COOH terminus of TIMP-3 is further
underlined by the fact that any of six mutations that
generate a free SH-group in this portion of the molecule
leads to the autosomal-dominant blindness, Sorsby’s fundus dystrophy (288). In plasma, the general protease inhibitor ␣2-macroglobulin may also be important. The
physiological relevance of other inhibitors including the
RECK protein (204) is unknown.
Disintegrin metalloproteinases (ADAMs) also contain an MMP-like catalytic domain, which in some cases
remains catalytically active. In general, TIMPs do not bind
to or inhibit the catalytic site of ADAMs, although TIMP-3
inhibits a number of ADAMs and TIMP-1 inhibits
ADAM-10 (8). Of the more than 30 members of this family,
only ADAM-10 (36), ADAM-15 (115), and ADAM-17 (31)
have been characterized in vascular cells. ADAMs will not
be discussed further, since there is insufficient evidence
to decide whether or not they have a specific role in
intimal thickening or plaque rupture.
Based on substrate specificity and structural homology, MMPs can be assigned to five subgroups: interstitial
collagenases, gelatinases, stromelysins/matrilysins, membrane-type MMPs (MT-MMPs), and others (Table 1).
MMPs appear to have distinct but overlapping specificities against purified matrix proteins in the test tube (see
Refs. 264, 283). Interstitial collagenases (MMP-1, MMP-8,
and MMP-13) cleave intact fibrillar interstitial collagens I,
II, and III, and MMP-14, an MT-MMP, also has this ability
(205). The gelatinases (MMP-2 and -9) have prominent
activity against basement membrane components including type IV collagen and laminin and also elastin (5, 134).
Stromelysins-1 and -2 (MMPs-3 and -10) and matrilysin
(MMP-7) have a wide substrate repertoire, which includes
most of the ECM proteins and proteoglycans except intact
fibrillar collagens. Stromelysin-3 (MMP-11) is related in
sequence to the other stromelysins, but its substrate specificity is unusual. Its main substrates may be serum pro-
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
at the cell surface by MT-MMPs, which is best understood
for MT1-MMP (264, 267). TIMP-2 bound to the catalytic
site of one MT1-MMP molecule acts as a receptor for
MMP-2 by interacting with the noncatalytic COOH-terminal domain. A second molecule of MT1-MMP then partially cleaves the MMP-2 prodomain, which is then fully
cleaved by autoproteolysis. None of the other TIMPs can
substitute for TIMP-2 during the activation of MMP-2
(299). One consequence is that MT-MMP-mediated MMP-2
activation is functionally impaired in TIMP-2 knockout
mice (264). Secreted MMPs, particularly, MMPs-3, -7, and
-10, can activate other secreted MMPs (283). Serine proteases, such as trypsin and mast cell-derived chymase and
tryptase, activate several MMPs in the test tube (149).
Hence, the mast cell enzymes could be significant activators of MMPs in atherosclerotic plaques in vivo (131). The
serine proteases, thrombin (87, 145), and Factor Xa (223)
promote activation of MMP-2, which suggests a link between thrombosis and activation of ECM turnover. Tissue
but not plasma kallikrein activates purified MMP-9 (69).
The abundant serine protease, plasmin, activates proMMPs-1, -3, -7, -9, -10, and -13 in vitro (159). Moreover,
plasminogen knockout in mice impairs MMP-9-mediated
elastin degradation and aneurysm formation, showing
that plasmin is an essential MMP activator in vivo (47).
Plasmin is, in turn, activated by plasminogen activators
that can be secreted or located at the cell surface by
binding to specific receptors (74). From knockout studies,
the urokinase-type plasminogen activator seems to be
particularly important for vascular remodeling (46). This
must be activated by yet other proteases, perhaps plasma
kallikrein (74). Hence, MMP activation is likely to require
a complex cascade of catalytic activation during which
the final proteolytic effect could be greatly amplified
(Fig. 3). The question arises as to which processes
initiate the cascade during vascular injury. Possibilities
worthy of consideration are release of lysosomal proteases during cell death or production of ROS during
oxidative stress (220).
The MMP catalytic domain contains the canonical
zinc-binding sequence HExGHxxGxxHS. Uniquely in the
gelatinases, MMP-2 and -9, the catalytic domain is interrupted by three repeats of a fibronectin type II-like sequence. The COOH-terminal hemopexin domain in MMP-1
aids in recognition of large matrix molecule substrates
and is important in dimerization and in interaction of
other pro-MMPs with TIMPs (283). Such remote interactions between MMP-9 and TIMP-1 or MMP-2 and TIMP-2
alter the kinetics of activation but do not inhibit catalytic
activity. The hemopexin domain in MMP-2 also functions
to anchor the enzyme to the cell membrane via integrin
binding (37). Similar mechanisms may underlie integrin
binding of MMP-1 and binding of MMP-9 to the CD44
hyaluronan receptor (264). The MT-MMPs are intrinsic
membrane proteins; MMPs-14 to -16 and -24 have a
METALLOPROTEINASES IN BLOOD VESSELS
1. Members of the MMP family expressed
in vascular tissues
These criteria are considered in the following sections.
TABLE
Group
Collagenases
Gelatinases
Stromelysins
Membrane-type MMPs
(MT-MMP)
MMPs
Trivial Names
MMP-1
MMP-8
MMP-13
MMP-2
MMP-9
MMP-3
MMP-10
MMP-7
MMP-14
MMP-15
MMP-16
MMP-17
MMP-11
MMP-12
Interstitial collagenase
Neutrophil collagenase
Collagenase-3
Gelatinase-A
Gelatinase-B
Stromelysin-1
Stromelysin-2
Matrilysin
MT1-MMP
MT2-MMP
MT3-MMP
MT4-MMP
Stromelysin-3
Macrophage metalloelastase
MMP, matrix metalloproteinase.
tease inhibitors, not matrix proteins (241, 264). Metalloelastase (MMP-12) is usually set apart from the other
groups of MMPs on sequence criteria and because of its
limited activity as a collagenase (264). The MT-MMPs
were first identified by their ability to activate progelatinase A (236), although MMP-17 does not, and all of the
MT-MMPs also cleave at least one matrix protein (283).
MMPs also cleave a variety of nonmatrix substrates (for
comprehensive listings, see Refs. 264, 283).
From the substrate specificities defined in vitro (264,
283), it appears that individual MMPs have only a limited
and inefficient capacity to remodel the ECM. However,
acting together, they could efficiently degrade all of the
major protein and proteoglycan-core-protein components
(195, 283). The ability of some MMPs to activate the
proforms of others, as discussed above (Fig. 3), further
suggests that individual MMPs need to act together and
with other classes of protease to achieve matrix turnover.
V. CRITERIA FOR MATRIX
METALLOPROTEINASE INVOLVEMENT
IN INTIMAL THICKENING AND
PLAQUE RUPTURE
A convincing case should consist of the following
elements.
1) MMPs are expressed and regulated in vascular
cells.
2) MMP gene expression and activity are temporally
and spatially related to intimal expansion and plaque
rupture.
3) Introduction of MMP genes mimics the events of
matrix remodeling.
4) Inhibition or knockout of MMP genes suppresses
remodeling.
5) Plausible mechanisms explain the actions of
MMPs.
Physiol Rev • VOL
VI. MATRIX METALLOPROTEINASE
AND TISSUE INHIBITOR OF
METALLOPROTEINASE GENE
TRANSCRIPTION IS DIFFERENTIALLY
REGULATED IN ISOLATED VASCULAR
CELLS IN CULTURE: MATRIX
METALLOPROTEINASE UPREGULATION
MAY OCCUR IN SEVERAL
DISTINCT STAGES
A. VSMC
Upregulation of MMP production from VSMC fits the
pattern of a series of stages (Fig. 4). VSMC constitutively
express the gelatinase MMP-2 (88, 211, 256, 304). Stretch
further upregulates MMP-2 via production of ROS in an
NAD(P)H oxidase-dependent manner (101). Upregulation
of MMP-2 production and dramatic induction of the other
gelatinase, MMP-9, occur rapidly after mechanical injury
(25, 95, 125, 257). These findings imply that stretch and
injury can promote MMP-mediated breakdown of basement membranes, for which there is direct evidence (1).
MMP-2 and -9 also have significant elastolytic activity that
could be important in remodeling of arteries in response
to altered hemodynamics (55). Inflammatory cytokines,
such as interleukin (IL)-1, IL-4 and tumor necrosis factor-␣ (TNF-␣), coordinately induce a broad range of
MMPs, including MMPs-1, -3, and -9 (88, 147, 234). Cytokines act synergistically with growth factors, such as
platelet-derived growth factor (PDGF) and fibroblast
growth factor-2 (FGF-2) (34, 75, 137, 213, 304). The presence of both inflammatory mediators and growth factors
in injured and atherosclerotic blood vessels could therefore drive the production of MMPs with the ability to
efficiently remodel both basement membranes and many
components of the interstitial matrix. Cell contact with
T-lymphocyte membranes and addition of recombinant
CD40 ligand induce MMPs-1, -3, -8, and -9 in VSMC (114,
241, 243), which implies a relationship between immune
activation and wide-ranging matrix remodeling.
The regulation of TIMPs shows a distinctly different
pattern from MMPs. TIMP-1 is either constitutive (75, 88)
or upregulated by the fibrogenic cytokines, PDGF, and
transforming growth factor-␤ (TGF-␤) (76). TIMP-2 secretion is constitutive (75, 88), while TIMP-3 expression is
upregulated by a combination PDGF and TGF-␤ (75).
Together these findings suggest that stretch, injury,
inflammation, and immune activation progressively move
the MMP/TIMP balance in VSMC towards proteolysis,
while fibrogenic stimuli tend to reverse this. However,
MMP activity cannot be directly measured in VSMC con-
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Others
7
8
ANDREW C. NEWBY
ditioned media (50) because of an excess of TIMPs (142).
This may imply that MMPs produced from VSMC alone
are unable to remodel the ECM. On the other hand, MMP
activity can be detected in VSMC in vascular tissues by in
situ zymography, a powerful methodology whereby frozen histological sections are coated with and allowed to
degrade MMP substrates that are subsequently visualized
(90). This suggests that MMP activity may not be completely abolished by TIMP binding but could be confined
temporally, or spatially, to the pericellular region surrounding VSMC (309).
B. EC
As in VSMC, MMP-2 expression is constitutive in EC
(106) and further upregulated by ROS (120). However,
induction of the MMPs is less obviously staged in EC.
MMP-1 and -2 are upregulated by high glucose concentrations (67), implying links to both basement membrane
and interstitial matrix degradation in diabetic vascular
disease. Similarly, concomitant upregulation of MMP-1,
-3, -8, and -9 occurs in response to TNF-␣ and IL-1␣ (106,
114) and on coculture with macrophages (117, 314). CD40
ligation also upregulates a broad spectrum of MMPs in
EC, including MMP-1, -3, -8, -9, and -11 (171, 241). Inflammatory and immune mechanisms therefore seem to be the
main drivers of matrix remodeling by EC, with no obvious
dissociation of basement membrane and interstitial maPhysiol Rev • VOL
trix degradation. Particularly relevant to atherosclerosis,
oxidized LDL increases MMP-1 and -3 expression (119,
155) via the Lox-1 receptor and activation of protein
kinase C-␤. Oscillatory but not laminar flow induced a
large increase in MMP-9 transcription and activation in a
murine endothelial cell line (174), and this could have
some bearing on the localization of atherosclerotic
plaques. Growth in three-dimensional collagen (103) and
cyclic strain (303) upregulate MT1-MMP (MMP-14), while
increased shear stress downregulates MMP-14 (307).
These phenomena are relevant to microvascular endothelium and angiogenesis (212).
EC express TIMP-1 and TIMP-2 constitutively (106),
and this is not increased by oxidized LDL (155). TIMP-1 is
further upregulated in response to CD40 ligation (171).
MMP activity is nevertheless directly detectable in conditioned media from EC (120), which implies that EC are
potentially more active in matrix remodeling than VSMC.
C. Macrophages
A similar multistage upregulation of MMP genes as
that found in VSMC (Fig. 4) is clearly evident in macrophages. At least in human monocyte-macrophages,
MMP-9 appears to be the most abundant gelatinase. Contact of peripheral blood monocytes with EC rapidly upregulates MMP-9, via a 30-kDa soluble mediator (7). Adhesion to matrix components including collagen, fi-
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
FIG. 4. Progressive upregulation of
diverse MMPs in VSMC and monocytes/
macrophages. Up to four notional stages
of MMPs activation are identified in monocyte macrophages (italics) and VSMC
(plain text). Early upregulation of gelatinases probably promotes vascular repair.
Later stages during the pathogenesis of
atherosclerosis may progressively recruit
a broader spectrum of MMPs whose combined substrate specificity could lead to
matrix destruction.
METALLOPROTEINASES IN BLOOD VESSELS
Physiol Rev • VOL
from isolated plaque caps in vitro (245). MMPs secreted
by macrophages could also function as activators of
MMPs derived from other cell types including VSMC.
D. T Lymphocytes
T lymphocytes in atherosclerotic plaques stain positive for MMPs-1, -2, -3, and -9 by immunocytochemistry
(90), but relatively few studies of their MMP secretion
have appeared. Interaction with fibronectin through ␣4␤1integrins upregulates MMP-2 and -9, while ligation of vascular cell adhesion molecule (VCAM)-1 selectively increases MMP-2 (302). The resulting conditioned media
contain MMP activity (302), and these proteases may
therefore have a role in transmigration of T cells into sites
of inflammation. MMP-2 is also increased in response to
the cytokine IL-2 (153).
E. Mast Cells
Mast cells constitutively secrete MMP-2 and upregulate MMP-9 secretion in response to TNF-␣ kit ligand (KL,
stem cell factor) and contact with activated T cells (17,
78). Induction of the MMP-9 gene and secretion of MMP-9
protein appear to be separately regulated by T-cell contact (17). T-cell contact also increases TIMP-1 secretion
(17); the net effect on MMP activity was not studied.
F. Adventitial Fibroblasts
Overall the pattern of constitutive MMP-2 secretion
and synergistic upregulation by cytokines and growth
factors of MMP-1, -3, and -9 seems very similar in fibroblasts and VSMC (33, 35). However, the levels of MMP-2
and -9 secretion from pig coronary adventitial fibroblasts
are significantly greater than from VSMC (247). Even
more strikingly, the levels of TIMP-1 and -2 expression are
more than 10-fold less in the fibroblasts (247). Fibroblasts
may therefore have a greater propensity to generate MMP
activity, which could give them an advantage over VSMC
when migrating into areas of vascular injury (247).
G. Transcriptional Control Mechanisms
The basis of the staged induction of different MMP
genes by stretch, injury, inflammation, and immune activation can be partially understood from the known structures of their proximal promoter regions (51). Among the
secreted MMPs, MMPs-2 and -11 are unusual in not having
a TATA or CAAT box, which implies that they are largely
constitutively expressed, housekeeping genes. Nevertheless, the transcription of MMP-2 can be upregulated by
two far upstream enhancer regions that respond to Y-box
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
bronectin, and tenascin-C also upregulates macrophage
MMP-9 secretion (91, 285, 290). Integrin-dependent adhesion to collagen acts synergistically with P-selectin-dependent adhesion to platelets to increase MMP-9 secretion by both transcriptional and translational mechanisms
(91). MMP-9 expression is further stimulated to a small
extent by soluble mediators IL-18 and TNF-␣ (202, 233)
and also by oxidized LDL (301). Proatherogenic cytokines
and growth factors, including IL-1␤, TNF-␣, macrophage
colony stimulating factor (M-CSF) and PDGF, upregulate
macrophage MT1-MMP (MMP-14) (221) and MT3-MMP
(MMP-16) expression (280) and could therefore activate
MMP-2 secreted constitutively from VSMC or EC. Because MMP-1 and -3 are not upregulated by cytokines in
macrophages (233), the increased production of MMP-9
and activation of MMP-2 could selectively mediate basement membrane turnover. Cytokines and growth factors
also increase macrophage MMP-12 (80), which aids monocyte migration into tissues (250). Immune activation via
CD40 ligand upregulates MMPs-1, -3, -8, -9, and -11 (114,
170, 172, 176, 241, 300), which have the ability to remodel
interstitial matrix also. MMP-1 secretion is also upregulated by contact with EC (117).
While these mechanisms are no doubt relevant to
atherosclerosis, they probably do not completely account
for the increase in MMP secretion observed from foam
cell macrophages. Isolated, lipid-laden, macrophages
from aortic atheroma or from subcutaneous granulomas
in cholesterol-fed rabbits continue to express MMPs-1, -3,
-9, and -13 for long periods in culture (50, 89). The upregulation of MMPs-1 and -3 depends on engorgement
with lipid because it does not occur in nonfoamy alveolar
macrophages from lipid-fed rabbits (89) or granuloma
macrophages from chow-fed rabbits (50). The mechanism
is apparently complex because simple addition of ox-LDL
to human macrophages does not upgregulate MMPs-1 and
-3 (191). This implies that foam cell formation somehow
activates the intrinsic transduction pathways leading to
MMP secretion or constitutive production of autocrine
factors. Consistent with the first possibility, treatment
with the scavenger N-acetyl-L-cysteine decreases MMP-9
expression, which implies that ROS are involved (85), and
foam cell macrophages show constitutive activation of
the redox-sensitive transcription factor NF-␬B (50). Consistent with the second possibility, preliminary work from
our laboratory suggests that upregulation of MMP-1 but
not MMP-3 from foam cells is in part mediated by a
soluble autocrine factor unrelated to CD40 ligand (22).
Human macrophages and rabbit foam cells secrete
TIMP-1, TIMP-2, and TIMP-3 constitutively (50, 76, 168),
while ox-LDL treatment decreases TIMP-1 secretion,
partly at least through autocrine action of IL-8 (191, 301).
Despite TIMP secretion, MMP activity is measurable in
macrophage and foam cell conditioned media (50, 168),
and macrophage-conditioned media degrade collagen
9
10
ANDREW C. NEWBY
VII. PARTICIPATION OF MATRIX
METALLOPROTEINASES AND TISSUE
INHIBITORS OF METALLOPROTEINASE IN
INTIMAL THICKENING BY REGULATION
OF CELL MIGRATION AND
PROLIFERATION
A. Methodologies
Well-established methodologies have been developed
to measure intimal expansion and its component processes. Endothelium-denuded medial tissue can be
stripped from the adventitia and VSMC isolated by outgrowth from explants (187) or by digestion with collagenase (43). Such cells progressively lose their normal complement of contractile and cytoskeletal proteins and increase their content of synthetic organelles, a process
Physiol Rev • VOL
known as phenotypic modulation (273). In fact, a variety
of different VSMC phenotypes have been isolated from
animal and human arteries and veins (108). Some are
fibroblast-like in shape and grow over each other in a
typical hill and valley formation, while others are epithelioid and grow as monolayers. EC can be selectively removed from vessels by brief collagenase digestion; depending on the culture conditions, they grow as monolayers or as capillary-like tubes (212).
Freshly isolated VSMC can be allowed to undergo
contractile to synthetic phenotype modulation under controlled tissue culture conditions, especially when grown
on the interstitial matrix component fibronectin (111,
112). Phenotypic change can be delayed by culture on the
basement membrane component laminin (110), while addition of heparin, TGF-␤, and, at least for human cells,
growth at high density tends to reverse the phenotypic
change (100). Growth of human SMC at high density can
give models for other pathological features including calcification (216).
Migration of isolated VSMC and EC can be measured
in wounded monolayers (161) or by seeding isolated cells
onto thin or thick layers of collagen and other synthetic
matrices, such as matrigel (82, 184). Measuring the rate of
emigration of cells from explants (256), especially in the
presence of hydroxyurea to inhibit cell proliferation
(136), allows studies of the effects of native ECM barriers.
Cell proliferation is commonly measured by cell counting,
incorporation of DNA precursors, measurement of cell
cycle specific proteins, and flow cytometry. Death is measured by cell counting, dye penetration, nuclear shape,
and a variety of assays selective for apoptosis, such as
caspase activation and DNA end-labeling (206, 286).
Organ culture (140, 259) gives a simple in vitro assay
for mechanistic studies of neointima formation and is one
of the few tools that can be directly used with human
tissue. Pulsed or continuous labeling of the cultures with
DNA precursors can be used to measure proliferation.
However, some VSMC that migrate to the neointima do
not subsequently proliferate and can be used as a measure
of migration alone (92, 93, 259). In vivo, rat, rabbit, and pig
models of arterial balloon injury have been widely used.
These show immediate endothelial denudation, apoptosis
of medial VSMC (175), and in some cases rupture of the
media (246). Early proliferation of VSMC follows in the
media. Migration of VSMC (57) (and fibroblasts, Ref. 246)
to the neointima and their proliferation occur later. Intimal VSMC lay down excess ECM, which contributes to
thickening (57). As in the organ cultures, some VSMC that
migrate to the neointima do not subsequently proliferate
and can be used as a measure of migration alone (59).
However, more commonly, migration is quantified by
measuring the number of cells that appear in the neointima at an early time point, e.g., 4 days (124). Neointima
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
protein-1, p53, activator protein-2, and GATA-2 transcription factors (105). The promoters of many secreted MMPs
have a TATA box and proximal activator protein-1 (AP-1)
binding site, which is essential for upregulation (reviewed
in Refs. 21, 80). There are also multiple AP-1 and polyomavirus enhancer-A-binding protein-3 (PEA-3)/ets (PEA3/ets) sites further upstream. Individual MMP gene promoters contain other unique transcription factor binding
sites. For example, a STAT-1 binding element (SBE) in
MMP-1, stromelysin PDGF response element (SPRE) in
MMP-3, Tcf/LEF in MMP-7, and nuclear factor ␬-B (NF␬B) sites in MMP-9 promoters, respectively, probably contribute to their staged induction (reviewed in Ref. 51).
These transcription factors apparently act cooperatively
with each other and the core AP-1 site, which in part
accounts for the synergistic effects of agonists (34, 75).
Oddly, activation of the NF-␬B transcription factor is
required for induction of MMP-1 and -3 in VSMC (34) and
macrophages (50), even though their proximal promoters
lack functional sites for binding NF-␬B. One explanation
for this could be induction through NF-␬B-dependent
pathways of other unknown transcription factors, although this has not been demonstrated. The MMP-9
promoter also has a c-Myc binding site, which participates in responses to oscillatory flow (174). The promoter region of MT1-MMP (MMP-14) is distinctly different from those of the secreted MMPs, since it lacks
a TATA box and contains a proximal Sp-1 rather than
AP-1 site (165). Activity of the MMP-14 promoter appears to be upregulated either by Sp-1 phosphorylation
or by its displacement with the Egr-1 transcription
factor (303, 307).
METALLOPROTEINASES IN BLOOD VESSELS
Physiol Rev • VOL
B. Patterns of MMP Expression and Activity
in Humans and in Animal Models
of Neointima Formation
Life-threatening complications early after angioplasty are thankfully rare. Hence, there have been few
histological and biochemical studies of MMPs in human
restenotic lesions and none in the crucial first few days
and weeks after injury. Nikkari et al. (200) observed increased collagen transcripts in restenotic lesions 6 –18 mo
after angioplasty. Levels of MMP-1 and TIMP-1 were reduced compared with normal tissue, which implies a
balance towards fibrosis at these relatively late time
points. In human saphenous veins, upregulation and activation of gelatinases (MMP-2 and -9) occurs within hours
after injury caused by surgical preparation and continues
during neointima formation in organ cultures (95). Active
gelatinases are detected in the media and neointima by in
situ zymography (95, 142), even though TIMP-1 and
TIMP-2 levels are also increased (142). Upregulation of
MMP-1 and MMP-3 is much less evident in human saphenous vein (132). Given the paucity of direct human pathological observations, other approaches including genetic
studies are appropriate. A single genetic study identified a
functional A-82G polymorphism in the MMP-12 promoter,
which affected the AP-1 binding site (133). The A allele
increased promoter activity and favored luminal narrowing in a small group of 71 diabetic patients, who underwent angioplasty and stenting.
There is abundant evidence of gelatinase upregulation in animal models of neointima formation. Induction
of MMP-9 and activation of MMP-2 occur rapidly after
balloon injury to rat (25, 311), pig (257), baboon (136),
rabbit (12), and mouse (98, 160) arteries. In the pig and
baboon models, induction of MMP-9 and activation of
MMP-2 occurred together (136, 257), but MMP-2 activation was delayed in the rat and mouse studies (25, 98, 160,
311), perhaps pointing to a preeminent role for MMP-9 in
small rodents (see below). Activation of MMP-2 is associated with upregulation of MMP-14 and -16 expression in
balloon-injured rat carotid arteries, implying that activation of MMP-2 by these MT-MMPs is feasible (251). Levels
of MMP-1, -3, -12, and -13 were also increased after femoral artery injury in mice (160). TIMP-1 and TIMP-2 expression are either not changed or increased after balloon
injury (109, 287), while levels of TIMP-3 (unpublished
observations) and TIMP-4 are clearly increased (73). Increased expression and activation of MMP-2 and -9 was
also observed in other in vivo models of neointima formation, namely, pig vein grafts (258) and the rabbit iliac
artery after angioplasty and stenting (81).
Hence the picture of early and possibly selective
upregulation of gelatinases is highly consistent across a
variety of models of neointima formation, irrespective of
the provoking stimulus. Levels of TIMPs are either main-
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
formation in balloon injury models is self-limiting, in part
by endothelial regrowth, and may actually regress by
enhanced apoptosis and compaction of the ECM (57).
Investigators have usually studied the response to injury
of normal blood vessels, although in a minority of cases
injury has been superimposed on an experimental plaque
(54). Even so, the relevance of any of these models to
clinical angioplasty in humans has been severely questioned. First, the ready proliferation of VSMC in the animal models does not seem to be observed in human
restenotic lesions (203). Second, clinical restenosis may
be more closely related to shrinking of the vessel wall
(negative remodeling) rather than to neointima formation
(71, 188). Recently, animal models of stent deployment in
normal arteries have been developed to study the phenomenon of in-stent restenosis (81, 138). These models
show foreign body reaction to the stent and localized
intimal growth that mirrors the human situation. However, these models do not usually consider the important
contribution of existing atherosclerosis to subsequent human in-stent restenosis (79). Rodent and large mammal
models of vein grafting have also been described. We
recently reviewed the comparative merits of these models, pointing out that only the large animal models reproduce the size and therefore the mechanical changes of
human bypass grafting (292). However, induction of vein
graft atherosclerosis is much easier in rabbit and mouse
models.
A particular cautionary note is necessary when considering the available models in mice, since so much
recent research has sought to harness the power of their
genetic manipulation. Because of their relative size, mice
are likely to have lesions less than 1,000 times smaller in
terms of mass and volume compared with human lesions
(62). Vessel diameters are correspondingly smaller, and
the thickness may be just a few cell layers. In addition,
normal mice carry most of their plasma cholesterol as
high-density lipoprotein (HDL), not LDL. Species-related
differences in protein expression (importantly MMP-1,
see below) also make extrapolation from mouse to human
a risky enterprise.
Injury to healthy mouse carotid artery has been conducted using filament loops, guide wires, dessication, adventitial cuffing, and flow cessation, although none of
these is the mechanical equivalent of clinical balloon
angioplasty. An ingenious mouse vena cava into carotid
artery vein-grafting model was developed by Xu and colleagues (315). However, this may differ crucially from
vein grafting in humans because the mouse vena cava is
so thin walled that all of its cells undergo apoptosis under
the strain of arterial pressure (315), and the graft becomes
repopulated with cells from the graft and the host (118).
The extent to which similar processes occur in the much
thicker walled human vein grafts is uncertain.
11
12
ANDREW C. NEWBY
C. Effects of MMP Overexpression
and TIMP Knockout
Clowes and colleagues (184) prepared rat VSMC stably transfected with the MMP-9 gene under a tetracyclineregulated promoter. They found that MMP-9 overexpression had no effect on VSMC proliferation but promoted
migration through matrigel and three-dimensional collagen in vitro, and invasion of cells seeded onto the adventitia of cryo-injured rat carotid arteries in vivo (184).
Luminal seeding of VSMC overexpressing MMP-9 after
balloon injury promoted vessel wall dilatation and, as
might be expected, reduced the accumulation of extracellular matrix in the neointima. However, there was no
effect on the eventual neointimal size (184). Lijnen et al.
(161) investigated knockout of TIMP-1 after electrical
injury to the mouse femoral artery. They found significantly greater neointima formation after 1–3 wk that was
associated with increased levels of the activated forms of
MMP-2 and -9. Paradoxically, they found that TIMP-1
knockout promoted matrix accumulation at 1 wk. There
was no effect on proliferation indices in vivo, but TIMP-1
knockout VSMC migrated faster in scratch-injured cell
cultures. The authors concluded that MMPs mediated
enhanced neointima formation primarily by stimulating
VSMC migration (161).
Physiol Rev • VOL
D. Effects of MMP Inhibition and Knockout
Two structurally unrelated synthetic MMP inhibitors
inhibited both proliferation and emigration of VSMC from
rabbit aortic explant cultures (256). The effects on migration but not proliferation were also found in baboon
saphenous artery explants (136). Studies with synthetic
MMP inhibitors in the rat carotid balloon injury model
showed a consistent effect on early SMC migration (23–
25, 121, 312). Two of the five studies found an effect also
on the first wave of medial (121, 312) and two on the
second wave of intimal (23, 121) VSMC proliferation.
However, except in one study (121), MMP inhibitors had
no effect on the final intimal size (23, 24, 312), possibly
because of late catch-up proliferation in the neointima. A
likely explanation for this is redundancy between the
MMP and other plasminogen-mediated proteolytic pathways (136). A study of balloon angioplasty to the atherosclerotic iliac arteries of Yucatan micropigs also showed
no effect of MMP inhibition on intimal growth (68). However, MMP inhibition significantly antagonized constrictive remodeling and therefore led to a decrease in late
lumen loss (68). In a recent, thorough preclinical study in
atherosclerotic primates, a broad spectrum MMP inhibitor was infused into animals for 28 days to achieve inhibitory plasma concentrations. MMP inhibitor treatment
failed to reduce neointima formation after either plain
balloon angioplasty or angioplasty with stenting (54). In
contrast to the study in pigs (68), no effect on constrictive
remodeling was observed. In contrast to these largely
negative results, it was very recently reported that a broad
spectrum MMP inhibitor reduced neointima formation at
the distal anastomoses of polytetrafluoroethylene arteriovenous shunts in pigs after 4 wk (230); longer follow up is
clearly warranted to see whether the benefit is maintained.
Given that high concentrations of synthetic inhibitors
might have effects other than on activity of MMPs, for
example on mitogen-activated protein kinases (167), it
was valuable to verify these results with TIMP gene transfer. Seeding of cells stably overexpressing TIMP-1 reduced neointima formation after balloon injury (82), as
did adenovirus-mediated gene transfer of TIMP-1 or
TIMP-2 (53, 72). TIMP-1, -2, and -3 gene transfer into
human saphenous vein prevented neointima formation in
organ cultures (92–94). For TIMP-1 and -2, this was
achieved by inhibition of migration not proliferation (92,
93). The effects of TIMP-3 were more complex because it
stimulated apoptosis as well as inhibiting migration (16).
This may explain why TIMP-3 was more effective than
TIMP-2 in inhibiting neointima formation in pig vein grafts
in vivo (94). Interestingly, TIMP-3 also inhibits signaling
through the vascular epidermal growth factor KDR receptor by a mechanism independent of MMP inhibition (218),
although there is no direct evidence that this contributed
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
tained constant or increased so that changes in TIMPs do
not amplify but tend to counteract the effects of MMP
upregulation. What then are the mechanisms responsible
for MMP upregulation? First, this could be the direct
result of injury because MMP-1 and -3 upregulation occur
in injured monolayers of isolated VSMC (125). MMP-9
induction and MMP-2 activation also occur in human
saphenous veins injured by hydrostatic distension ex vivo
even before culturing (95). Increased intraluminal pressure produces a similar response in pig carotid arteries
too (55), although this may be related to stretch per se
rather than injury. Inflammation is another possible cause
of MMP upregulation, although neointima formation in
organ cultures of human saphenous vein proceeds in the
presence of only scattered resident macrophages (60).
Balloon injury to the rat carotid artery also provokes little
inflammatory response (277). However, balloon injury to
other arteries (270), stent implantation (138), and vein
grafting (291) provoke a vigorous inflammatory response.
As expected, there is initial neutrophil infiltration followed by more sustained macrophage deposition (79,
291). Lymphocytes may also be present especially after
stent implantation (138). Hence, there is potential for
MMP induction by soluble inflammatory mediators and
CD40 ligation, as identified from in vitro studies (see
above).
METALLOPROTEINASES IN BLOOD VESSELS
VSMC could then gain traction. For example, Gavrilovic’s
group showed that cleavage of collagen I into one-fourth
and three-fourth length fragments using MMP-13 produced a substrate upon which PDGF stimulated VSMC
could migrate more rapidly than on intact collagen I (266).
Moreover, adhesion and migration on cleaved collagen
was mediated by newly induced ␣v␤3-integrins, while migration on native collagen I was mediated by constitutive
␣2␤1-integrins. This observation exemplifies a fourth
mechanism, namely, that MMPs might modify the cell-tomatrix interactions of VSMC, which in turn changes their
behavior by phenotypic modulation. Modulation of contractile VSMC towards a more synthetic phenotype accompanies neointima formation (42, 49, 274). During phenotypic modulation, basement membrane components,
for example, laminin, are downregulated, while hyaluronic acid production (237, 293) and interstitial matrix
components, monomeric type I collagen, elastin, and fibronectin are greatly increased (9, 273, 275) (Fig. 5).
Matrix remodeling is of key importance because laminin
E. Putative Mechanisms
MMPs could facilitate VSMC migration by a variety of
mechanisms. First, they could simply relieve the direct
binding between basement membrane components and
cell surface integrins that physically restrict movement.
Second, MMPs could aid invasion of already freely moving VSMC by degrading the physical ECM barriers they
encounter. Consistent with this, addition or gene transfer
of MMPs promotes (184) and gene transfer of TIMPs
inhibits (16) invasion of collagenase-isolated VSMC
through synthetic matrix. Third, cleavage by MMPs could
expose adhesion sites on matrix molecules over which
Physiol Rev • VOL
FIG. 5. Changes in matrix protein and surface integrin interaction
between contractile (A) and synthetic (B) phenotype VSMC. Important
changes in matrix protein and surface integrin interactions that are
known to occur during phenotypic modulation of VSMC are summarized. For full details of integrin changes, see the review by Moiseeva
(189).
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
to its effects on vein grafts. From these studies, catch up
growth does not seem to compensate for the effects on
neointima formation of TIMP gene transfer in contrast to
those of synthetic MMP inhibitors, at least over the 2- to
4-wk time periods studied. The reasons for this are obscure but could involve any of the several effects of
TIMPs that are unrelated to MMP inhibition (15, 218).
While synthetic inhibitors and TIMP gene transfer
target a broad spectrum of MMPs, knockout studies have
the potential to elucidate the role of individual MMPs.
Knockout of MMP-11, the unusual MMP that degrades
serum proteinase inhibitors (see Table 1), increases neointima formation after injury in mice (162). MMP-11
knockout was associated with a paradoxical increase in
elastolysis and increased cellularity of the neointima
rather than matrix accumulation (162). Two groups independently studied the effect of MMP-9 knockout on responses to filament loop injury (56) or arterial occlusion
(86) in different background strains of mice. In wild-type
mice, both groups observed early upregulation of MMP-9
and later activation of MMP-2 that was apparently unrelated to inflammation. MMP-9 knockout impaired neointima formation by inhibiting VSMC migration. One of the
groups (56) also observed delayed inhibition of VSMC
proliferation. Interestingly, MMP-9 knockout caused excess collagen accumulation and impaired outward remodeling in the occlusion model (86). More recently, two
groups also found that knockout of the other gelatinase,
MMP-2, also decreased neointima formation in the carotid
ligation model and that this was associated with decreased VSMC migration in vitro (128, 144). Hence,
MMP-2 and -9 appear to serve complementary rather than
redundant functions in neointima formation, despite similar structure and substrate specificity and the compensatory upregulation of MMP-9 and downregulation of
TIMP-1 expression evident in MMP-2 knockouts in one of
the studies (144). The ability of MMP-9 but not MMP-2 to
participate in CD44-mediated matrix attachment of VSMC
and to organize collagen fibrils may account in part for the
unique contribution of this MMP (128).
13
14
ANDREW C. NEWBY
membranes around VSMC and an increase in fibronectin
synthesis were demonstrated during neointima formation
in balloon-injured rat carotid arteries (275). These
changes track the changes in MMP expression established
in other studies (25, 311), but the influence of MMP inhibition on ECM proteins was not tested directly. To
achieve this, we investigated the effect of TIMP-1 and -3
gene transfer on expression of basement membranes in
human saphenous vein undergoing neointima formation
in organ culture (1). Medial VSMC were normally surrounded by basement membranes, but a proportion became negative during culture. All VSMC that migrated into
the neointima lacked basement membranes. TIMPs-1 and
-3 reduced the numbers of medial VSMC lacking basement
membranes and inhibited migration into the neointima.
This implies that MMP-mediated loss of basement membrane is essential for medial to intimal migration of
VSMC. Proliferating VSMC were more likely to be negative for basement membranes than nonproliferating
VSMC. On the other hand, 30 – 40% of proliferating medial
VSMC retained some basement membrane, which shows
that complete basement membrane degradation is not
necessary for VSMC proliferation. Furthermore, TIMPs
did not affect either basement membrane degradation in
proliferating VSMC or the rate of medial VSMC proliferation. Hence, MMPs are not essential for basement membrane degradation in proliferating VSMC, presumably because of redundancy with other proteases. These conclusions are summarized in Figure 6.
Many of the nonmatrix substrates of MMPs (see Refs.
264, 283 for listings) may also be relevant to neointima
formation and plaque instability, but as yet, there have
been few direct studies in VSMC. The arguments seem
particularly clear for MMP-11, however, which is only
weakly active against matrix proteins. Proteolysis of insulin-like growth factor binding protein (IGFBP)-1 by
MMP-11 (177) and IGFBP-3 and -5 by MMP-1, -2, and -3
(83) could have implications both for phenotypic modulation (110) and survival (210) of VSMC. The ability of the
gelatinases, MMP-2 and -9, to activate TGF-␤ (306) could
feed forward to promote matrix protein synthesis after
FIG. 6. Summary of the effects of MMPs on
VSMC basement membranes, migration, and proliferation. Growth factors acting together with inflammatory agents, stretch, and oxidative stress
stimulate the production of basement membrane
degrading MMPs. Complete MMP-dependent removal of the basement membrane is associated
with intimal migration. Proliferating VSMC are
only partially free of basement membrane, and
MMPs are not essential for this. For details, see
Reference 1.
Physiol Rev • VOL
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
retards or partially reverses phenotypic modulation, while
fibronectin promotes it (110, 111). Hence, MMPs could
promote phenotypic modulation by relieving interactions
with inhibitory components or promoting interactions
with modified stimulatory components. These effects of
matrix proteins on migration are likely to be mediated by
concomitant changes in expression of their cell surface
integrin receptors (189) (Fig. 5).
One mechanism by which proteases might influence
intimal growth is by the release of sequestered cytokines,
such as FGF-2 and TGF-␤ (264). MMPs might also degrade
matrix proteins with inhibitory effects on VSMC proliferation. For example, heparan sulfate proteoglycan (HSPG)
components of the basement membrane, such as syndecans and perlecan, inhibit VSMC proliferation in culture
and in vivo (29, 139). Hence, the ability of MMPs to
degrade core proteins of HSPGs could underlie their effect on VSMC proliferation. Alternatively, basement membrane remodeling could permit new contacts with interstitial matrix components that promote cell cycle progression. Contractile VSMC in arteries exhibit very low rates
of proliferation, most likely because they fail to downregulate cyclin-dependent kinase inhibitors (123, 271,
272). Components of the ECM of normal arteries, e.g.,
laminin and polymerized collagen, do not support downregulation of cyclin-dependent kinase inhibitors or proliferation of isolated VSMC (141). On the other hand, components of the remodeling matrix such as monomeric
collagen and fibronectin support G1 cell cycle progression
and VSMC proliferation (141, 244). Again, these actions of
matrix proteins are believed to be mediated by binding to
appropriate integrin receptors (244).
Few studies have directly measured the influence of
MMPs on matrix protein turnover in blood vessels.
Strauss et al. (265) found that MMP inhibition decreased
collagen breakdown after balloon injury to rabbit femoral
arteries, as might be expected. However, collagen synthesis was also inhibited, presumably because MMP inhibition prevented VSMC transforming into the synthetic phenotype. The net effect on neointima formation was neutral (265). A reversible disappearance of basement
METALLOPROTEINASES IN BLOOD VESSELS
F. Conclusions
The evidence for MMP-9 upregulation and MMP-2
activation early during neointima formation after vascular
injury is overwhelming. Evidence for upregulation of
other classes of MMPs is less abundant. Rather than
decreasing to exaggerate the effect of MMP induction,
TIMPs are concomitantly upregulated, presumably to prevent excessive matrix degradation. From studies with
synthetic MMP inhibitors or TIMP gene transfer, MMPs
are proven to remodel the VSMC basement membrane,
and this is required for VSMC migration and phenotypic
modulation. Effects of MMP inhibition on VSMC proliferation appear restricted to certain models and early time
points, probably because of redundancy with other proteases. As a result, there is catch up growth so that MMP
inhibition does not lead to a change in final intimal size.
MMPs are also expressed in fibroblasts and may therefore
play a part in adventitial remodeling or migration of myofibroblasts into the intima.
VIII. ROLE OF MATRIX METALLOPROTEINASES
IN ATHEROSCLEROTIC PLAQUE
DESTABILIZATION
A. Methodologies
In humans, correlative histological studies have been
the main investigational approach. Tissue from aortic,
carotid, and to a lesser extent coronary plaques at all
stages of their development, including ruptured plaques,
are available from post mortem, endarterectomy, and
atherectomy specimens. Human studies correlating presence of unstable coronary disease with serum MMP measurements (32) or MMP genotypes (313) have also recently emerged. Rabbit, pig, and primate models of dietinduced atherosclerosis have also been used. At early
times, the animal lesions resemble human fatty streaks,
although fibrous cap development does occur within
weeks, especially after episodic removal of cholesterolrich diet (2). More complex lesions occur spontaneously
in rabbit (249) and pig (96) models, albeit slowly, and so
have been less studied. So-called humanlike atherosclerotic plaques occur in the aortic root, thoracic aorta, and
brachiocephalic arteries of susceptible strains and genetically modified mice (196, 207, 227), although caveats
have been raised (see above) about their small size and
the altered lipid metabolism in mice compared with hu-
FIG. 7. MMP-dependent shedding of N-cadherin from human VSMC. Expression of N-cadherin by Western blotting in control human saphenous
vein VSMC is increased by treatment with the MMP inhibitor BB-94 or after adenovirus-mediated transfer of tissue inhibitor of metalloproteinase
(TIMP)-1 or TIMP-2. The same treatments increase N-cadherin in the membrane (M) but not the cytosolic (C) or nuclear (N) fractions of the cells.
[From Uglow et al. (277).]
Physiol Rev • VOL
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
basement membrane remodeling, although this has not
been shown in vascular tissue. The potential of at least
seven MMPs to activate TNF-␣ (264) invites the speculation that they further contribute to the inflammatory milieu in injured or atherosclerotic vessels. Direct experiments to test these ideas would be welcome. In fibrosarcoma cells, MT1-MMP (MMP-14) can be involved as well
as furinlike proprotein convertases in the processing of
␣v-integrin subunits, and this affects attachment to type I
collagen (14, 222). However, the thiol proprotein convertase PC5 rather than MMP-14 appears to be responsible
for processing of ␣v-integrin subunits in rat VSMC (262).
Expression of the MT-MMPs, MMP-14 and -16 has recently
been linked to degradation of focal adhesion kinase, cell
rounding, decreased adhesion, and increased migration in
baboon aortic VSMC (252), although this occurred independently of changes in integrin levels (252). A synthetic
metalloproteinase inhibitor concomitantly reversed all
these events (252). However, no evidence was presented
that focal adhesion kinase is a direct substrate for MTMMPs, the topography of which makes it unlikely. The
identity of the matrix or nonmatrix substrates responsible
for this interesting phenomenon therefore remains obscure.
Using human VSMC, George’s group (277) recently
reported that MMP-mediated cell surface shedding of Ncadherin occurs after serum or PDGF stimulation (Fig. 7).
This releases ␤-catenin, which translocates to the nucleus
and participates in stimulating proliferation (277). Finally,
the evidence that MMP-9 can promote matrix attachment
of VSMC through binding to CD44 and that this promotes
collagen assembly demonstrates the possibility of noncatalytic mechanisms by which MMPs could influence
intimal thickening (128).
15
16
ANDREW C. NEWBY
aortic root (207), or defined points in the aorta (255) and
lesion extension measured by lipophilic staining of the
aorta en face is popular. Multiple anatomic sites have
occasionally been investigated. Measurement of plaque
composition in relation to known features of human vulnerable plaques has been conducted. According to this, a
relatively large proportion of the plaque occupied by lipid
core or monocytes, a low proportion occupied by smooth
muscle cells and a low content of collagen is taken as
indicative of plaque vulnerability. Most interestingly, a
recent study (296) compared occurrence of ruptures in
mice brachiocephalic arteries, defined by discontinuity of
the fibrous cap and thrombus penetrating into the lipid
core, with several of these surrogate markers. Consistent
with clinical data, ruptured plaques were larger and had a
larger proportion of the plaque occupied by lipid core,
fewer VSMC, and a thinner fibrous cap. They also had
more buried plaque caps, consistent with more previously
silent plaque ruptures.
Because of the similar inflammatory origin of aneurysms and unstable plaques (see sect. II), results from
models of atherosclerotic aneurysm formation are also
relevant. The ApoE knockout mouse shows frequent
breaches of the medial elastic fibers that can be interpreted as microaneurysms (47). Galis and co-workers
(122) recently showed that expansive remodeling after
carotid artery ligation is greatly increased in ApoE knockout compared with wild-type mice. This may therefore
also serve as a model of atherosclerotic aneurysm formation. Other mouse models of aortic aneurysm not linked
to atherosclerosis use elastase (217) or calcium chloride
(166) treatment to provoke the initial inflammatory insult.
FIG. 8. Plaque ruptures in the brachiocephalic artery of apolipoprotein E (ApoE)
knockout mice. Examples are shown of
plaque ruptures in ApoE knockout mice that
died suddenly after being fed a lard fat diet for
up to 1 year. Note the discontinuity of the
elastic layer (arrows) that normally separated
the lumen from the plaque lipid core. Thrombus (Thr) occludes the lumen and has apparently spread from with the plaque. [From
Johnson and Jackson (130), with permission
from Elsevier.]
Physiol Rev • VOL
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
mans (62). There is also evidence of coronary atherosclerosis leading to myocardial infarction in mice, although
probably through vasoconstriction rather than plaque
rupture (41). Myocardial infarction apparently unrelated
to plaque rupture also occurs in a strain of Watanabe
rabbits (249).
Although two reviews (62, 225) concluded that there
is no universally accepted animal model for spontaneous
plaque rupture, substantial progress has been made recently using mice. Calara et al. (40) observed rare plaque
instability in the aortas and coronary arteries of ApoE and
LDL receptor double knockout mice fed cholesterol for 1
year. Rosenfeld et al. (227) and Johnson and Jackson
(130) described a higher frequency of intraplaque hemorrhage in the brachiocephalic arteries of fat-fed ApoE
knockout mice. Discontinuity of the very thin (2 ␮m)
fibrous cap suggested that these lesions result from
plaque ruptures (Fig. 8), in some degree analogous to
those in humans (130). Plaque rupture occurred both in
mice that died spontaneously and in those culled according to protocol (296), which implies that not all ruptures
were fatal. Moreover, just as with lesions in humans,
many of the mouse plaques had buried fibrous caps, consistent with previous silent plaque ruptures. Models of
induced plaque rupture have also been described (62,
225), but their use is probably restricted to investigating
plaque cap mechanical properties or subsequent thrombosis.
In the absence of widely accepted models of plaque
rupture, most work has used surrogate end points in
rabbit or mouse models of atherosclerosis progression.
Lesion size measured by standardized histology of the
METALLOPROTEINASES IN BLOOD VESSELS
Another model in rats involved xenotransplantation of
guinea pig aortas (6).
B. Patterns of MMP Expression and Activity in
Human Pathological Tissues and Experimental
Models of Atherosclerosis
Physiol Rev • VOL
Upregulation of MMPs-1, -2, -3, and -9 is readily detected in models of lipid-induced atherosclerosis in rabbits (2, 310), and MMPs-3, -11, -12, and -13 are also upregulated in mouse plaques (126, 231, 241). Upregulation
of MMPs is an early event in fatty streak formation in
rabbits and mice and is therefore associated with plaques
at all stages, not just in the late events of plaque instability. In cholesterol-fed rabbits, the levels of TIMP-1 and
TIMP-2 clearly rise in plaques, and this partly compensates for the increase in MMP activity (309). In particular,
it was suggested that this confines MMP activity to the
pericellular region, stabilizes the base of the lesions, and
may prevent plaque penetration into the media (i.e., aneurysm) (309). Similar conclusions can be reached for
TIMP-3 (C. Aguilera, A. Zaltsman, and A. C. Newby, unpublished observations).
Further correlative studies have attempted to establish a link between MMP overexpression and destruction
of individual matrix components. For example, MMP-7 is
apparently the most active versican-degrading enzyme in
human carotid artery plaques (104). On the other hand,
and perhaps most convincingly, Sukhova et al. (268)
showed that MMP-1 and MMP-13 in human lipid-rich atherosclerotic plaques are closely colocalized with neoepitopes of cleaved collagen (Fig. 9) (268).
Other studies have related MMP levels to clinical or
histological features associated with plaque instability.
Most simply, Schonbeck et al. (241) found that MMP-11
immunoreactivity is confined to advanced atherosclerotic
plaques, not fatty streaks. In carotid endarterectomy specimens, Nikkari et al. (200) noted that positivity for MMP-1
correlates with the percentage of the lipid core occupied
with hemorrhage. However, there was no correlation between MMP-1 expression and presence of rupture or clinical symptoms of instability. Loftus et al. (164) found no
difference in MMP-1, -2, and -3 or TIMP-1 and -2 levels in
carotid endarterectomy tissue from patients that had recent (⬍1 mo) clinical evidence of instability, even though
this group had a greater prevalence of ruptured plaques,
intraplaque hemorrhage, and distal embolization. In contrast, the same study showed a significant two- to fourfold
increase in MMP-9 levels in the most recently symptomatic plaques (164). A small atherectomy study also suggested that MMP-9 expression is more prevalent in patients with unstable versus stable coronary disease (38).
Finally, in 25 patients with unstable and 10 with stable
angina, intense MMP-3 expression was found selectively
in outwardly remodeled plaques (239), but there was no
relationship to clinical presentation. From these studies
the clearest evidence is for a positive relationship between MMP-9 expression and plaque instability. However,
these case-control studies cannot distinguish whether differences in the levels of MMPs were a cause or an effect
of plaque instability. Moreover, increased MMP-9 levels
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
A landmark study by Henney et al. (113) demonstrated upregulation in atherosclerotic plaques relative to
normal artery of MMP-3 mRNA, and its location within
macrophages and VSMC. Galis in Libby’s group (90) performed a more exhaustive study showing MMP-1, -3, and
-9 protein in macrophages, VSMC, lymphocytes, and EC
especially at the vulnerable shoulder regions of atherosclerotic plaques. Moreover, the authors developed the in
situ zymography technique to localize MMP activity and
showed that this was present in plaques but not normal
media (90). Subsequent work confirmed and extended
these results. Elevated levels of MMP-1 (90, 200, 201),
MMP-2 (156), MMP-3 (90, 113), MMP-7 (104), MMP-9 (38,
90), MMP-11 (241), MMP-12 (104), MMP-13 (268), MMP-14
(MT1-MMP) (221), and MMP-16 (280) are all found in
human atherosclerotic plaques, especially at the macrophage-rich shoulder regions. Enhanced MMP-1 overexpression is located with areas of increased circumferential tensile stress in the fibrous cap (148) where ruptures
are likely to occur. MMP-7 and lesser amounts of MMP-12
are confined to the borders between the lipid core and the
macrophage-rich shoulder regions (104). MMP expression
is prominent in macrophages but also present in VSMC,
lymphocytes, and EC (38, 90, 104, 221, 268, 280). TIMP-1
levels are unchanged (90) or elevated (200) in atherosclerotic plaques. TIMP-2 is also abundant in plaques (221),
and TIMP-3 is clearly increased because it is a product of
inflammatory macrophages (76).
Henney’s group was also the first study to relate
polymorphisms in any of the MMP genes to the incidence
or severity of coronary artery disease. They reported a
5A6A polymorphism in the MMP-3 promoter for which the
6A allele was associated with greater progression of coronary disease in a small cohort of patients (305). They
later found a C-1562T polymorphism in the MMP-9 gene
(313). The T allele resulted in greater promoter activity
(313) and was subsequently shown to influence MMP
serum levels (32). The T allele was associated with increased disease severity (192, 313), although it had no
impact on prognosis in patients with existing coronary
disease (32). On the other hand, increased MMP-9 serum
levels were strongly associated with other markers of
inflammation and were significantly associated with cardiovascular death (32). These results support a role for
MMP-9 as a marker or etiological factor in atherosclerosis
progression and possibly instability.
17
18
ANDREW C. NEWBY
could be an epiphenomenon, simply reflecting the increased prevalence of macrophages in unstable plaques.
Upregulation of MMPs-1, -3, -9, -12, -13, and -14 is also
seen in association with inflammatory matrix destruction
in human aortic aneurysms (11, 84, 116, 179, 186, 199).
TIMP-1 is expressed prominently in aortic aneurysm tissue (11, 116), TIMP-2 is secreted constitutively, and
TIMP-3 increases as in atherosclerotic plaques (11). Outward vessel remodeling also correlates with accumulation of foam cell macrophages and increases in MMP-2
and -9 expression after carotid ligation in ApoE knockout
mice (122).
Based on extensive histological evidence, macrophage-derived MMPs are particularly implicated in plaque
instability. In addition, an increase in the proportion of
macrophages in relation to VSMC occurs in areas of
plaques prone to rupture and also in aneurysms. Furthermore, isolated macrophages secrete an excess of active
MMPs over TIMPs (50). Rabbit foam cell macrophages
isolated from atherosclerotic plaques produce MMPs-1
and -3, while alveolar macrophages do not (89). Furthermore, decreases in MMP levels closely parallel reduction
of macrophage numbers in rabbit atherosclerotic plaques
after cessation of cholesterol feeding or use of cholesterol-lowering drugs (2, 3).
Even though they fall short of direct proof, these
correlative studies provide persuasive evidence that
MMPs, particularly from macrophages but also from EC,
VSMC, and other inflammatory cells, mediate the loss of
matrix that underlies weakening of the fibrous cap and
provoke plaque rupture.
Physiol Rev • VOL
C. Effects of MMP Overexpression
and TIMP Knockout
MMP-1 is not widely expressed in the mouse, where
MMP-13 may substitute. This species difference prevents
the use of MMP-1 knockout but presents a unique opportunity to investigate the effect of transgenic overexpression of MMP-1. D’Armiento and colleagues (150) targeted
MMP-1 overexpression to macrophages, and this had no
effect on migration. Somewhat surprisingly, MMP-1 overexpression reduced the progression of atherosclerosis in
ApoE knockout mice (150), perhaps because of less collagenous matrix accumulation. MMP-1 overexpression
did not cause plaque ruptures, arguably because the
plaques were less advanced in the transgenic mice. This
experiment illustrates the potential complexities of manipulating a system where MMPs have a dual role in
plaque growth by VSMC migration and matrix deposition
and instability by matrix destruction. It would be interesting to know the effect of MMP-1 overexpression in
already established plaques.
Two groups have examined the effect of TIMP-1
knockout, which was shown directly to increase local
vessel wall MMP activity, in the ApoE knockout mouse
model (151, 254). Somewhat discordant results, either no
change or a 30% decrease, were found in the extent of
aortic atherosclerosis. However, both groups found that
TIMP-1 knockout significantly increased destruction of
medial elastic fibers (Fig. 10), i.e., pseudoaneurysm formation (151, 254). The results support a pathogenic role
for MMPs in atherosclerotic aneurysm formation. How-
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
FIG. 9. Colocalization of epitopes of cleaved collagen with MMP-1 and -13 in human atherosclerotic plaques. Epitopes of cleaved collagen (green
fluorescence) and total collagen (red fluorescence) are shown in a human atherosclerotic plaque. Cleaved collagen colocalizes with MMP-1 and
MMP-13 immunocytochemistry and the location of macrophages (M␾). [From Sukhova et al. (268).]
METALLOPROTEINASES IN BLOOD VESSELS
19
ever, no luminal plaque ruptures were observed in the
aorta in either study (151, 254). In unpublished studies,
we also observed no effect of TIMP-1 knockout on ruptures in the brachiocephalic artery. Given the presence of
other TIMPs in these knockout models, the results are
perhaps to be expected. They do, however, expose an
interesting mechanistic difference between aneurysm formation and plaque rupture, at least in the mouse.
D. Effects of MMP Inhibition and Knockout
The effect on atherosclerosis of systemic delivery of
an adenovirus that caused expression of human TIMP-1
was investigated in ApoE knockout mice fed a lipid-rich
diet. This increased plasma TIMP-1 levels for at least 28
days and reduced aortic plaque area measured 4 wk later
in groups of four mice by ⬃30% (231). Qualitative histological analysis suggested that TIMP-1 overexpression enhanced collagen, elastin, and smooth muscle cell ␣-actin
Physiol Rev • VOL
content and reduced macrophage number, all consistent
with greater plaque stability. In contrast, oral administration of synthetic MMP inhibitors showed no effect on
plaque development in LDL receptor knockout mice (215)
after dietary intervention or angiotensin II treatment
(178). Hence, TIMP gene transfer had a greater effect on
atherosclerosis than synthetic MMP inhibitors, as found
for neointima formation. The contribution of individual
MMPs to plaque formation and stability is only beginning
to be investigated by knockouts. MMP-3, ApoE double
knockout mice had increased collagen and decreased
macrophage content in plaques consistent with greater
stability, although plaque size was increased overall (255).
MMP-9 knockout decreased plaque size as well as macrophage and collagen content in the aortas of chow-fed
ApoE knockout mice, which suggests a beneficial effect
of this knockout also (169). In the same study, MMP-12
knockout had no effect on plaque size or composition in
the aorta (169). In preliminary studies of the brachioce-
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
FIG. 10. Effect of TIMP-1 knockout
on atherosclerosis and microaneurysm
formation in ApoE knockout mice.
TIMP-1 is on the X chromosome, and the
study used male TIMP-1⫺/0, ApoE⫺/⫺
compound knockout mice. Medial ruptures (arrows in B) are observed in the
aortic root of TIMP-1, ApoE compound
knockout mice but not in Apo E knockout alone (A). C shows the morphology
of a rupture, including loss of elastic fibers at higher magnification. Scale bar ⫽
50 ␮m. [From Lemaitre et al. (151).]
20
ANDREW C. NEWBY
E. Putative Mechanisms
Efficient degradation of collagens, proteoglycan core
proteins, and glycoproteins clearly requires the substrate
Physiol Rev • VOL
repertoire of several MMPs. In addition, MMPs need to act
in concert with each other and with other classes of
protease to completely degrade ECM components. An
example of this is fibrillar collagen degradation, where
MMPs-1, -2, -8, -13, and -14 can mediate only the initial
cleavage of triple-helical domains to one-fourth and threefourths fragments, but other proteases are needed to
complete degradation (30). In addition, proteases act together in an activation cascade (Fig. 3). Hence, conditions
leading to the coordinated upregulation of several MMPs
(Fig. 4), and other proteases, are those most likely to be
associated with destruction of the extracellular matrix
(51). This principle was clearly demonstrated in the study
by Baxter and colleagues (166), where knockout of either
MMP-2 or -9 was sufficient to prevent calcium-induced
aortic aneurysm formation in mice. MMP-9 from macrophages and MMP-2 most likely from VSMC cooperated to
mediate matrix degradation, either directly or by activating other proteases (166).
Atherosclerosis is a complex process, which MMPs
could influence in a host of ways. Gelatinases presumably
facilitate VSMC phenotypic modulation and migration in
the same way in atherosclerotic plaques as they do consistently in other models of intimal growth. From studies
in knockout mice, MMP-12 appears to have an important
role in invasion of macrophages into ECM (250). The
phenotype of MMP-9 knockout mice also includes a deficit in bone growth-plate invasion by monocytes and capillaries (284). Indeed, MMPs have an established role in
angiogenesis (212), which appears to contribute to plaque
growth (193) as well as being a histological feature associated with unstable plaques (127, 185). Hence, MMPs
could influence plaque stability indirectly through any of
these processes in addition to direct effects on degradation of ECM components.
Non-ECM substrates might also be involved. For example, the ability of MMP-11-mediated degradation of
␣2-antiplasmin and ␣1-antitrypsin could increase activity
of cathepsins, plasmin, and leukocyte elastase (241).
F. Conclusions
In principle, several MMPs (and other proteases)
with complementary substrate repertoires should be
needed to mediate plaque rupture. Descriptive and correlative studies consistently demonstrate MMP overexpression and matrix destruction at the macrophage-rich
regions of atherosclerotic plaques that are prone to rupture. On the other hand, early fatty streaks also show
upregulation of MMPs, which could therefore be involved
in plaque building by intimal expansion as well as plaque
rupture by matrix destruction. TIMPs are upregulated,
especially at the base of plaques, and in part counteract
the destructive potential of MMPs. Gene disruption and
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
phalic artery of lipid-fed ApoE knockout mice, Jackson
and colleagues (129) observed that MMP-9 knockout increased plaque size and the occurrence of buried fibrous
caps, implying a contradictory harmful effect of this
knockout on plaque stability. In this study, knockout of
MMP-12 significantly decreased plaque size and number
of buried fibrous caps (129), implying a protective effect.
Taken together, these findings imply a harmful effect of
MMP-3, either a harmful or protective role for MMP-9, and
either no role or a harmful one for MMP-12 in plaque
instability. Clearly more studies of MMP knockouts are
needed to resolve the apparent discrepancies that may
result from different sites of plaque development, measures of plaque rupture, different dietary regimes, and the
use of different background mouse strains.
Using inhibitors and knockouts, MMPs have been
more clearly implicated in aneurysm formation whether
related or not to atherosclerosis. Some studies have used
doxycycline, an antibiotic and nonselective synthetic
MMP inhibitor that also decreases MMP-2 and -9 secretion
at least in part by destabilizing MMP-2 mRNA (163). Treatment with pharmacologically relevant concentrations of
doxycycline decreased aortic aneurysm formation in mice
induced by elastase (214) or angiotensin II (178) treatment. Local delivery of VSMC stably transduced to overexpress TIMP-1 decreased aneurysmal dilatation and rupture in an aortic xenotransplantation model (6). This was
associated with inhibition of gelatinase activity contributed by MMP-2 and -9 as well as unidentified 54- and
28-kDa MMP-related species (6). Either MMP-2 or MMP-9
knockout abolished calcium chloride-induced aortic aneurysms (166), which demonstrates that the two gelatinases act cooperatively rather than redundantly, similar
to the situation in neointima formation (128, 144). As with
atherosclerosis progression, there is some discordance
over the relative importance of MMP-9 and MMP-12.
MMP-12 but not MMP-9 was implicated as the downstream protease responsible for plasmin-dependent microaneurysm formation in ApoE knockout mice (47). On
the other hand, knockout of MMP-9, but not MMP-12,
reduced delayed aortic aneurysm formation after elastase
treatment in mice (217). More recently, both MMP-9 and
MMP-12 knockout were shown to reduce transmedial
elastin degradation and ectasia in ApoE knockout mice
(169). Knockout of MMP-3 also reduces the incidence of
these aortic “pseudoaneurysms” in ApoE knockout mice
(255). Broadly speaking, therefore, a wide range of MMPs
has been implicated in aneurysm formation with some
minor model-dependent differences.
METALLOPROTEINASES IN BLOOD VESSELS
overexpression studies in atherosclerosis-prone mice suggest essential roles for MMPs-2, -3, -9, and -12 in aneurysm
formation, but only preliminary data are yet available with
regard to plaque rupture. Studies in progress, for example, in the ApoE knockout mouse brachiocephalic artery
model, should further clarify the role of individual MMPs.
IX. PHARMACOTHERAPY
A. Direct Inhibition by Synthetic Inhibitors
and Gene Therapy with TIMPs
There is already some direct clinical experience with
MMP inhibitors. MMP inhibitors have been given for quite
prolonged periods to patients with advanced malignancies, albeit with no proven benefit (61). Early trials revealed the somewhat unexpected side effect of tendonitis,
although this was avoided by dose adjustment and different drug specificity in other studies. Doxycycline, an antibiotic and broad-spectrum MMP inhibitor, is quite
widely used to treat acne and in malarial prophylaxis; it
has been given orally to patients with asymptomatic aortic aneurysms for up to 6 mo (214). The action of broadspectrum MMP inhibitors to prevent intimal expansion
could therefore be evaluated in clinical trials.
However, almost all preclinical trials with broadspectrum MMP inhibitors failed to show long-term reduction of neointima formation after balloon injury with or
without stenting (24, 54, 215, 265, 312). In most cases,
other classes of protease appear to substitute the function
of MMPs, particularly in proliferating VSMC (1), and there
is therefore catch-up after the effect of early MMP inhibition (24). Only Li et al. (154) showed a significant reduction in in-stent restenosis at 10 wk in a rabbit doubleinjury model. An open label trial of an MMP inhibitoreluting stent (The Brilliant 1 study) was halted early
because it did not apparently show benefit. On the other
hand, MMP inhibitors decrease constrictive remodeling
after angioplasty without stenting in pigs (68) so that a
human trial in this context could still be justified.
The relatively primitive state of development, high
relative production costs, and complex regulatory issues
surrounding TIMP gene therapy are obstacles to its clinical application. However, proof of principle studies are
still valuable because slowly developing pathologies, in
particularly vein-graft disease, might be more amenable to
gene therapy than one-off local drug treatments. In addition, veins used for grafting can be treated ex vivo before
Physiol Rev • VOL
reimplantation, and hence, exposure of the patient to
gene therapy reagents can be minimized.
Given the dual role of MMPs in fibrous cap formation
(i.e., intimal growth) and cap rupture (i.e., matrix destruction), the effect of a broad-spectrum MMP inhibitor on
acute coronary events is difficult to predict. Nevertheless,
further preclinical studies of MMP inhibitors and knockouts in models of unstable atherosclerosis are clearly
appropriate. Greater knowledge of the specific MMPs or
groups of MMPs causing plaque instability will justify
trials of inhibitors with the correct specificity.
B. Inhibition of MMP Production
Quercitin, a dietary flavonoid related to those present
in red wine, inhibits MMP-9 secretion by effects on AP-1
and NF-␬B transcription factors (190). Several other physiological mediators probably suppress MMP induction locally in the vasculature. Heparin and HSPG inhibit the
release of several proteases, including MMPs from VSMC
(13, 135). This implies that the basement membrane could
suppress MMP secretion from normal EC and VSMC.
Reports regarding the effects of nitric oxide are conflicting. Nitric oxide was reported to tonically inhibit MMP-9
but not MMP-2 production from VSMC in one study (278)
but to enhance stimulated MMP-9 expression in another
(180). A recent study shows that nitric oxide inhibits
MMP-2 transcription in EC by activating the repressor
protein ATF3 (52). TGF-␤ inhibits induction of MMP-1, -3,
and -7, although paradoxically upregulates MMP-13, at
least in fibroblasts (279). TGF-␤ also inhibits MMP-9 secretion in mast cells (78) and MMP-7 (39) and MMP-12
(80) secretion in macrophages. MMP-7 secretion is also
inhibited by IL-4 and IL-10 (39). Given the broad range of
MMPs induced by the CD40 ligation in isolated cell cultures (173, 176, 241–243, 300), one may speculate that
interruption of this signaling system would have a profound effect in MMP activity in plaques. Physiologically,
interferon-␣ and/or interferon-␥ inhibit the CD40 ligationinduced secretion of MMP-1 and -9 from VSMC (243) and
MMP-1, -3, -9, and -12 from macrophages (170, 300).
MMPs-1, -3, -7, and -9 are all downregulated by nuclear hormone receptor (NHR) agonists, which include
corticosteroids, retinoids, thyroid hormones, and sex hormones (238). Steroid hormones also stimulate TGF-␤1
production (80), which indirectly inhibits MMP induction,
as described above. Activation of the Liver X receptor
(LXR) inhibited MMP-9 but not MMP-12 or -13 secretion
from mouse bone marrow-derived macrophages stimulated with lipopolysaccharide, TNF-␣, or IL-1␤ (48). The
mechanism was apparently not by direct binding to the
MMP-9 promoter, and while it was downstream of NF-␬B
activation, LXR activation did not prevent activation or
binding of NF-␬B (48). Perhaps of greatest current clinical
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
The possible routes for reducing MMP activity during
intimal thickening and in atherosclerotic plaques comprise 1) direct inhibition of enzyme activity and 2) inhibition of MMP production.
21
22
ANDREW C. NEWBY
X. SUMMARY: WHAT MEDIATES THE
TRANSITION FROM PHYSIOLOGICAL
REMODELING TO MATRIX DESTRUCTION?
From the work cited above, MMPs have been implicated both in intimal thickening, which involves net matrix deposition, and plaque rupture, which involves net
matrix destruction. Indeed, there is substantial supporting evidence for both propositions. If both are correct, the
idea merits consideration that MMP activity is dysregulated during the transition from plaque building to plaque
disruption.
The null hypothesis is that there is no dysregulation
as such, merely that MMP activity is appropriately regulated but occurs in the wrong place at the wrong time
relative to chance mechanical factors. Early matrix destruction is a prerequisite for intimal expansion because it
permits entry of inflammatory cells and frees VSMC to
Physiol Rev • VOL
migrate, change phenotype, and proliferate. Later, there is
fibrosis that more than compensates for the initial destruction, the same sequence observed for example in
dermal wound healing. Consistent with this, fibrous cap
formation is a late event in atherosclerosis. If the shoulder
regions of plaques simply represent new, active areas of
plaque growth, the status of their matrix might simply
reflect the early (destructive) stages of remodeling. Were
it not for a mechanical accident leading to rupture, these
areas would also eventually become fibrous and safe. The
corollary of this null hypothesis is that inhibiting plaque
progression will inevitably stabilize plaques, a concept
that fits well with the results from lipid-lowering trials
(219).
A second hypothesis is that matrix destruction reflects an imbalance between the production of “good” and
“bad” MMPs. Gelatinases (MMP-2 and -9) could represent
good MMPs because basement membrane degradation
plays a key role in liberating contractile VSMC to participate in repair. The effect of MMP-9 knockout to decrease
VSMC migration and repair after vascular injury (56, 86)
and increase plaque rupture (129) is consistent with this
idea. On the other hand, collagenases (e.g., MMPs-1, -8,
and -13) and stromelysins (e.g., MMPs-3 and -7) are generally thought of as bad MMPs because they are closely
associated histologically with degraded collagen in areas
prone to plaque rupture (268). The corollary of this hypothesis is that selective inhibitors of some MMPs might
be an effective treatment for plaque instability that would
spare repair mechanisms. Conversely, broad-spectrum
MMP inhibitors might be ineffective, as suggested by the
current experimental evidence (215), or even harmful.
These ideas could be investigated by a comprehensive
survey of drug treatments and MMP knockouts in the
same standardized model of plaque growth and rupture.
Even so, the results could only be cautiously extrapolated
to humans.
A third hypothesis is that a greater extent of expression of the same MMPs present during physiological remodeling can lead to aneurysms or rupture. Data that
MMP-9 knockout reduces neointima formation after
mouse carotid artery injury (56, 86) but also protects
against aneurysm formation in other mouse models (166,
217) fit with this hypothesis. It could be tested directly by
selectively overexpressing individual MMPs in a suitable
animal model. The corollary of this hypothesis is first that
general MMP inhibitors should be an effective treatment.
Second, it focuses attention on the factors that might be
driving MMP overexpression, which are most commonly
believed to be inflammatory and immune phenomena.
A fourth hypothesis that we recently proposed (51) is
that increasingly diverse stimuli (i.e., injury, inflammation, immune mechanisms, oxidative stress) upregulate
an ever-broader spectrum of MMPs. This eventually includes members of each of the gelatinase, interstitial
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
relevance are peroxisome proliferator-activated receptor
(PPARs), transcription factors that also belong to the
NHR superfamily, that are widely expressed in vascular
cells (182, 183, 226). PPAR␣ and -␥ ligands selectively
inhibit phorbol ester-induced MMP-9 secretion by VSMC
(183), monocytic cell lines (253), and monocyte-derived
macrophages (182). Moreover, treatment of diabetic patients with the PPAR␥ ligand rosiglitazone reduced
plasma MMP-9 levels within 2 wk, implying direct inhibition of MMP-9 secretion at a pharmacologically relevant
concentration in vivo (181). Inhibition of MMP-9 production might therefore be an important component of the
pleiotropic effects of PPAR ligands, which are already in
trial for prevention of acute coronary events (18).
Statins inhibit mevanolate formation by hydroxymethylglutaryl (HMG)-CoA reductase, the rate-limiting
step in cholesterol and isoprenoid synthesis. Their cholesterol-lowering effects are associated with reduction of
unstable coronary events in several large clinical trials
(219). Statins dramatically inhibit secretion of MMP-1, -3,
and -9 from macrophages and MMPs-1, -2, -3, and -9 but
not TIMP-1 or -2 from VSMC (3, 20, 168). The mechanism
is posttranscriptional, overcome by mevanolate, and mediated by inhibition of prenylation (168). The effects of
cerivastatin are obtained at 10 –50 nM, within the range of
concentrations obtained in humans (143) and known to
cause other non-lipid-lowering effects (reviewed in Refs.
208, 269). Statins reduce MMP protein expression and
activities when administered to hyperlipidemic rabbits,
and this changes plaque morphology consistent with increased stability (2– 4). Statins also decrease markers of
instability in the coronary arteries of cynomolgous monkeys (297) and in the brachiocephalic artery of mice (19)
independently of lipid-lowering effects. Hence, a direct
effect on MMP secretion could well contribute.
METALLOPROTEINASES IN BLOOD VESSELS
Address for reprint requests and other correspondence:
A. C. Newby, Bristol Heart Institute, Bristol Royal Infirmary,
Bristol BS2 8HW, UK (E-mail: [email protected]).
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
REFERENCES
1. Aguilera CM, George SJ, Johnson JL, and Newby AC. Relationship between type IV collagen degradation, metalloproteinase
activity and smooth muscle cell migration and proliferation in
cultured human saphenous vein. Cardiovasc Res 58: 679 – 688,
2003.
2. Aikawa M, Rabkin E, Okada Y, Voglic SJ, Clinton SK, Brinckerhoff CE, Sukhova GK, and Libby P. Lipid lowering by diet
reduces matrix metalloproteinase activity and increases collagen
Physiol Rev • VOL
19.
20.
content of rabbit atheroma. A potential mechanism of lesion stabilisation. Circulation 97: 2433–2444, 1998.
Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y,
Furukawa Y, Shiomi M, Schoen FJ, and Libby P. An HMG-CoA
reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in
vivo and in vitro. Circulation 103: 276 –283, 2001.
Aikawa M, Rabkin E, Voglic SJ, Shing H, Nagai R, Schoen FJ,
and Libby P. Lipid lowering promotes accumulation of mature
smooth muscle cells expressing smooth muscle myosin heavy
chain isoforms in rabbit atheroma. Circ Res 83: 1015–1026, 1998.
Aimes RT and Quigley JP. Matrix metalloproteinase-2 is an interstitial collagenase: inhibitor-free enzyme catalyzes the cleavage
of collagen fibrils and soluble native type I collagen generating the
specific 3/4 and 1/4 length fragments. J Biol Chem 270: 5872–5876,
1995.
Allaire E, Forough R, Clowes M, Starcher B, and Clowes AW.
Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest 102: 1413–1420,
1998.
Amorino GP and Hoover Rl. Interactions of monocytic cells with
human endothelial cells stimulate monocytic metalloproteinase
production. Am J Pathol 152: 199 –207, 1998.
Amour A, Slocombe PM, Webster A, Butler M, Knight CG,
Smith BJ, Stephens PE, Shelley C, Hutton M, Knauper V,
Docherty AJP, and Murphy G. TNF-alpha converting enzyme
(TACE) is inhibited by TIMP-3. FEBS Lett 435: 39 – 44, 1998.
Ang AH, Tachas G, Campbell JH, Bateman JF, and Campbell
GR. Collagen synthesis by cultured rabbit aortic smooth muscle
cells. Biochem J 265: 461– 469, 1990.
Angelini GD and Newby AC. The future of saphenous vein as a
coronary artery bypass conduit. Eur Heart J 10: 273–280, 1989.
Annabi B, Shedid D, Ghosn P, Kenigsberg RL. Desrosiers RR,
Bojanowski MW, Beaulieu E, Nassif E, Moumdjian R, and
Beliveau R. Differential regulation of matrix metalloproteinase
activities in abdominal aortic aneurysms. J Vasc Surg 35: 539 –546,
2002.
Aoyagi M, Yamamoto M, Azuma H, Nagashima G, Niimi Y,
Tamaki M, Hirakawa K, and Yamamoto K. Immunolocalization
of matrix metalloproteinases in rabbit carotid arteries after balloon
denudation. Histochem Cell Biol 109: 97–102, 1998.
Au YP, Montgomery KF, and Clowes AW. Heparin inhibits collagenase gene expression mediated by phorbol ester-responsive
element in primate arterial smooth muscle cells. Circ Res 70:
1062–1069, 1992.
Baciu PC, Suleiman EA, Deryugina EI, and Strongin AY. Membrane-type-1 matrix metalloproteinase (MT1-MMP) processing of
pro-␣v integrin regulates cosstalk between ␣v␤3 and ␣2␤1 integrins
in breast carcinoma cells. Exp Cell Res 291: 161–175, 2003.
Baker AH, Edwards DR, and Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci
115: 3719 –3727, 2002.
Baker AH, Zaltsman AB, George SJ, and Newby AC. Divergent
effects of tissue inhibitors of metalloproteinase-1, -2 or -3 on rat
vascular smooth muscle cell invasion, proliferation and death in
vitro: TIMP-3 promotes apoptosis. J Clin Invest 101: 1478 –1487,
1998.
Baram D, Vaday GG, Salamon P, Drucker I, Hershkoviz R, and
Mekori YA. Human mast cells release metalloproteinase-9 on contact with activated T cells: juxtacrine regulation by TNF-␣. J Immunol 167: 4008 – 4016, 2001.
Barbier O, Torra IP, Duguay Y, Blanquart C, Fruchart JC,
Glineur C, and Staels B. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 22: 717–726, 2002.
Bea F, Blessing E, Bennett B, Levitz M, Wallace EP, and
Rosenfeld ME. Simvastatin promotes atherosclerotic plaque stability in ApoE-deficient mice independently of lipid lowering. Arterioscl Thromb Vasc Biol 22: 1832–1837, 2002.
Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti
R, and Bernini F. Hmg-CoA reductase inhibitors reduce MMP-9
secretion by macrophages. Arterioscler Thromb Vasc Biol 18:
1671–1678, 1998.
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
collagenase, stromelysin, metalloelastase, and MT-MMP
subfamilies. Because of the limited capacity of individual
MMPs to remodel the ECM, a broad spectrum of MMPs
(and indeed other proteases) would be more likely to
catalyze matrix destruction rather than physiological remodeling. Given the overlapping specificities of the individual MMPs, there is likely to be a high degree of redundancy. The implication of this hypothesis is that targeting
individual MMPs might have a relatively minor impact on
pathology, whereas targeting the processes that upregulate several MMPs (e.g., inflammatory mediators, oxidative stress) might be more effective.
Whether on not MMPs provide a new route to therapies, just over 10 years of intensive MMP research has
contributed to a revolutionary change in the way we think
about blood vessels. This new perspective counters the
notion that the ECM is simply an amorphous filler between the cells, which responded on demand to growth
factors. It emphasizes that the behavior of all vascular
cells, indeed their very composition, is dictated by connections principally with the ECM and with each other
through cell contacts. Binding to the ECM can block
growth factor availability, and signals from the ECM and
cell contacts can completely negate the effect of growth
factors. In turn, the rate-limiting process of proteolysis, in
which MMPs are key players, regulates the composition
of ECM as well as many cell-to-cell contacts. Hence,
according to this view, MMPs and other extracellular
proteases are as important as growth factors in their
ability to orchestrate the behavior of vascular cells. The
very importance of extracellular proteolysis is probably
responsible for the complexity of the MMP system and its
inherent redundancy. Much as the internet is robust because of its many nodes, extracellular proteolysis is reliably effective because of the concerted action of many
overlapping components. As such, it will be a challenge to
identify specific roles for each of the MMPs. Instead,
ingenious experimentation may be needed to unravel the
web of interactions between individual MMPs and between MMPs and other proteases. Nevertheless, this research will be driven forward by the importance of its
goals and the many opportunities for new insights.
23
24
ANDREW C. NEWBY
Physiol Rev • VOL
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
sis in apolipoprotein E-deficient and LDL receptor-deficient mice.
J Pathol 195: 257–263, 2001.
Caligiuri G, Levy B, Pernow J, Thoren P, and Hansson GK.
Myocardial infarction mediated by endothelin receptor signaling in
hypercholesterolemic mice. Proc Natl Acad Sci USA 96: 6920 –
6924, 1999.
Campbell GR and Campbell JH. Smooth muscle phenotypic
changes in arterial wall homeostasis: implications for the pathogenesis of atherosclerosis. Exp Mol Pathol 42: 139 –162, 1985.
Campbell JH and Campbell GR. Culture techniques and their
applications to studies of vascular smooth-muscle. Clin Sci 85:
501–513, 1993.
Caplice NM, Bunch TJ, Stalboerger PG, Wang S, Simper D,
Miller DV, Russell SJ, Litzow MR, and Edwards WD. Smooth
muscle cells in human coronary atherosclerosis can originate from
cells administered at marrow transplantation. Proc Natl Acad Sci
USA 100: 4754 – 4759, 2003.
Carmeliet P. Proteinases in cardiovascular aneurysms and rupture: targets for therapy? J Clin Invest 105: 1519 –1520, 2000.
Carmeliet P, Moons L, Herbert JM, Crawley J, Lupu F, Lijnen
R, and Collen D. Urokinase but not tissue plasminogen activator
mediates arterial neointima formation in mice. Circ Res 81: 829 –
839, 1997.
Carmeliet P, Moons L, Lijnen R, Baes M, Lemaitre V, Tipping
P, Drew A, Eckhout Y, Shapiro S, Lupu F, and Collen D.
Urokinase-generated plasmin activates matrix metalloproteinases
during aneurysm formation. Nature Genet 17: 439 – 444, 1997.
Castrillo A, Joseph SB, Marathe C, Mangelsdorf DJ, and
Tontonoz P. Liver X receptor-dependent repression of matrix
metalloproteinase-9 expression in macrophages. J Biol Chem 278:
10443–10449, 2003.
Chamley-Campbell JH and Cambell GR. What controls smooth
muscle phenotype? Atherosclerosis 40: 347–357, 1981.
Chase A, Bond M, Crook MF, and Newby AC. Role of NF-␬B
activation in metalloproteinase-1, -3 and -9 secretion by human
macrophages in vitro and rabbit foam cells produced in vivo.
Arterioscler Thromb Vasc Biol 22: 765–771, 2002.
Chase AJ and Newby AC. Regulation of matrix metalloproteinase
(matrixin) genes in blood vessels: a multi-step recruitment model
for pathological remodelling. J Vasc Res 40: 329 –343, 2003.
Chen HH and Wang DL. Nitric oxide inhibits matrix metalloproteinase-2 expression via the induction of activating transcription
factor 3 in endothelial cells. Mol Pharmacol 65: 1130 –1140, 2004.
Cheng L, Mantile G, Pauly R, Nater C, Felici A, Monticone R,
Bilato C, Gluzband YA, Crow MT, Stetler-Stevenson W, and
Capogrossi MC. Adenovirus-mediated gene transfer of the human
tissue inhibitor of metalloproteinase-2 blocks vascular smooth
muscle cell invasiveness in vitro and modulates neointimal development in vivo. Circulation 98: 2195–2201, 1998.
Cherr GS, Motew SJ, Travis JA, Fingerle J, Fisher L, Brandl
M, Williams JK, and Geary RL. Metalloproteinase inhibition and
the response to angioplasty and stenting in atherosclerotic primates. Arterioscler Thromb Vasc Biol 22: 161–166, 2002.
Chesler NC, Ku DN, and Galis ZS. Transmural pressure induces
matrix-degrading activity in porcine arteries ex vivo. Am J Physiol
Heart Circ Physiol 277: H2002–H2009, 1999.
Cho A and Reidy MA. Matrix metalloproteinase-9 is necessary for
the regulation of smooth muscle cell replication and migration
after arterial injury. Circ Res 91: 845– 851, 2002.
Clowes AW, Clowes MM, and Reidy MA. Kinetics of cellular
proliferation after arterial injury. III. Endothelial and smooth muscle growth in chronically denuded vessels. Lab Invest 54: 295–303,
1986.
Clowes AW, Clowes MM, Reidy MA, and Belin D. Smooth
muscle cells express urokinase during mitogenesis and tissue-type
plasminogen activator during migration in injured rat carotid artery. Circ Res 67: 61– 67, 1990.
Clowes AW and Schwartz SM. Significance of quiescent smooth
muscle migration in the injured rat carotid artery. Circ Res 56:
139 –145, 1985.
Cooper JP and Newby AC. Monocyte adhesion to human saphenous vein in vitro. Atherosclerosis 91: 85–95, 1991.
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
21. Benbow U and Brinkerhoff CE. The AP-1 site and MMP gene
regulation: what is all the fuss about. Matrix Biol 15: 519 –526,
1997.
22. Benbow U, Chase AJ, and Newby AC. Rabbit foam cell media
induce collagenase-1 and -8 expression in human monocyte/macrophages independently of CD40 ligand (Abstract). Eur Heart J 24
Suppl: 336, 2003.
23. Bendeck MP, Conte M, Zhang M, Nili N, Strauss BH, and
Farwell SM. Doxycycline modulates smooth muscle cell growth,
migration, and matrix remodeling after arterial injury. Am J Pathol
160: 1089 –1095, 2002.
24. Bendeck MP, Irvin C, and Reidy MA. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but
not neointimal thickening after arterial injury. Circ Res 78: 38 – 43,
1996.
25. Bendeck MP, Zempo N, Clowes AW, Galardy RE, and Reidy
MA. Smooth muscle cell migration and matrix metalloproteinase
expression after arterial injury in the rat. Circ Res 75: 539 –545,
1994.
26. Benditt EP and Benditt JM. Evidence for a monoclonal origin of
human atherosclerotic plaques. Proc Natl Acad Sci USA 70: 1753–
1756, 1973.
27. Bennett MR. In-stent stenosis: pathology and implications for the
development of drug-eluting stents. Heart 89: 218 –224, 2003.
28. Bennett MR and O’Sullivan M. Mechanisms of angioplasty and
stent restenosis: implications for design of rational therapy. Pharmacol Ther 91: 149 –166, 2001.
29. Bingley JA, Hayward IP, Campbell JH, and Campbell GR.
Arterial heparan sulfate proteoglycans inhibit vascular smooth
muscle cell proliferation and phenotype change in vitro and neointimal formation in vivo. J Vasc Surg 28: 308 –318, 1998.
30. Birkedal-Hansen H, Moore WGI, Bodden MK, Windsor LJ,
Birkedal-Hansen B, De Carlo A, and Engler JA. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4: 197–250, 1993.
31. Black RA. Tumor necrosis factor-␣ converting enzyme. Int J Biochem Cell Biol 34: 1–5, 2002.
32. Blankenberg S, Rupprecht HJ Poirier O, Bickel C, Smieja M,
Hafner G, Meyer J, Cambien F, Tiret L, and The Atherogene
Investigators. Plasma concentrations and genetic variation of
matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 107: 1579 –1585, 2003.
33. Bond M, Baker AH, and Newby AC. Nuclear factor kappa-B
activity is essential for matrix metalloproteinase-1 and -3 upregulation in rabbit dermal fibroblasts. Biochem Biophy Res Comm 264:
561–567, 1999.
34. Bond M, Chase AJ, Baker AH, and Newby AC. Inhibition of
transcription factor NF-␬B reduces matrix metalloproteinase-1, -3
and -9 production by vascular smooth muscle cells. Cardiovasc Res
50: 556 –565, 2001.
35. Bond M, Fabunmi RP, Baker AH, and Newby AC. Synergistic
upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor
NF-Kb. FEBS Lett 435: 29 –34, 1998.
36. Boulday G, Coupel S, Coulon F, Soulillou JP, and Charreau B.
Antigraft antibody-mediated expression of metalloproteinases on
endothelial cells: differential expression of TIMP-1 and ADAM-10
depends on antibody specificity and isotype. Circ Res 88: 430 – 437,
2001.
37. Brooks PC, Silletti S, Von Schalscha TL, Friedlander M, and
Cheresh DA. Disruption of angiogenesis by PEX, a noncatalytic
metalloproteinase fragment with integrin binding activity. Cell 92:
391– 400, 1998.
38. Brown D, Hibbs MS, Kearney M, Loushin C, and Isner JM.
Identification of 92-kDa gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable
angina. Circulation 91: 2125–2131, 1995.
39. Busiek DF, Baragi V, Nehring LC, Parks WC, and Welgus HG.
Matrilysin expression by human mononuclear phagocytes and its
regulation by cytokines and hormones. J Immunol 154: 6484 – 6491,
1995.
40. Calara F, Silvestre M, Casanada F, Yuan N, Napoli C, and
Palinski W. Spontaneous plaque rupture and secondary thrombo-
METALLOPROTEINASES IN BLOOD VESSELS
Physiol Rev • VOL
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
man metalloelastase in macrophages. J Biol Chem 275: 25766 –
25773, 2000.
Feldman LJ, Mazighi M, Scheuble A, Deux JF, De Benedetti
E, Badier-Commander C, Brambilla E, Henin D, Steg PG, and
Jacob MP. Differential expression of matrix metalloproteinases
after stent implantation and balloon angioplasty in the hypercholesterolemic rabbit. Circulation 103: 3117–3122, 2001.
Forough R, Koyama M, Hasenstab D, Lea H, Clowes M, Nikkari ST, and Clowes AW. Overexpression of tissue inhibitor of
matrix metalloproteinase-1 inhibits vascular smooth muscle cell
functions in vitro and in vivo. Circ Res 79: 812– 820, 1996.
Fowlkes JL, Serra DM, Nagase H, and Thrailkill KM. MMPs are
IGFBP-degrading proteinases: implications for cell proliferation
and tissue growth. Ann NY Acad Sci 878: 696 – 699, 1999.
Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh
RM, and Powell JT. Inflammation and matrix metalloproteinases
in the enlarging abdominal aortic aneurysm. Arterioscler Thromb
Vasc Biol 15: 1145–1151, 1995.
Galis Z, Asanuma K, Godin D, and Meng X. N-acetyl-cysteine
decreases the matrix-degrading capacity of macrophage-derived
foam cells. New target for antioxidant therapy? Circulation 97:
2445–2453, 1998.
Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior
RM, and Ivan E. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical
arterial remodeling. Circ Res 91: 852– 859, 2002.
Galis ZS, Kranshöfer R, Fenton JW, and Libby P. Thrombin
promotes activation of matrix metalloproteinase-2 produced by
cultured vascular smooth muscle cells. Arterioscler Thromb Vasc
Biol 17: 483– 489, 1997.
Galis ZS, Muszynski M, Sukhova GK, Simon-Morissey E, Unemori E, Lark MW, Amento E, and Libby P. Cytokine-stimulated
human vascular smooth muscle cells synthesize a complement of
enzymes required for extracellular matrix digestion. Circ Res 75:
181–189, 1994.
Galis ZS, Sukhova GK, Kranzhöfer R, Clark S, and Libby P.
Macrophage foam cells from experimental atheroma constitutively
express matrix-degrading proteases. Proc Natl Acad Sci USA 92:
402– 406, 1995.
Galis ZS, Sukhova GK, Lark MW, and Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin
Invest 94: 2493–2503, 1994.
Galt SP, Lindemann S, Medd D, Allen LL, Kraiss LW, Harris
ES, Prescott SM, McIntryre TM, Weyrich AS, and Zimmerman
GA. Differential regulation of matrix metalloproteinase-9 by monocytes adherent to collagen and platelets. Circ Res 89: 509 –516,
2001.
George SJ, Angelini GD, Newby AC, and Baker AH. Adenovirus mediated gene transfer of the human TIMP-1 gene inhibits
smooth muscle cell migration and neointima formation in human
saphenous vein. Hum Gene Ther 9: 867– 877, 1998.
George SJ, Baker AH, Angelini GD, and Newby AC. Gene
transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous
veins. Gene Therapy 5: 1552–1560, 1998.
George SJ, Lloyd CT, Angelini GD, Newby AC, and Baker AH.
Gene therapy for vein graft disease: tissue inhibitor of metalloproteinase-3 inhibits metalloproteinases, promotes apoptosis and reduces neointima formation in vitro and in vivo. Circulation 101:
296 –304, 2000.
George SJ, Zaltsman AB, and Newby AC. Surgical preparative
injury and neointima formation increase MMP-9 expression and
MMP-2 activation in human saphenous vein. Cardiovasc Res 33:
447– 459, 1997.
Gerrity RG, Natarajan R, Nadler JL, and Kimsey T. Diabetesinduced accelerated atherosclerosis in swine. Diabetes 50: 1654 –
1665, 2001.
Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, and
Kolettis GJ. Compensatory enlargement of human atherosclerotic
coronary arteries. N Engl J Med 316: 1371–1375, 1987.
Godin D, Ivan E, Johnson C, Magid R, and Galis ZS. Remodeling of carotid artery is associated with increased expression of
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
61. Coussens LM, Fingleton B, and Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science
295: 2387–2392, 2002.
62. Cullen P, Baetta R, Bellosta S, Bernini F, Chinetti G,
Cignarella A, Von Eckardstein A, Exley A, Goddard M,
Hofker M, Hurt-Camejo E, Kanters E, Kovanen P, Lorkowski
S, McPheat W, Pentikainen M, Rauterberg J, Ritchie A, Staels
B, Weitkamp B, and De Winther M. Rupture of the atherosclerotic plaque. Does a good animal model exist? Arterioscler Thromb
Vasc Biol 23: 535–542, 2003.
63. Davies MJ. Coronary disease: the pathophysiology of acute coronary syndromes. Heart 83: 361–366, 2000.
64. Davies MJ and Thomas A. Thrombosis and acute coronary artery
lesions in sudden cardiac ischemic death. N Engl J Med 310:
1137–1140, 1984.
65. Davies MJ and Thomas AC. Plaque fissuring: the cause of acute
myocardial infarction, sudden ischaemic death and crescendo angina. Br Heart J 53: 363–373, 1985.
66. Davies MJ and Woolf N. Atherosclerosis in Ischaemic Heart
Disease. The Mechanisms. London: Science, 1990.
67. Death AK, Fisher EJ, McGrath KCY, and Yue DK. High glucose
alters matrix metalloproteinase expression in two key vascular
cells: potential impact on atherosclerosis in diabetes. Atherosclerosis 168: 263–269, 2003.
68. De Smet BJGL, De Kleijn D, Hanemaaijer R, Verheijen JH,
Robertus L, Van Der Helm YJM, Borst C, and Post MJ. Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan
Micropig. Circulation 101: 2962–2967, 2000.
69. Desrivieres S, He L, Peyri N, Soria C, Legrand Y, and Menashi
S. Activation of the 92-Kda type-IV collagenase by tissue kallikrein.
J Cell Physiol 157: 587–593, 1993.
70. Dilley RJ, McGeachie JK, and Prendergast FJ. A review of the
histological changes in vein to artery grafts, with particular reference to intimal hyperplasia. Arch Surg 123: 691– 696, 1988.
71. Di Mario C, Gil R, Camenzind E, Ozaki Y, Von Birgelen C,
Umans V, De Jaegere P, De Feyter PJ, Roelandt TC Jr, and
Serruys PW. Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional coronary atherectomy. Am J Cardiol 75: 772–777, 1995.
72. Dollery CM, Humphries SE, McClelland A, Latchman DS, and
McEwan JR. Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle
cell migration and reduces neointimal hyperplasia in the rat model
of vascular balloon injury. Circulation 99: 3199 –3205, 1999.
73. Dollery CM, McEwan JR, Wang MS, Sang QXA, Liu YLE, and
Shi YE. TIMP-4 is regulated by vascular injury in rats. Circ Res 84:
498 –504, 1999.
74. Ellis V. Plasminogen activation at the cell surface. Curr Top Dev
Biol 54: 263–312, 2003.
75. Fabunmi RP, Baker AH, Murray EJ, Booth RFG, and Newby
AC. Divergent regulation by growth factors and cytokines of 95kDa and 72-kDa gelatinases and tissue inhibitors of metalloproteinases-1, -2 and -3 in rabbit aortic smooth muscle cells. Biochem J
315: 335–342, 1996.
76. Fabunmi RP, Sukhova GK, Sugiyama S, and Libby P. Expression of TIMP-3 in human atheroma and regulation in lesion-associated cells: a potential protective mechanism in plaque stability.
Circ Res 83: 270 –278, 1998.
77. Falk E, Shah PK, and Fuster V. Coronary plaque disruption.
Circulation 92: 657– 671, 1995.
78. Fang KC, Wolters PJ, Steinhoff M, Bidgol A, Blount JL, and
Caughey GH. Mast cell expression of gelatinases A and B is
regulated by kit ligand and TGF-␤. J Immunol 162: 5528 –5535,
1999.
79. Farb A, Sangiorgi G, Carter AJ, Walley VM, Edwards WD,
Schwartz RS, and Virmani R. Pathology of acute and chronic
coronary stenting in humans. Circulation 99: 44 –52, 1999.
80. Feinberg MW, Jain MK, Werner F, Sibinga NES, Wiesel P,
Wang H, Topper JN, Perrella MA, and Lee ME. Transforming
growth factor-beta 1 inhibits cytokine-mediated induction of hu-
25
26
99.
100.
101.
102.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
matrix metalloproteinases in mouse blood flow cessation model.
Circulation 102: 2861–2866, 2000.
Gomis-Ruth FX, Maskos K, Betz M, Bergner A, Huber R,
Suzuki K, Yoshida N, Nagase H, Brew K, Bourenkov GP,
Bartunik H, and Bode W. Mechanism of inhibition of the human
matrix metalloproteinase stromelysin-1 by TIMP-1. Nature 389:
77– 81, 1997.
Grainger DJ, Witchell CM, Watson JV, Metcalfe JC, and
Weissberg PL. Heparin decreases the rate of proliferation of rat
vascular smooth muscle cells by releasing transforming growth
factor ␤-like activity from serum. Cardiovasc Res 27: 2238 –2247,
1993.
Grote K, Flach I, Luchtefeld M, Akin E, Holland SM, Drexler
H, and Schieffer B. Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2)
via NAD(P)H oxidase-derived reactive oxygen species. Circ Res 92:
80e– 86e, 2003.
Gu ZZ, Kaul M, Yan BX, Kridel SJ, Cui JK, Strongin A, Smith
JW, Liddington RC, and Lipton SA. S-nitrosylation of matrix
metalloproteinases: signaling pathway to neuronal cell death. Science 297: 1186 –1190, 2002.
Haas TL, Davis SJ, and Madri JA. Three-dimensional type I
collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial
cells. J Biol Chem 273: 3604 –3610, 1998.
Halpert I, Sires UI, Roby JD, Potterperigo S, Wight TN, Shapiro SD, Welgus HG, Wickline SA, and 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
USA 93: 9748 –9753, 1996.
Han XY, Boyd PJ, Colgan S, Madri JA, and Haas TL. Transcriptional up-regulation of endothelial cell matrix metalloproteinase-2
in response to extracellular cues involves GATA-2. J Biol Chem
278: 47785– 47791, 2003.
Hanemaaijer R, Koolwijk P, Le Clercq L, De Vrie WJA, and
Van Hinsbergh VWM. Regulation of matrix metalloproteinase
expression in human vein and microvascular endothelial cells.
Effects of tumour necrosis factor ␣, interleukin 1 and phorbol
ester. Biochem J 296: 803– 809, 1993.
Hansson GK, Libby P, Schonbeck U, and Yan ZQ. Innate and
adaptive immunity in the pathogenesis of atherosclerosis. Circ Res
91: 281–291, 2002.
Hao H, Gabbiani G, and Bochaton-Piallat M-L. Arterial smooth
muscle cell heterogeneity. Implications for atherosclerosis and
restenosis development. Arterioscler Thromb Vasc Biol 23: 1510 –
1520, 2003.
Hasenstab D, Forough R, and Clowes AW. Plasminogen activator inhibitor type 1 and tissue inhibitor of metalloproteinases-2
increase after arterial injury in rats. Circ Res 80: 490 – 496, 1997.
Hayashi K, Saga H, Chimori Y, Kimura K, Yamanaka Y, and
Sobue K. Differentiated phenotype of smooth muscle cells depends on signaling pathways through insulin-like growth factors
and phosphatidylinositol 3-kinase. J Biol Chem 273: 28860 –28867,
1998.
Hedin U, Bottger BA, Forsberg E, Johansson S, and Thyberg
J. Diverse effects of fibronectin and laminin on phenotypic properties of cultured arterial smooth muscle cells. J Cell Biol 107:
307–319, 1988.
Hedin U, Bottinger BA, Lutham J, Johansson S, and Thyberg
J. A substrate of the cell attachment sequence of fibronectin (ArgGly-Asp-Ser) is sufficient to promote transition of arterial smooth
muscle cells from a contractile to a synthetic phenotype. Dev Biol
133: 489 –501, 1989.
Henney AM, Wakely PR, Davies MJ, Foster K, Hembry R,
Murphy G, and Humphries S. Localization of stromelysin gene
expression in atherosclerotic plaques by in situ hybridization. Proc
Natl Acad Sci USA 88: 8154 – 8158, 1991.
Herman MP, Sukhova GK, Libby P, Gerdes N, Tang N, Horton
DB, Kilbride M, Breitbart RE, Chun MY, and Schonbeck U.
Expression of neutrophil collagenase (matrix metalloproteinase-8)
in human atheroma: a novel collagenolytic pathway suggested by
transcriptional profiling. Circulation 104: 1899 –1904, 2001.
Physiol Rev • VOL
115. Herren B, Raines EW, and Ross R. Expression of a disintegrinlike protein in cultured human vascular cells and in vivo. FASEB J
11: 173–180, 1997.
116. Herron SG, Unemori E, Wong M, Rapp JH, Hibbs MH, and
Stoney RJ. Connective tissue proteinases and inhibitors in abdominal aortic aneurysms. Involvement of the vasa vasorum in the
pathogenesis of aortic aneurysms. Atheroscl Thromb 11: 1667–
1677, 1991.
117. Hojo Y, Ikeda U, Takahashi M, Sakata Y, Takizawa T, Okada
K, Saito T, and Shimada K. Matrix metalloproteinase-1 expression by interaction between monocytes and vascular endothelial
cells. J Mol Cell Cardiol 32: 1459 –1468, 2000.
118. Hu Y, Mayr M, Metzler B, Erdel M, Davison F, and Xu Q. Both
donor and recipient origins of smooth muscle cells in vein graft
atherosclerotic lesions. Circ Res 91: 13–20, 2002.
119. Huang Y, Mironova M, and Lopes-Virella MF. Oxidized LDL
stimulates matrix metalloproteinase-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol 19: 2640 –2647,
1999.
120. Inoue N, Takeshita S, Gao D, Ishida T, Kawashima S, Akita H,
Tawa R, Sakurai H, and Yokoyama M. Lysophosphatidylcholine
increases the secretion of matrix metalloproteinase 2 through the
activation of NADH/NADPH oxidase in cultured aortic endothelial
cells. Atherosclerosis 155: 45–52, 2001.
121. Islam MM, Franco CD, Courtman DW, and Bendeck MP. A
nonantibiotic chemically modified tetracycline (CMT-3) inhibits
intimal thickening. Am J Pathol 163: 1557–1566, 2003.
122. Ivan E, Khatri JJ, Johnson C, Magid R, Godin D, Nandi S,
Lessner S, and Galis ZS. Expansive arterial remodeling is associated with increased neointimal macrophage foam cell content:
the murine model of macrophage-rich carotid artery lesions. Circulation 105: 2686 –2691, 2002.
123. Izzard TD, Taylor C, Birkett SD, Jackson CL, and Newby AC.
Mechanisms underlying maintenance of smooth muscle cell quiescence in rat aorta: role of the cyclin dependent kinases and their
inhibitors. Cardiovasc Res 53: 242–252, 2002.
124. Jackson CL and Reidy MA. The role of plasminogen activation in
smooth muscle cell migration after arterial injury. Ann NY Acad Sci
667: 141–150, 1992.
125. James TW, Wagner R, White LA, Zwolak RM, and Brinkerhoff
CE. Induction of collagenase gene expression by mechanical injury
in a vascular smooth muscle cell derived cell line. J Cell Physiol
157: 426 – 437, 1993.
126. Jeng AY, Chou M, Sawyer WK, Caplan SL, Von Linden-Reed J,
Jeune M, and Prescott MF. Enhanced expression of matrix
metalloproteinase-3, -12, and -13 mRNAs in the aortas of apolipoprotein E-deficient mice with advanced atherosclerosis. Ann NY
Acad Sci 878: 555–558, 1999.
127. Jeziorska M and Woolley DE. Local neovascularization and cellular composition within vulnerable regions of atherosclerotic
plaques of human carotid arteries. J Pathol 188: 189 –196, 1999.
128. Johnson C and Galis ZS. Matrix metalloproteinase-2 and -9 differentially regulate smooth muscle cell migration and cell-mediated
collagen organization. Arterioscler Thromb Vasc Biol 24: 54 – 60,
2004.
129. Johnson JL, George SJ, Newby AC, and Jackson CL. Matrix
metalloproteinases-9 and -12 have opposite effects on atherosclerotic plaque stability. Eur Heart J 24 Suppl: 118, 2003.
130. Johnson JL and Jackson CL. Atherosclerotic plaque rupture in
the apolipoprotein E knockout mouse. Atherosclerosis 154: 399 –
406, 2001.
131. Johnson JL, Jackson CL, Angelini GD, and George SJ. Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler Thromb Vasc Biol
18: 1707–1715, 1998.
132. Johnson JL, Van Eys GJJM, Angelini GD, and George SJ.
Injury induces dedifferentiation of smooth muscle cells and increased matrix-degrading metalloproteinase activity in human saphenous vein. Arterioscler Thromb Vasc Biol 21: 1146 –1151, 2001.
133. Jormsjo S, Ye S, Moritz J, Walter DH, Dimmeler S, Zeiher AM,
Henney A, Hamsten A, and Eriksson P. Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
103.
ANDREW C. NEWBY
METALLOPROTEINASES IN BLOOD VESSELS
134.
135.
136.
137.
138.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
Physiol Rev • VOL
153. Leppert D, Waubant E, Galardy R, Bunnett NW, and Hauser
SL. T cell gelatinases mediate basement membrane transmigration
in vitro. J Immunol 154: 4379 – 4389, 1995.
154. Li C, Cantor WJ, Nili N, Robinson R, Fenkell L, Tran YLE,
Whittingham HA, Tsui W, Cheema AN, Sparkes JD, Pritzker
K, Lewy DE, and Strauss BH. Arterial repair after stenting and
the effects of GM6001, a matrix metalloproteinase inhibitor. J Am
Coll Cardiol 39: 1852–1858, 2002.
155. Li D, Liu L, Chen H, Sawamura T, Ranganathan S, and Mehta
JL. Lox-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery
endothelial cells. Circulation 107: 612– 617, 2003.
156. Li Z, Li L, Zielke R, Cheng L, Xiao R, Crow MT, StetlerStephenson WG, Froehlich J, and Lakatta EG. Increased expression of 72-kd type IV collagenase in human aortic atherosclerotic lesions. Am J Pathol 148: 121–128, 1996.
157. Libby P. Inflammatory and immune mechanisms in atherogenesis.
Atheroscl Rev 21: 79 – 89, 1990.
158. Libby P and Aikawa M. Stabilization of atherosclerotic plaques:
new mechanisms and clinical targets. Nature Med 8: 1257–1262,
2002.
159. Lijnen HR. Plasmin and matrix metalloproteinases in vascular
remodeling. Thromb Haemostasis 86: 324 –333, 2001.
160. Lijnen HR, Lupu F, Moons L, Carmeliet P, Goulding D, and
Collen D. Temporal and topographic matrix metalloproteinase
expression after vascular injury in mice. Thromb Haemostasis 81:
799 – 807, 1999.
161. Lijnen HR, Soloway P, and Collen D. Tissue inhibitor of matrix
metalloproteinases-1 impairs arterial neointima formation after
vascular injury in mice. Circ Res 85: 1186 –1191, 1999.
162. Lijnen HR, Van Hoef B, Vanlinthout I, Verstreken M, Rio MC,
and Collen D. Accelerated neointima formation after vascular
injury in mice with stromelysin-3 (MMP-11) gene inactivation. Arterioscler Thromb Vasc Biol 19: 2863–2870, 1999.
163. Liu J, Xiong WF, Baca-Regen L, Nagase H, and Baxter BT.
Mechanism of inhibition of matrix metalloproteinase-2 expression
by doxycycline in human aortic smooth muscle cells. J Vasc Surg
38: 1376 –1383, 2003.
164. Loftus IM, Naylor AR, Goodall S, Crowther M, Jones L, Bell
PRF, and Thompson MM. Increased matrix metalloproteinase-9
activity in unstable carotid plaques: a potential role in acute plaque
disruption. Stroke 31: 40 – 47, 2000.
165. Lohi J, Lehti K, Valtanen H, Parks WC, and Keski-Oja J.
Structural analysis and promoter characterization of the human
membrane-type matrix metalloproteinase-1 (MT1-MMP) gene.
Gene 242: 75– 86, 2000.
166. Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, and Baxter
BT. Matrix metalloproteinases 2 and 9 work in concert to produce
aortic aneurysms. J Clin Invest 110: 625– 632, 2002.
167. Lovdhal C, Thyberg J, and Hultgardh-Nilsson A. The synthetic
metalloproteinase inhibitor batimastat suppresses injury-induced
phosphorylation of of MAP kinase ERK1/ERK2 and phenotypic
modification of arterial arterial smooth muscle cells in vitro. J Vasc
Res 37: 345–54, 2000.
168. Luan Z, Chase AJ, and Newby AC. Statins inhibit secretion of
metalloproteinases-1, -2, -3, and -9 from vascular smooth muscle
cells and macrophages. Arterioscler Thromb Vasc Biol 23: 769 –775,
2003.
169. Luttun A, Lutgens E, Manderveld A, Maris K, Collen D, Carmeliet P, and Moons L. Loss of matrix metalloproteinase-9 or
matrix metalloproteinase-12 protects apolipoprotein E-deficient
mice against atherosclerotic media destruction but differentially
affects plaque growth. Circulation 109: 1408 –1414, 2004.
170. Mach F, Schonbeck U, Bonnefoy JY, Pober JS, and Libby P.
Activation of monocyte macrophage functions related to acute
atheroma complication by ligation of CD40. Induction of collagenase, stromelysin, and tissue factor. Circulation 96: 396 –399, 1997.
171. Mach F, Schonbeck U, Fabunmi RP, Murphy C, Atkinson E,
Bonnefoy JY, Graber P, and Libby P. T lymphocytes induce
endothelial cell matrix metalloproteinase expression by a CD40Ldependent mechanism: implications for tubule formation. Am J
Pathol 154: 229 –238, 1999.
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
139.
coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease. Circ Res 86: 998 –1003, 2000.
Kahari V and Saarialho-Kere U. Matrix metalloproteinases in
skin. Exp Dermatol 6: 199 –213, 1997.
Kenagy RD, Nikarri ST, Welgus HG, and Clowes AW. Heparin
inhibits the induction of three matrix metalloproteinases (Stromelysin, 92-kDa gelatinase, and collagenase) in primate arterial
smooth muscle cells. J Clin Invest 93: 1987–1993, 1994.
Kenagy RD, Vergel S, Mattsson E, Bendeck M, Reidy MA, and
Clowes AW. The role of plasminogen, plasminogen activators, and
matrix metalloproteinases in primate arterial smooth muscle cell
migration. Arterioscler Thromb Vasc Biol 16: 1373–1382, 1996.
Kennedy SH, Qin H, Lin L, and Tan EML. Basic fibroblast
growth factor regulates type-1 collagen and collagenase gene expression in human smooth muscle cells. Am J Pathol 146: 764 –771,
1995.
Kim WH, Hong MK, Virmani R, Kornowski R, Jones R, and
Leon MB. Histopathologic analysis of in-stent neointimal regression in a porcine coronary model. Coronary Art Dis 11: 273–277,
2000.
Kinsella MG, Tran PK, Weiser-Evans MCM, Reidy M, Majack
RA, and Wight TN. Changes in perlecan expression during vascular injury: role in the inhibition of smooth muscle cell proliferation
in the late lesion. Arterioscler Thromb Vasc Biol 23: 608 – 614, 2003.
Koo EWY and Gotlieb AI. Endothelial stimulation of intimal cell
proliferation in a porcine aortic organ culture. Am J Pathol 134:
497–503, 1989.
Koyama H, Raines EW, Bornfeldt KE, Roberts JM, and Ross
R. Fibrillar collagen inhibits arterial smooth muscle proliferation
through regulation of Cdk2 inhibitors. Cell 87: 1069 –1078, 1996.
Kranzhöfer A, Baker AH, George SJ, and Newby AC. Expression of tissue inhibitor of metalloproteinases-1, -2 and -3 during
neointima formation in organ cultures of human saphenous vein.
Arterioscler Thromb Vasc Biol 19: 255–265, 1999.
Krol GJ, Beck GW, Ritter W, and Lettieri JT. LC separation and
induced fluorometric detection of rivastatin in blood plasma.
J Pharm Biomed Anal 11: 1269 –1275, 1993.
Kuzuya M, Kanda S, Sasaki T, Tamaya-Mori N, Cheng XW,
Itoh T, Itohara S, and Iguchi A. Deficiency of gelatinase A
suppresses smooth muscle cell invasion and development of experimental intimal hyperplasia. Circulation 108: 1375–1381, 2003.
Lafleur MA, Hollenberg MD, Atkinson SJ, Knauper V, Murphy
G, and Edwards DR. Activation of pro-(matrix metalloproteinase-2) (pro-MMP-2) by thrombin is membrane-type-MMP-dependent in human umbilical vein endothelial cells and generates a
distinct 63 kDa active species. Biochem J 357: 107–115, 2001.
Leco KJ, Khokha R, Pavloff N, Hawkes SP, and Edwards DR.
Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 269: 9352–9360, 1994.
Lee E, Grodzinsky AJ, Libby P, Clinton SK, Lark MW, and Lee
RT. Human vascular smooth muscle cell-monocyte interactions
and metalloproteinase secretion in culture. Arterioscler Thromb
Vasc Biol 15: 2284 –2289, 1995.
Lee RT, Schoen FJ, Loree HM, Lark MW, and Libby P. Circumferential stress and matrix metalloproteinase 1 in human atherosclerosis. Implications for plaque rupture. Arterioscler Thromb
Vasc Biol 16: 1070 –1073, 1996.
Lees M, Taylor DJ, and Woolley DE. Mast cell proteinases
activate precursor forms of collagenase and stromelysin, but not of
gelatinases A and B. Eur J Biochem 223: 171–177, 1994.
Lemaitre V, O’Byrne TK, Borczuk AC, Okada Y, Tall AR, and
D’Armiento J. ApoE knockout mice expressing human matrix
metalloproteinase-1 in macrophages have less advanced atherosclerosis. J Clin Invest 107: 1227–1234, 2001.
Lemaitre V, Soloway PD, and D’Armiento J. Increased medial
degradation with pseudo-aneurysm formation in apolipoprotein
E-knockout mice deficient in tissue inhibitor of metalloproteinases-1. Circulation 107: 333–338, 2003.
Lendon CL, Davies MJ, Born GVR, and Richardson PD. Atherosclerotic plaque caps are locally weakened when macrophage
density is increased. Atherosclerosis 87: 87–91, 1991.
27
28
ANDREW C. NEWBY
Physiol Rev • VOL
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
eling after coronary angioplasty: a serial intravascular ultrasound
study. Circulation 94: 35– 43, 1996.
Moiseeva EP. Adhesion receptors of smooth muscle cells and
their functions. Cardiovasc Res 52: 372–386, 2001.
Moon SK, Cho GO, Jung SY, Gal SW, Kwon TK, Lee YC,
Madamanchi NR, and Kim CH. Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2,
cell-cycle regulation, and matrix metalloproteinase-9. Biochem
Biophys Res Commun 301: 1069 –1078, 2003.
Moreau M, Brocheriou I, Petit L, Ninio E, Chapman MJ, and
Rouis M. Interleukin-8 mediates downregulation of tissue inhibitor
of metalloproteinase-1 expression in cholesterol-loaded human
macrophages: relevance to stability of atherosclerotic plaque. Circulation 99: 420 – 426, 1999.
Morgan AR, Fzhang B, Tapper W, Collins A, and Ye S. Haplotypic analysis of the MMP-9 gene in relation to coronary artery
disease. J Mol Med 81: 321–326, 2003.
Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W,
and Folkman J. Angiogenesis inhibitors endostatin or TNP-470
reduce intimal neovascularisation and plaque growth in apolipoprotein E-deficient mice. Circulation 99: 1726 –1732, 1999.
Murry CE, Gipaya CT, Bartosek T, Benditt EP, and Schwartz
SM. Monoclonality of smooth muscle cells in human atherosclerosis. Am J Pathol 151: 697–705, 1997.
Nagase H and Woessner JF Jr. Matrix metalloproteinases. J Biol
Chem 274: 21491–21494, 1999.
Nakashima Y, Plump AS, Raines EW, Breslow JL, and Ross R.
ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14: 133–140,
1994.
Newby AC. Vitronectin is implicated as the matrix takes control of
neointima formation. Cardiovasc Res 53: 779 –781, 2002.
Newby AC and George SJ. Proposed roles for growth factors in
mediating smooth muscle proliferation in vascular pathologies.
Cardiovasc Res 27: 1173–1183, 1993.
Newman KM, Ogata Y, Malon AM, Irizarry E, Gandhi RH, and
Nagase HT. Identification of matrix metalloproteinases 3 (stromelysin-1) and 9 (gelatinase B) in abdominal aortic aneurysm. Arterioscler Thromb 14: 1315–1320, 1994.
Nikkari ST, Geary RL, Hatsukami T, Ferguson M, Forough R,
Allpers CE, and Clowes AW. Expression of collagen, interstitial
collagenase, and tissue inhibitor of metalloproteinases-1 in restenosis after carotid endarterectomy. Am J Pathol 148: 777–783, 1996.
Nikkari ST, O’Brien KD, Ferguson M, Hatsukami T, Welgus
HG, Alpers CE, and Clowes AW. Interstitial collagenase (MMP-1)
expression in human carotid atherosclerosis. Circulation 92: 1393–
1398, 1995.
Nold M, Goede A, Eberhardt W, Pfeilschifter J, and Muhl H.
IL-18 initiates release of metalloproteinase-9 from peripheral blood
mononuclear cells without affecting tissue inhibitor of metalloproteinases-1: suppression by TNFa blockage and modulation by IL-10.
Naunyn-Schmiedeberg’s Arch Pharmacol 367: 68 –75, 2003.
O’Brien ER, Alpers CE, Stewart DK, Ferguson M, Tran N,
Gordon D, Benditt EP, Hinohara T, Simpson JB, and
Schwartz SM. Proliferation in primary and restenotic coronary
atherectomy tissue: implications for antiproliferative therapy. Circ
Res 73: 223–231, 1993.
Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara
RM, Nishimura S, Imamura Y, Kitayama H, Alexander DB, Ide
C, Horan TP, Arakawa T, Yoshida H, Nishikawa SI, Itoh Y,
Seiki M, Itohara S, Takahashi C, and Noda M. The membraneanchored MMP inhibitor RECK is a key regulator of extracellular
matrix integrity and angiogenesis. Cell 107: 789 – 800, 2001.
Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, and Okada Y.
Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol
Chem 272: 2446 –2451, 1997.
Otsuki Y, Li ZL, and Shibata MA. Apoptotic detection methods:
from morphology to gene. Prog Histochem Cytochem 38: 275–339,
2003.
Paigen B, Ishida BY, Verstuyft J, Winters RB, and Albee D.
Atherosclerosis susceptibility differences among progenitors of
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
172. Mach F, Schonbeck U, Sukhova GK, Bonnefoy JY, and Libby
P. Ligation of CD40 on macrophage induces matrix metalloproteinases and tissue factor expression. Atherosclerosis 134: 280 –281,
1997.
173. Mach F, Schonbeck U, Sukhova GK, Bourcier T, Bonnefoy JY,
Pober JS, and Libby P. Functional CD40 ligand is expressed on
human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA 94: 1931–1936, 1997.
174. Magid R, Murphy TJ, and Galis ZS. Expression of matrix metalloproteinase-9 in endothelial cells is differentially regulated by
shear stress: role of c-Myc. J Biol Chem 278: 32994 –32999, 2003.
175. Malik N, Francis SE, Holt CM, Gunn J, Thomas GL, Shepherd
L, Chamberlain J, Newman CMH, Cumberland DC, and Crossman DC. Apoptosis and cell proliferation after porcine coronary
angioplasty. Circulation 98: 1657–1665, 1998.
176. Malik N, Greenfield BD, Wahl AF, and Kiener PA. Activation of
human monocytes through CD40 induces matrix metalloproteinases. J Immunol 156: 3952–3960, 1996.
177. Manes S, Mira E, Barbacid MDM, Cipres A, Fernandez-Resa
P, Buesa JM, Merida I, Aracil M, Marquez G, and Martinez
AC. Identification of insulin-like growth factor-binding protein-1 as
a potential physiological substrate for human stromelysin-3. J Biol
Chem 272: 25706 –25712, 1997.
178. Manning MW, Cassis LA, and Daugherty A. Differential effects
of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 23: 483– 488, 2003.
179. Mao DL, Lee JK, Van Vickle SJ, and Thompson RW. Expression
of collagenase-3 (MMP-13) in human abdominal aortic aneurysms
and vascular smooth muscle cells in culture. Biochem Biophys Res
Commun 261: 904 –910, 1999.
180. Marcet-Palacios M, Graham K, Cass C, Befus AD, Mayers I,
and Radomski MW. Nitric oxide and cyclic GMP increase the
expression of matrix metalloproteinase-9 in vascular smooth muscle. J Pharmacol Exp Ther 307: 429 – 436, 2003.
181. Marx N, Froehlich J, Siam L, Ittner J, Wierse G, Schmidt A,
Scharnagl H, Hombach V, and Koenig W. Antidiabetic PPAR␥activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. Arterioscler Thromb
Vasc Biol 23: 283–288, 2003.
182. Marx N, Schonbeck U, Lazar MA, Libby P, and Plutzky J.
Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth
muscle cells. Circ Res 83: 1097–1103, 1998.
183. Marx N, Sukhova G, Murphy C, Libby P, and Plutzky J. Macrophages in human atheroma contain PPAR gamma. Differentiation-dependent peroxisomal proliferator-activated receptor gamma
expression and reduction of MMP activity through PPARgamma
activation in mononuclear phagocytes in vitro. Am J Pathol 153:
17–23, 1998.
184. Mason DP, Kenagy RD, Hasenstab D, Bowen-Pope DF, Seifert
RA, Coats S, Hawkins SM, and Clowes AW. Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell
migration and alters remodeling in the injured rat carotid artery.
Circ Res 85: 1179 –1185, 1999.
185. McCarthy MJ, Loftus IM, Thompson MM, Jones L, London
NJM, Bell PRF, Naylor AR, and Brindle NPJ. Angiogenesis and
the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology. J Vasc Surg 30: 261–268, 1999.
186. McMillan WD, Patterson BK, Keen RR, Shively VP, Cipollone
M, and Pearce WH. In situ localisation and quantification of
mRNA for 92-kD type IV collagenase and its inhibitor in aneurysmal, occlusive, and normal aorta. Arterioscler Thromb Vasc Biol
15: 1139 –1144, 1995.
187. McMurray H, Parrott DP, and Bowyer DE. A standardised
method of culturing aortic explants, suitable for the study of factors affecting the phenotypic modulation, migration and proliferation of aortic smooth muscle cells. Atherosclerosis 86: 227–237,
1991.
188. Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Chiu
Wong S, Hong MK, Kovach JA, and Leon MB. Arterial remod-
METALLOPROTEINASES IN BLOOD VESSELS
208.
209.
210.
211.
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
223.
Physiol Rev • VOL
224.
225.
226.
227.
228.
229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
239.
240.
241.
242.
smooth muscle cells and stimulates the conversion of pro-MMP-2
to MMP-2: role of MMP-2 in factor Xa-induced DNA synthesis and
matrix invasion. Circ Res 90: 1122–1127, 2002.
Reed D, Reed C, Stemmermann G, and Hayashi T. Are aortic
aneurysms caused by atherosclerosis? Circulation 85: 205–211,
1992.
Rekhter MD. How to evaluate plaque vulnerability in animal models of atherosclerosis? Cardiovasc Res 54: 36 – 41, 2002.
Ricote M, Huang JT, Welch JS, and Glass CK. The peroxisome
proliferator-activated receptor (PPARgamma) as a regulator of
monocyte/macrophage function. J Leukoc Biol 66: 733–739, 1999.
Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G,
and Schwartz SM. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb
Vasc Biol 20: 2587–2592, 2000.
Ross R. Mechanisms of disease. Atherosclerosis: an inflammatory
disease. N Engl J Med 340: 115–126, 1999.
Ross R and Glomset JA. Atherosclerosis and the arterial smooth
muscle cell. Proliferation of smooth muscle is a key event in the
genesis of the lesions of atherosclerosis. Science 180: 1332–1339,
1973.
Rotmans JI, Velema E, Verhagen HJM, Blankensteijn JD, De
Kleijn DPV, Stroes ESG, and Pasterkamp G. Matrix metalloproteinase inhibition reduces intimal hyperplasia in a porcine arteriovenous-graft model. J Vasc Surg 39: 432– 439, 2004.
Rouis M, Adamy C, Duverger N, Lesnik P, Horellou P, Moreau
M, Emmanuel F, Caillard JM, Laplaud PM, Dachet C, and
Chapman MJ. Adenovirus-mediate overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E deficient mice. Circulation 100: 533–540, 1999.
Salomon RN, Hughes CCW, Schoen FJ, Payne DD, Pober JS,
and Libby P. Human transplant coronary arteriosclerosis: evidence for a chronic immune reaction to activated graft endothelium. Am J Pathol 138: 791–798, 1991.
Sarén P, Welgus HG, and Kovanen PT. TNF-␣ and IL-1␤ selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol 157: 4159 – 4165, 1996.
Sasaguri T, Arima N, Tanimoto A, Shimajiri S, Hamada T, and
Sasaguri Y. A role for interleukin 4 in production of matrix metalloproteinase 1 by human aortic smooth muscle cells. Atherosclerosis 138: 247–254, 1998.
Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T,
Hirai H, Makuuchi M, Hirata Y, and Nagai R. Hematopoietic
stem cells differentiate into vascular cells that participate in the
pathogenesis of atherosclerosis. Nature Med 8: 403– 409, 2002.
Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E,
and Seiki M. A matrix metalloproteinase expressed on the surface
of invasive tumour cells. Nature 370: 61– 65, 1994.
Savani RC, Wang C, Yang BH, Zhang SW, Kinsella MG, Wight
TN, Stern R, Nance DM, and Turley EA. Migration of bovine
aortic smooth muscle cells after wounding injury: the role of hyaluronan and rhamm. J Clin Invest 95: 1158 –1168, 1995.
Schneikert J, Peterziel H, Defossez PA, Klocker H, Delaunoit
Y, and Cato ACB. Androgen receptor-Ets protein interaction is a
novel mechanism for steroid hormone-mediated down-modulation
of matrix metalloproteinase expression. J Biol Chem 271: 23907–
23913, 1996.
Schoenhagen P, Vince DG, Ziada KM, Kapadia SR, Lauer MA,
Crowe TD, Nissen SE, and Tuzcu EM. Relation of matrix-metalloproteinase 3 found in coronary lesion samples retrieved by
directional coronary atherectomy to intravascular ultrosound observations of coronary remodeling. Am J Cardiol 89: 1354 –1359,
2002.
Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE,
and Tuzcu EM. Extent and direction of arterial remodeling in
stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 101: 598 – 603, 2000.
Schonbeck U, Mach F, Sukhova GK, Atkinson E, Levesque E,
Herman M, Graber P, Basset P, and Libby P. Expression of
stromelysin-3 in atherosclerotic lesions: regulation via CD40-CD40
ligand signaling in vitro and in vivo. J Exp Med 189: 843– 853, 1999.
Schonbeck U, Mach F, Sukhova GK, Bonnefoy JY, and Libby
P. CD40 ligation on smooth muscle cells induces expression of
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
212.
recombinant inbred strains of mice. Arterioscler Thromb Vasc Biol
10: 316 –323, 1990.
Palinski W and Napoli C. Unraveling pleiotropic effects of statins
on plaque rupture. Arterioscler Thromb Vasc Biol 22: 1745–1750,
2002.
Pasterkamp G, Schoneveld AH, Van Der Wal AC, Haudenschild CC, Clarijs RJD, Becker AE, Hillen B, and Borst C.
Relation of arterial geometry to luminal narrowing and histologic
markers for plaque vulnerability: the remodeling paradox. J Am
Coll Cardiol 32: 655– 662, 1998.
Patel VA, Zhang QJ, Siddle K, Soos MA, Goddard M, Weissberg PL, and Bennett MR. Defect in insulin-like growth factor-1
survival mechanism in atherosclerotic plaque-derived vascular
smooth muscle cells is mediated by reduced surface binding and
signaling. Circ Res 88: 895–902, 2001.
Pauly RR, Passaniti A, Bilato C, Monticone R, Cheng L, Papadaopoulos N, Gluzband YA, Smith L, Weinstein C, Lakatta
EG, and 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
75: 41– 45, 1994.
Pepper MS. Role of the matrix metalloproteinase and plasminogen
activator-plasmin systems in angiogenesis. Arterioscler Thromb
Vasc Biol 21: 1104 –1117, 2001.
Pickering JG, Ford CM, Tang B, and Chow LH. Coordinated
effects of fibroblast growth factor-2 on expression of fibrillar collagens, matrix metalloproteinases, and tissue inhibitors of matrix
metalloproteinases by human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 17: 475– 482, 1997.
Prall AK, Longo GM, Mayhan WG, Waltke EA, Fleckten B,
Thompson RW, and Baxter BT. Doxycycline in patients with
abdominal aortic aneurysms and in mice: comparison of serum
levels and effect on aneurysm growth in mice. J Vasc Surg 35:
923–929, 2002.
Prescott MF, Sawyer WK, Von Linden-Reed J, Jeune M, Chou
M, Caplan SL, and 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 NY Acad
Sci 878: 179 –90, 1999.
Proudfoot D, Davies JD, Skepper JN, Weissberg PL, and
Shanahan CM. Acetylated low-density lipoprotein stimulates human vascular smooth muscle cell calcification by promoting osteoblastic differentiation and inhibiting phagocytosis. Circulation 106:
3044 –3050, 2002.
Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, Ziporin SJ, Ennis
TL, Shapiro SD, Senior RM, and Thompson RW. Targeted gene
disruption of matrix metalloproteinase-9 (gelatinase B) suppresses
development of experimental abdominal aortic aneurysms. J Clin
Invest 105: 1641–1649, 2000.
Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L,
Bond M, Baker A, and Anand-Apte B. A novel function for tissue
inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Med
9: 407– 415, 2003.
Rabbani R and Topol EJ. Strategies to achieve coronary artery
stabilization. Cardiovasc Res 41: 402– 417, 1999.
Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, and
Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. J Clin Invest 98: 2572–2579, 1996.
Rajavashisth TB, Xu XP, Jovinge S, Meisel S, Xu XO, Chai NN,
Fishbein MC, Kaul S, Cercek B, Sharifi B, and Shah PK.
Membrane type 1 matrix metalloproteinase expression in human
atherosclerotic plaques. Evidence for activation by proinflammatory mediators. Circulation 99: 3103–3109, 1999.
Ratnikov BI, Rozanov DV, Postnova TI, Baciu PG, Zhang H,
Discipio RG,, Chestukhina GG, Smith JW, Deryugina EI, and
Strongin AY. An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase.
J Biol Chem 277: 7377–7385, 2002.
Rauch BH, Bretschneider E, Braun M, and Schror K. Factor Xa
releases matrix metalloproteinase-2 (MMP-2) from human vascular
29
30
243.
244.
245.
246.
248.
249.
250.
251.
252.
253.
254.
255.
256.
257.
258.
259.
matrix metalloproteinases: implication for plaque rupture? Atherosclerosis 134: 252–252, 1997.
Schonbeck U, Mach F, Sukhova GK, Murphy C, Bonnefoy JY,
Fabunmi RP, and Libby P. Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? Circ Res 81:
448 – 454, 1997.
Schwartz MA and Assoian RK. Integrins and cell proliferation:
regulation of cyclin-dependent kinases via cytoplasmic signaling
pathways. J Cell Sci 114: 2553–2560, 2001.
Shah PK, Falk E, Badimon JJ, Fernandezortiz A, Mailhac A,
Villareal-Levy G, Fallon JT, Regnstrom J, and Fuster V. Human monocyte-derived macrophages induce collagen breakdown
in fibrous caps of atherosclerotic plaques: potential role of matrixdegrading metalloproteinases and implications for plaque rupture.
Circulation 92: 1565–1569, 1995.
Shi Y, Obrien JE, Fard A, Mannion JD, Wang D, and Zalewski
A. Adventitial myofibroblasts contribute to neointimal formation in
injured porcine coronary arteries. Circulation 94: 1655–1664, 1996.
Shi Y, Patel S, Niculescu R, Chung W, Desrochers P, and
Zalewski A. Role of matrix metalloproteinases and their tissue
inhibitors in the regulation of coronary cell migration. Arterioscler
Thromb Vasc Biol 19: 1150 –1155, 1999.
Shimada T, Nakamura H, Ohuchi E, Fujii Y, Murakami Y, Sato
H, Seiki M, and Okada Y. Characterization of a truncated recombinant form of human membrane type 3 matrix metalloproteinase.
Eur J Biochem 262: 907–914, 1999.
Shiomi M, Ito T, Yamada S, Kawashima S, and Fan J. Development of an animal model for spontaneous myocardial infarction
(WHHLMI rabbit). Arterioscler Thromb Vasc Biol 23: 1239 –1244,
2003.
Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, and
Shapiro SD. Metalloelastase is required for macrophage-mediated
proteolysis and matrix invasion in mice. Proc Natl Acad Sci USA
93: 3942–3946, 1996.
Shofuda K, Nagashima Y, Kawahara K, Yasumitsu H, Miki K,
and Miyazaki K. Elevated expression of membrane-type 1 and 3
matrix metalloproteinases in rat vascular smooth muscle cells
activated by arterial injury. Lab Invest 78: 915–923, 1998.
Shofuda T, Shofuda KI, Ferri N, Kenagy RD, Raines EW, and
Clowes AW. Cleavage of focal adhesion kinase in vascular smooth
muscle cells overexpressing membrane-type matrix metalloproteinases. Arterioscler Thromb Vasc Biol 24: 839 – 844, 2004.
Shu H, Wong BM, Zhou GC, Li Y, Berger J, Woods JW, Wright
SD, and Cai TQ. Activation of PPAR alpha or gamma reduces
secretion of matrix metalloproteinase 9 but not interleukin 8 from
human monocytic THP-1 cells. Biochem Biophys Res Commun
267: 345–349, 2000.
Silence J, Collen D, and Lijnen HR. Reduced atherosclerotic
plaque but enhanced aneurysm formation in mice with inactivation
of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ
Res 90: 897–903, 2002.
Silence J, Lupu F, Collen D, and Lijnen HR. Persistence of
atherosclerotic plaque but reduced aneurysm formation in mice
with stromelysin-1 (MMP-3) gene inactivation. Arterioscler Thromb
Vasc Biol 21: 1440 –1445, 2001.
Southgate KM, Davies M, Booth RFG, and Newby AC. Involvement of extracellular matrix degrading metalloproteinases in rabbit
aortic smooth muscle cell proliferation. Biochem J 288: 93–99,
1992.
Southgate KM, Fisher M, Banning AP, Thurston VJ, Baker
AH, Fabunmi RP, Groves PH, Davies M, and Newby AC. Upregulation of basement-membrane-degrading metalloproteinase secretion following balloon angioplasty of pig carotid arteries. Circ
Res 79: 1177–1187, 1996.
Southgate KM, Mehta D, Izzat MB, Newby AC, and Angelini
GD. Increased secretion of basement membrane degrading metalloproteinases in pig saphenous vein into carotid artery interposition grafts. Arterioscler Thromb Vasc Biol 19: 1640 –1649, 1999.
Soyombo AA, Angelini GD, Bryan AJ, Jasani B, and Newby
AC. Intimal proliferation in an organ culture of human saphenous
vein. Am J Pathol 137: 1401–1410, 1990.
Physiol Rev • VOL
260. Springman EB, Angleton EL, Birkedal-Hansen H, and Van
Wart HE. Multiple mode of activation of latent human fibroblast
collagenase: evidence for the role of a cys73 active-site zinc complex in latency and a “cysteine switch” mechanism for activation.
Proc Natl Acad Sci USA 87: 364 –368, 1990.
261. Stary HC. The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. Eur
Heart J 11 Suppl E: 3–19, 1990.
262. Stawowy P, Kallisch H, Veinot JP, Kilimnik A, Prichett W,
Goetze S, Seidah NG, Chretien M, Fleck E, and Graf K. Endoproteolytic activation of ␣v integrin by proprotein convertase
PC5 is required for vascular smooth muscle cell adhesion to vitronectin and integrin-dependent signaling. Circulation 109: 770 –776,
2004.
263. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, and Witztum JL. Beyond cholesterol modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320: 915–924,
1989.
264. Sternlicht MD and Werb Z. How matrix metalloproteinases regulate cell behaviour. Annu Rev Cell Dev Biol 17: 463–516, 2001.
265. Strauss BH, Robinson R, Batchelor WB, Chisholm RJ, Ravi G,
Natarajan MK, Logan RA, Mehta SR, Levy DE, Ezrin AM, and
Keeley FW. In vivo collagen turnover following experimental balloon angioplasty injury and the role of metalloproteinases. Circ Res
79: 541–550, 1996.
266. Stringa E, Knauper V, Murphy G, and Gavrilovic J. Collagen
degradation and platelet-derived growth factor stimulate the migration of vascular smooth muscle cells. J Cell Sci 113: 2055–2064,
2000.
267. Strongin AY, Collier I, Bannikov BL, Grant GA, and Goldberg
GI. Mechanism of cell surface activation of 72 kDa type IV collagenase. J Biol Chem 270: 5331–5338, 1995.
268. Sukhova GK, Schonbeck U, Rabkin E, Schoen FJ, Poole AR,
Billinghurst RC, and Libby P. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human
atheromatous plaques. Circulation 99: 2503–2509, 1999.
269. Takemoto M and Liao JK. Pleiotropic effects of 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors. Arterioscl
Thromb Vasc Biol 21: 1712–1719, 2001.
270. Tanaka H, Sukhova GK, Swanson SJ, Clinton SK, Ganz P,
Cybulsky MI, and Libby P. Sustained activation of vascular cells
and leukocytes in the rabbit aorta after balloon injury. Circulation
88: 1788 –1803, 1993.
271. Tanner FC, Boehm M, Akyurek LM, San H, Yang ZY, Tashiro
J, Nabel GJ, and Nabel EG. Differential effects of the cyclindependent kinase inhibitors p27kip1, p21cip1 and p16Ink4 on vascular smooth muscle cell proliferation. Circulation 101: 2022–2025,
2000.
272. Tanner FC, Yang ZY, Duckers E, Gordon D, Nabel GJ, and
Nabel EG. Expression of cyclin-dependent kinase inhibitors in
vascular disease. Circ Res 82: 396 – 403, 1998.
273. Thyberg J. Differentiated properties and proliferation of arterial
smooth muscle cells in culture. Int Rev Cytol 169: 183–265, 1996.
274. Thyberg J. Phenotypic modulation of smooth muscle cells during
formation of neointimal thickenings following vascular injury. Histol Histopathol 13: 871– 891, 1998.
275. Thyberg J, Blomgren K, Roy J, Tran PK, and Hedin U. Phenotypic modulation of smooth muscle cells after arterial injury is
associated with changes in the distribution of laminin and fibronectin. J Histochem Cytochem 45: 837– 846, 1997.
276. Timpl R. Macromolecular organization of basement membrane.
Curr Opin Cell Biol 8: 618 – 624, 1996.
277. Uglow EB, Slater S, Sala-Newby GB, Aguilera-Garcia CM,
Angelini GD, Newby AC, and George SJ. Dismantling of cadherin-mediated cell-cell contacts modulates smooth muscle cell
proliferation. Circ Res 92: 1314 –1321, 2003.
278. Upchurch GR, Ford JW, Weiss SJ, Knipp BS, Peterson DA,
Thompson RW, Eagleton MJ, Broady AJ, Proctor MC, and
Stanley JC. Nitric oxide inhibition increases matrix metalloproteinase-9 expression by rat aortic smooth muscle cells in vitro. J
Vasc Surg 34: 76 – 83, 2001.
279. Uria JA, Jimenez MG, Balbin M, Freije JMP, and Lopez-Otin
C. Differential effects of transforming growth factor-beta on the
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
247.
ANDREW C. NEWBY
METALLOPROTEINASES IN BLOOD VESSELS
280.
281.
282.
283.
284.
286.
287.
288.
289.
290.
291.
292.
293.
294.
295.
296.
297.
298.
Physiol Rev • VOL
299. Worley Thompkins PB, Lee MH, Hutton M Jr, Soloway P,
Edwards DR, Murphy G, and Knauper V. Sequence motifs of
tissue inhibitor of metalloproteinases 2 (TIMP-2) determining
progelatinase A (proMMP-2) binding and activation by membranetype metalloproteinase 1 (MT1-MMP). Biochem J 372: 799 – 809,
2003.
300. Wu L, Fan J, Matsumoto S, and Watanabe T. Induction and
regulation of matrix metalloproteinase-12 by cytokines and CD40
signaling in monocyte/macrophages. Biochem Biophys Res Commun 269: 808 – 815, 2000.
301. Xu XP, Meisel SR, Ong JM, Kaul S, Cercek B, Rajavashisth
TB, Sharifi B, and Shah PK. Oxidized low-density lipoprotein
regulates matrix metalloproteinase-9 and its tissue inhibitor in
human monocyte-derived macrophages. Circulation 99: 993–998,
1999.
302. Yakubenko V, Lobb R, Plow E, and Ugarova T. Differential
induction of gelatinase B (MMP-9) and gelatinase A (MMP-2) in T
lymphocytes upon ␣4␤1 mediated adhesion to VCAM-1 and the CS-1
peptide of fibronectin. Exp Cell Res 260: 73– 84, 2000.
303. Yamaguchi S, Yamaguchi M, Yatsuyanagi E, Yun SS, Nakajima
N, Madri JA, and Sumpio BE. Cyclic strain stimulates early
growth response gene product 1-mediated expression of membrane type 1 matrix metalloproteinase in endothelium. Lab Invest
82: 949 –956, 2002.
304. Yanagi H, Sasaguri Y, Sugama K, Morimatsu M, and Nagasi H.
Production of tissue collagenase (matrix metalloproteinase 1) by
human aortic smooth muscle cells in response to platelet-derived
growth factor. Atherosclerosis 91: 207–216, 1992.
305. Ye S, Watts GF, Mandalia S, Humphries SE, and Henney AM.
Preliminary report: genetic variation in the human stromelysin
promoter is associated with progression of coronary atherosclerosis. Br Heart J 73: 209 –215, 1995.
306. Yu Q and Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14: 163–176, 2000.
307. Yun SS, Dardik A, Haga M, Yamashita A, Yamaguchi S, Koh Y,
Madri JA, and Sumpio BE. Transcription factor Sp1 phosphorylation induced by shear stress inhibits membrane type 1-matrix
metalloproteinase expression in endothelium. J Biol Chem 277:
34808 –34814, 2002.
308. Zalewski A, Shi Y, and Johnson AG. Diverse origin of intimal
cells: smooth muscle cells, myofibroblasts, fibroblasts, and beyond? Circ Res 91: 652– 655, 2002.
309. Zaltsman AB, George SJ, and Newby AC. Increased secretion of
tissue inhibitors of metalloproteinases-1 and -2 from the aortas of
cholesterol fed rabbits partially counterbalances increased metalloproteinase activity. Arterioscler Thromb Vasc Biol 19: 1700 –1707,
1999.
310. Zaltsman AB and Newby AC. Increased secretion of gelatinases
A and B from the aortas of cholesterol fed rabbits: relationship to
lesion severity. Atherosclerosis 130: 61–70, 1997.
311. Zempo N, Kenagy RD, Au YP, Bendeck M, Clowes MM, Reidy
MA, and Clowes AW. Matrix metalloproteinases of vascular wall
cells are increased in balloon-injured rat carotid artery. J Vasc Surg
20: 209 –217, 1994.
312. Zempo N, Koyama N, Kenagy RD, Lea HJ, and Clowes AW.
Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix
metalloproteinase inhibitor. Arterioscler Thromb Vasc Biol 16: 28 –
33, 1996.
313. Zhang B, Ye S, Herrmann SM, Eriksson P, De Maat M, Evans
A, Arveiler D, Luc G, Cambien F, Hamsten A, Watkins H, and
Henney AM. Functional polymorphism in the regulatory region of
gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation 99: 1788 –1794, 1999.
314. Zhu Y, Hojo Y, Ikeda U, Takahashi M, and Shimada K. Interaction between monocytes and vascular smooth muscle cells enhances matrix metalloproteinase-1 production. J Cardiovasc Pharmacol 36: 152–161, 2000.
315. Zou Y, Dietrich H, Hu Y, Metzler B, Wick G, and Xu Q. Mouse
model of vein bypass graft arteriosclerosis. Am J Pathol 153:
1301–1310, 1998.
85 • JANUARY 2005 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
285.
expression of collagenase-1 and collagenase-3 in human fibroblasts. J Biol Chem 273: 9769 –9777, 1998.
Uzui H, Harpf A, Liu M, Doherty TM, Shukla A, Chai NN,
Tripathi PV, Jovinge S, Wilkin DJ, Asotra K, Shah PK, and
Rajavashisth TB. Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque: role of
activated macrophages and inflammatory cytokines. Circulation
106: 3024 –3030, 2002.
Van Der Giessen WJ, Lincoff AM, Schwartz RS, Van
Beusekom HMM, Serruys PW, Holmes DR, Ellis SG, and Topol
EJ. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries.
Ciculation 94: 1690 –1697, 1996.
Virchow R. Cellular Pathology. London: John Churchill, 1860.
Visse R and Nagase H. Matrix metalloproteinases and tissue
inhibitors of metalloproteinases: structure function and biochemistry. Circ Res 92: 827– 839, 2003.
Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan
D, Shapiro SD, Senior RM, and Werb Z. MMP-9/gelatinase B is a
key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 99: 411– 422, 1998.
Wallner K, Li C, Shah PK, Fishbein MC, Forrester JS, Kaul S,
and Sharifi BG. Tenascin-C is expressed in macrophage-rich human coronary atherosclerotic plaque. Circulation 99: 1284 –1289,
1999.
Watanabe M, Hitomi M, Van Der Wee K, Rothenberg F, Fisher
SA, Zucker R, Svoboda KKH, Goldsmith EC, Heiskanen KM,
and Nieminen AL. The pros and cons of apoptosis assays for use
in the study of cells, tissues, and organs. Microsc Microanal 8:
375–391, 2002.
Webb KE, Henney AM, Anglin S, Humphries SE, and McEwan
JR. Expression of matrix metalloproteinases and their inhibitor
TIMP-1 in the rat carotid artery after balloon injury. Arteriosclr
Thromb Vasc Biol 17: 1837–1844, 1997.
Weber BHF, Vogt G, Pruett RC, Stohr H, and Felbor U. Mutations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) in
patients with Sorsby’s fundus dystrophy. Nature Genet 8: 352–356,
1994.
Weiser MCM, Majack RA, Tucker A, and Orton EC. Static
tension is associated with increased smooth muscle cell DNA
synthesis in rat pulmonary arteries. Am J Physiol Heart Circ
Physiol 268: H1133–H1138, 1995.
Wesley RB, Meng X, Godin D, and 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 18: 432– 440, 1998.
West NEJ, Qian HS, Guzik TJ, Black E, Cai S, George SE, and
Channon KM. Nitric oxide synthase (nNOS) gene transfer modifies venous bypass graft remodeling: effects on vascular smooth
muscle cell differentiation and superoxide production. Circulation
104: 1526 –1532, 2001.
White SJ and Newby AC. Gene therapy for all aspects of vein
graft disease. J Cardiac Surg 17: 549 –555, 2002.
Wight TN. The extracellular matrix and atherosclerosis. Curr
Opin Lipidol 6: 326 –334, 1995.
Wight TN. The vascular extracellular matrix. In: Atherosclerosis
and Coronary Artery Disease, edited by Fuster V, Ross R, and
Topol EJ. Philadelphia, PA: Lippincott-Raven, 1996, p. 421– 440.
Will H, Atkinson SJ, Butler GS, Smith B, and Murphy G. The
soluble catalytic domain of membrane type 1 matrix metalloproteinase cleave the propeptide of progelatinase A and initiates autoproteolytic activation. J Biol Chem 271: 17119 –17123, 1996.
Williams H, Johnson JL, Carson KGS, and Jackson CL. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 22: 788 –792, 2002.
Williams JK, Sukhova GK, Herrington DM, and Libby P. Pravastatin has cholesterol-lowering independent effects on the artery
wall of atherosclerotic monkeys. J Am Coll Cardiol 31: 684 – 691,
1998.
Woods A, Oh ES, and Couchman JR. Syndecan proteoglycans
and cell adhesion. Matrix Biol 17: 477– 483, 1998.
31