© 1995 American Heart Association, Inc.
Articles |
Human Vascular Smooth Muscle Cell–Monocyte Interactions and Metalloproteinase Secretion in Culture
From the Harvard-MIT Division of Health Sciences and Technology, Cambridge, Mass (E.L., A.J.G., R.T.L.); the Department of Mechanical Engineering, MIT, Cambridge, Mass (A.J.G., R.T.L.); the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (P.L., R.T.L.); the Dana-Farber Cancer Institute, Boston, Mass (S.K.C.); and Merck Research Laboratories, Rahway, NJ (M.W.L.).
Correspondence to Richard T. Lee, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail rtlee@bics.bwh.harvard.edu.
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Abstract |
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Abstract Degradation of the atherosclerotic plaque extracellular matrix could destabilize the lesion, rendering it more prone to rupture. Both macrophages and vascular smooth muscle cells (SMCs) are potential sources of matrix metalloproteinases (MMPs), secreted enzymes that can digest vascular matrix. We explored interactions between human vascular SMCs and human monocytes that result in the secretion of interstitial collagenase (MMP-1) and stromelysin (MMP-3). Monocytes alone or those treated with SMC-conditioned media did not secrete these metalloproteinases as detectable by Western blot analysis. SMCs increased secretion of both MMP-1 and MMP-3 greater than 20-fold when cocultured with monocytes or when treated with monocyte-conditioned media. Addition of macrophage colony stimulating factor (
1000
U/mL) to cocultures of monocytes and SMCs did not affect
metalloproteinase secretion. Recombinant interleukin (IL)-1 receptor
antagonist inhibited MMP-1 and MMP-3 induction in SMC
cultures treated with monocyte-conditioned media (94% and 96%
reduction, respectively), while a neutralizing antibody to tumor
necrosis factor-
had no significant effect on metalloproteinase
secretion. In contrast to the induction by monocyte-conditioned
media of MMP-1 and MMP-3 secretion by SMCs, monocyte-conditioned
media did not increase secretion of 72-kD gelatinase (MMP-2). Thus,
monocytes induce MMP-1 and MMP-3 secretion by vascular SMCs through an
IL-1–dependent mechanism. This response of SMCs to a defined
macrophage product may contribute to plaque destabilization
by mononuclear phagocytes in the lesion.
Key Words: monocytes • vascular smooth muscle cells • metalloproteinases • plaque rupture
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Mechanical factors that contribute to atherosclerotic plaque rupture include the imposed hemodynamic stresses,1 2 stress concentrations that result from plaque composition and geometry,3 4 5 and mechanical properties of the fibrous-cap tissue.6 7 Extracellular matrix molecules are primarily responsible for maintaining the mechanical integrity of the fibrous cap. These matrix components may be degraded by matrix metalloproteinases such as MMP-1 and MMP-3, which can be produced by SMCs8 9 as well as by macrophages.9 10 11 A local excess of these metalloproteinases in a fibrous cap could lead to weakening of the extracellular matrix, rendering the plaque more likely to rupture. Recent studies have demonstrated that greater densities of macrophages appear at rupture-prone sites in plaques12 13 and correlate with weaker fibrous cap tissue,14 and increased metalloproteinase activity colocalizes with macrophages in the vulnerable shoulder region of plaques.15 Thus, macrophages may play an important role in promoting matrix degradation that leads to rupture.
While macrophages are potentially a major source of
metalloproteinases in a plaque, metalloproteinase overexpression by
SMCs may also be important. Cytokines such as IL-1 and TNF-
can stimulate secretion of metalloproteinases by SMCs,16
and monocyte-derived macrophages in atherosclerotic lesions
can produce these cytokines.17 18 Thus,
macrophages might, through the release of cytokines,
increase the secretion of metalloproteinases by neighboring SMCs by a
paracrine pathway. The present study examined the role of
interactions between SMCs and monocytes in metalloproteinase synthesis.
The results demonstrate that cultured human vascular SMCs can increase
MMP-1 and MMP-3 secretion in response to non–cell-contact
stimulation by human monocytes via an IL-1–dependent pathway.
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Methods |
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Culture of Smooth Muscle Cells
Medial-layer explants were cultured from unused portions of human saphenous veins from coronary bypass surgery. The culture medium was DMEM (BioWhittaker) with 10% fetal calf serum (Hyclone), 25 mmol/L HEPES, 100 U/mL penicillin, 100 µg/mL streptomycin, 1.25 µg/mL amphotericin B, and 2 mmol/L-glutamine. This medium is selective for SMCs over endothelial cells.19 SMCs from the explants were grown in tissue-culture flasks (Corning). The cells were cultured in monolayer for three to six passages before use in experiments.
Experiments were performed with SMCs in monolayers or in
three-dimensional collagen gels containing similar numbers of
cells. To establish collagen-gel cultures, the SMCs were
transferred from monolayers to collagen gels in plastic 24-well
(16-mm-diameter) culture plates (Costar). In each well, 250 000 to
300 000 cells were suspended in a volume of 1.25 mL with 2.8 mg of
Vitrogen 100 bovine dermal collagen (Celtrix) at neutral pH. After 2
hours of gelation in a 37°C incubator, the gel cultures were gently
detached from the plastic with a fine metal spatula, and 1 mL of
culture medium was added to each well. The culture medium for the gel
cultures was the same as for the monolayer cultures in flasks, with the
addition of 0.07 mmol/L ascorbate-2-phosphate (Wako Pure Chemical
Industries), 0.1 mmol/L nonessential amino acids (Sigma), and 0.75
mmol/L sodium sulfate. The medium was changed three times a week. Over
the course of a 2-week culture in a humid, 37°C, 5% CO2
incubator, the gel cultures contracted to a diameter of 4.5 to 5.0 mm
and a thickness of 
1.5 mm. After 11 or 12 days of culture, serum was
removed from the gel cultures by washing six times for 10 minutes with
1 mL of serum-free "IT medium" (equal volumes of DMEM and
Ham's F-12 medium [BioWhittaker], with 12.5 mmol/L HEPES, 100 U/mL
penicillin, 100 µg/mL streptomycin, 1.25 µg/mL amphotericin B, 1.5
mmol/L -glutamine, 0.07 mmol/L ascorbate-2-phosphate, 0.1
mmol/L nonessential amino acids, 0.75 mmol/L sodium sulfate, 1 µmol/L
insulin [Collaborative Research], and 5 µg/mL transferrin
[Collaborative Research]). After the last wash, 1 mL of IT medium was
added to each well. The IT medium was changed after 2 more days. One
day later, the gel cultures were washed an additional 12 times with IT
medium. After the last wash, 1 mL of IT medium was added to each well.
Experimental treatment of the cultures began the following day.
Monocyte Preparation
Human monocytes were isolated from the
peripheral blood of healthy donors undergoing
plateletpheresis procedures. Each experiment was repeated with
cells from at least two different donors. The leukocyte pack was
layered over Histopaque 1077 (Sigma), diluted with RPMI (RPMI-1640
medium [BioWhittaker] containing 10% fetal calf serum, 100 U/mL
penicillin, 100 µg/mL streptomycin, 1.25 µg/mL amphotericin B, and
1.5 mmol/L -glutamine), and centrifuged at
1200g at room temperature. The mononuclear cell layer above
the Histopaque was collected and pelleted with RPMI, decanted, and
dispersed in 12 to 18 mL of RPMI. Aliquots of 1 mL were placed in 12 to
18 150-cm2 polystyrene flasks containing 19 mL of RPMI. The
flasks were incubated for 2 hours (37°C, 5% CO2) to
allow monocytes to adhere. Nonadherent lymphocytes were then removed,
and the flasks were washed three times with 15 mL of Dulbecco's PBS
(GIBCO). After a wash with 5 mL of Hanks' balanced salt solution
without calcium or magnesium (GIBCO), 4 mL of 0.25% trypsin and EDTA
were added to each flask, followed by 15 minutes of incubation.
Monocytes were then harvested with a cell scraper. Flasks were washed
with RPMI, and the washes were pooled with the monocytes, which were
then pelleted, decanted, and washed two times with IT medium to remove
serum. Isolated cells were identified as 90% to 95% monocytes by
Wright's staining.
Conditioning of Media
Each aliquot of SMC-conditioned medium was prepared by
incubating 1 mL of IT medium with an SMC-collagen–gel culture for
24 hours. Monocyte-conditioned medium was prepared by placing
105 freshly trypsin-harvested monocytes in plastic
tissue-culture wells. In some experiments, a film of Vitrogen 100
bovine dermal collagen was cast onto the bottom of the wells before
monocytes were added. One milliliter of IT medium containing 1000 U/mL
of M-CSF (Genetics Institute) was incubated with the cells for 24
hours. All conditioned media were filtered in 0.2-µm Spin-X tubes
(Costar).
Experimental Treatment of Cells
The media in SMC-collagen–gel culture wells were
replaced with media conditioned by SMCs or monocytes. The desired
combination of recombinant human cytokines,
antagonists, and neutralizing antibodies was added to the
conditioned media. These included IL-1ra (Synergen), anti-TNF (R&D
Systems), IL-1ß (Genzyme), and TNF- (Genzyme). M-CSF was added to
wells containing SMC-conditioned media for a final concentration of
1000 U/mL (concentrations of 0 to 1000 U/mL were used in
dose-response experiments). Freshly harvested monocytes were added
in a small volume to some of these wells (105 per well).
Polymyxin B sulfate (Sigma), an inhibitor of endotoxin, was
added to some of the wells containing monocyte-conditioned media.
The media were collected after 3 days of incubation.
Some monocytes were treated with SMC-conditioned media. In these experiments, 105 freshly harvested monocytes in a small volume were placed in a well with an aliquot of SMC-conditioned medium and 1000 U/mL of M-CSF. Control wells of 105 monocytes were treated with IT medium containing 1000 U/mL of M-CSF. After 3 days of incubation, the media were collected and filtered through 0.2-µm Spin-X tubes.
Western Blot Analysis of Metalloproteinases
Samples underwent electrophoresis (20 µL of medium
per lane) on sodium dodecyl sulfate/10% polyacrylamide
mini-gels under reducing conditions (SDS-PAGE). The proteins were
transferred to nitrocellulose membranes (Bio-Rad), and an enhanced
chemiluminescence detection system (Amersham) was used to detect MMP-1
or MMP-3. A 5% solution of defatted dried milk in PBS containing 0.1%
Tween 20 was used to block nonspecific binding and to dilute the
primary and secondary antibodies. The primary antibodies were rabbit
anti-human MMP-1 and rabbit anti-human MMP-3, prepared as
previously described.20 The secondary antibody was goat
anti-rabbit IgG conjugated with horseradish peroxidase
(Bio-Rad).
Zymography of Gelatinolytic
Proteins
Samples (45 µL of medium per lane) underwent SDS-PAGE in
10% polyacrylamide gels containing 1 mg/mL
gelatin.21 SDS was then removed from gels in two washes
with 2.5% Triton X-100 (Sigma). After the washes, gels were incubated
overnight at 37°C with gentle shaking in 50 mmol/L Tris, 10 mmol/L
CaCl2, and 0.05% Brij 35 (Sigma), pH 7.3. Gels were
then stained with Coomassie brilliant blue R-250 (Sigma).
Data Analysis
Western blots and zymograms were scanned and relative
intensity of bands was determined with OPTIMAS 4.1 image
analysis software (Optimas Corporation). Each treatment on
cultures of SMCs or monocytes was performed at least twice in
independent experiments, and representative results are
shown.
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Results |
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Effect of Monocytes on MMP-1 and MMP-3 Secretion by SMCs
Little or no MMP-1 or MMP-3 was detected in media from 1-day (conditioned media) or 3-day cultures of SMCs alone (Fig 1
, lanes 4 and 1, respectively). No MMP-1 or MMP-3 was
detected in media from 1-day or 3-day cultures of monocytes alone
(lanes 7 and 3, respectively). Increasing the cell number 10-fold to
106 per well did not induce detectable amounts of
these metalloproteinases in monocyte-conditioned media (lane 8). In
contrast, cocultures of SMCs with monocytes consistently
contained markedly increased MMP-1 and MMP-3 levels compared with
controls, as determined by Western blot analysis of the culture
media (lane 2). These metalloproteinases were present in proenzyme,
partially activated, and fully activated forms; the
extent of activation varied among experiments using SMCs and monocytes
from different sources.
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These results indicated an interaction between SMCs and monocytes, leading to increased metalloproteinase synthesis. To determine whether cell contact was required between monocytes and SMCs, monocytes were cocultured on a porous membrane over SMC monolayers. MMP-1 and MMP-3 levels were elevated in cocultures without cell-cell contact compared with cultures of either cell type alone (data not shown).
We next used conditioned media to investigate the possible role of
soluble mediators and the cellular source of MMP-1 and MMP-3 in
SMC-monocyte cocultures (Fig 1
). SMCs treated with
monocyte-conditioned media (Fig 1, lane 6) increased their
secretion of MMP-1 and MMP-3 more than 20-fold compared with control
(lane 1), as determined by scanning densitometry of Western blots.
Polymyxin B did not block this effect (not shown), suggesting that
metalloproteinase induction was not caused by endotoxin contamination.
Monocytes treated with SMC-conditioned media produced no more MMP-1 or
MMP-3 than was already present in the SMC-conditioned media (lane
5). Thus, a soluble mediator secreted by monocytes could stimulate
MMP-1 and MMP-3 secretion by SMCs, but SMCs did not secrete a soluble
mediator that could induce secretion of these proteases by
monocytes.
The substrate on which the monocytes were cultured, either bare plastic or collagen films, did not affect their ability to produce MMP-1 or MMP-3 or their ability to induce SMCs to secrete metalloproteinases. We also compared monocyte interactions with SMCs cultured on different substrates, either on plastic in monolayer cultures or in three-dimensional collagen-gel cultures, finding similar results in both configurations (data not shown).
Effects of Cytokine Inhibitors on Induction of
Metalloproteinase Secretion
To identify the potential soluble mediators inducing SMC
metalloproteinases, IL-1ra or anti-TNF was added to cocultures and to
SMC cultures treated with monocyte-conditioned media (Fig 2). Scanning densitometry of Western blots of culture
media showed that IL-1ra at a concentration of 10 µg/mL (lane 4
versus lane 2) blocked 94% of the MMP-1 and 96% of MMP-3 secretion
that was induced by monocyte-conditioned media. Induction by
monocyte coculture with SMCs was inhibited by a similar amount (lane 3
versus lane 1). Anti-TNF at a concentration of 10 µg/mL did not
decrease the levels of these induced metalloproteinases (lanes 5 and
6).
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Control experiments on SMC-collagen–gel cultures treated with
SMC-conditioned media showed that IL-1ra alone did not affect MMP-1 and
MMP-3 levels, while anti-TNF alone increased these levels slightly (Fig 2). Positive controls showed that 10 ng/mL IL-1ß increased MMP-1 and
MMP-3 levels more than 20-fold (lane 9), an effect that was blocked
100% and 99%, respectively, by 10 µg/mL IL-1ra (lane 10).
Similarly, 10 µg/mL anti-TNF blocked 96% of the MMP-1 secretion
induced by 10 ng/mL TNF- in SMC cultures treated with
SMC-conditioned media. In this experiment, TNF- did not induce
significant secretion of MMP-3 (lane 12), while monocytes markedly
increased MMP-3 secretion (lane 1).
Effect of M-CSF on Monocyte-Induced
Secretion of MMP-1 and MMP-3
To determine whether M-CSF was responsible for
monocyte-induced metalloproteinase secretion, SMCs were cocultured
with monocytes in the presence of 0 to 1000 U/mL of M-CSF. This
hematopoietic growth factor did not affect the total quantity or level
of activation of monocyte-induced MMP-1 (Fig 3), as
determined by Western blot analysis. M-CSF also had no apparent
effect on monocyte-induced MMP-3 (not shown).
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Effect of Monocytes on Gelatinase Secretion by SMCs
Gelatin zymography of culture media (Fig 4)
indicated that SMCs in collagen-gel cultures constitutively
secreted 72-kD gelatinase (MMP-2), appearing mostly in the
activated form (67 kD). Monocytes alone did not secrete
detectable quantities of MMP-2. Treatment of SMCs with monocytes or
monocyte-conditioned medium did not affect the quantity or
activation of MMP-2 but induced the appearance of
gelatinolytic bands at molecular weights
corresponding to forms of MMP-1. Monocyte-induced secretion of
MMP-9 by SMCs, as detected by gelatinolytic bands
corresponding to a 94-kD enzyme, was not observed. In some experiments,
media conditioned by SMCs induced MMP-9 secretion by monocytes.
However, unlike the induction of SMC MMP-1 and MMP-3 by monocytes, this
effect was inconsistent in four independent experiments,
and these data are not presented.
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Discussion |
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Atherosclerotic plaque rupture is the immediate cause of most fatal myocardial infarctions.22 Several recent studies of processes that may lead to this acute event have implicated macrophages as a potential critical cell in compromising the integrity of the extracellular matrix in a plaque.15 23 24 Vascular SMCs and macrophages are both capable of metalloproteinase secretion, so that both cell types may participate in matrix degradation. This study investigated the possible role of macrophage-stimulated SMCs as a source of metalloproteinases. Our results indicate that monocytes can stimulate secretion of MMP-1 and MMP-3 by SMCs through signaling pathways that do not require cell contact and are inhibited almost completely by an antagonist of IL-1. TNF-
did not appear to play a
critical role in this interaction. The simplest interpretation of the data would be that monocytes release IL-1, which directly stimulates SMCs to secrete metalloproteinases. Macrophage-rich foam-cell lesions show an enhanced capacity to produce IL-1 in experimental models, and metalloproteinases have been identified in human atheroma SMCs in regions of high macrophage density.15 25 26 Our observations, however, do not exclude more complex pathways. For example, the effects of monocyte-derived IL-1 or other cytokines may be amplified by inducing autocrine secretion of IL-1 or other cytokines, such as IL-6, by SMCs.27 28 29
Monocytes and macrophages in various states of differentiation and activation have been demonstrated to produce metalloproteinases.10 11 24 In particular, macrophages within atherosclerotic plaques have been associated with metalloproteinase secretion.9 15 23 In contrast, under the experimental conditions and cell numbers of the present study, monocytes did not secrete detectable quantities of MMP-1 or MMP-3; yet under the same conditions, they stimulated significant increases in MMP-1 and MMP-3 secretion by SMCs. In similar experiments in our laboratory with cultured monocyte-derived macrophages instead of monocytes, macrophages also did not secrete detectable quantities of these metalloproteinases but stimulated their production by SMCs (data not shown). Secretion of metalloproteinases by macrophages may require an activated state, as exhibited by foam cells in atherosclerotic plaques.24
We hypothesized that M-CSF might play a role in the monocyte-SMC interactions. M-CSF, a factor required by monocytes for survival,30 31 is produced by vascular endothelial cells and SMCs in vitro and has been detected in atheromatous plaques in humans and experimental animals.32 M-CSF stimulates differentiation of monocytes to macrophages,31 activates or enhances monocyte and macrophage functions such as phagocytosis of tumor cells,33 and induces IL-1 production by macrophages.34 Although elimination of exogenous M-CSF from the culture media did not decrease the secretion of MMP-1 and MMP-3 in cocultures of monocytes with SMCs, the possible role of M-CSF has not been excluded; M-CSF may have been present in the cultures because of production by monocytes.35
An increase in metalloproteinase synthesis does not necessarily lead to
matrix degradation, because the metalloproteinases are secreted in
zymogen form and require activation. In the present study, the
degree of activation of MMP-1 and MMP-3 varied from no activation to
complete activation among repeated experiments using different sources
of SMCs and using the same or different donors of monocytes (eg, Fig 3). Activation also varied among experiments using monocytes donated on
different days by the same individual. Metalloproteinase activation
also appeared to depend on the culture configuration of the SMCs. In
experiments comparing similar numbers of SMCs in collagen gel cultures
versus monolayer cultures, monocytes induced the activation of more
MMP-1 and MMP-3 in gel cultures than in monolayers (data not shown).
Mechanisms of metalloproteinase activation are thought to involve
plasmin-dependent and plasmin-independent pathways, including
autolytic reactions,36 37 but regulation of these
processes is incompletely understood.
Even an increase in levels of activated metalloproteinases may not result in matrix degradation if TIMPs are also upregulated. Western blot analysis of culture media from multiple experiments did not reveal a consistent effect of monocytes or monocyte-conditioned media on TIMP-1 secretion by SMCs; TIMP-1 levels were at times modestly increased or decreased compared with controls. At no time did we observe changes in TIMP-1 levels of the dramatic magnitude seen in the studies of MMP-1 and MMP-3. Furthermore, increased matrix degradation may not lead to matrix weakening if synthesis rates of matrix molecules also increase. Effects of monocytes on matrix-degrading activity and on matrix synthesis were not examined in the present study.
Davies and coworkers12 found that the ratio of macrophages to SMCs was higher in ruptured plaques than in intact plaques. It is possible, therefore, that progressive increases in macrophage density near SMCs in the plaque may tip the balance of extracellular matrix regulation by SMCs toward increased degradation. Our studies indicate the possible importance of local cell-cell interactions and paracrine signaling in the regulation of SMC functions that may critically regulate plaque stability.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Elaine Lee is supported by a Department of Defense National Science and Engineering Graduate fellowship. This work was supported by a grant-in-aid from the American Heart Association (Massachusetts Affiliate) and grant HL34636 from the National Heart, Lung, and Blood Institute. The authors thank William Briggs for excellent technical assistance.
Received August 3, 1995; accepted September 27, 1995.
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