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1- induced proliferation of vascular smooth
muscle cells
Sealy Center for Molecular Cardiology, University of Texas Medical Branch, Galveston, Texas 77555
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Transforming
growth factor (TGF)-
1 has been implicated in vascular healing
responses after mechanical injury. Using cultured rat aortic smooth
muscle cells (RASMC), we examined the hypothesis that production and
secretion of thrombospondin (TSP) contributes to TGF-1-induced
proliferation. We found that TGF-1 enhanced production and secretion
of TSP, with peak levels of secreted TSP observed 24 h after
treatment. RASMC treated with TGF-1 secreted a mitogenic activity
that was transferable in conditioned media and partially inhibited by
C6.7, a monoclonal anti-TSP antibody. Exogenous TSP stimulated a
proliferative response, with maximal [3H]thymidine
incorporation occurring 24 h earlier than maximal [3H]thymidine incorporation in response to
TGF-1-treatment. Pretreatment with C6.7 or polyclonal anti-TSP
neutralizing antibodies inhibited TGF-1-induced proliferation of
RASMC. Proliferative responses to TGF-1 were also inhibited by
pretreatment with an anti-3 integrin monoclonal blocking
antibody (F11), RGD peptides, and the
anti-
v3 disintegrin echistatin. Treatment
with TSP and TGF-1 increased c-Jun NH2-terminal kinase
(JNK)1 activity, with peak effects observed at 15 min and 4 h,
respectively. Treatment with C6.7 or F11 inhibited TGF--induced
activation of JNK1. In summary, these studies support the hypothesis
that TGF--induced JNK1 activation and proliferation of RASMC require
secretion of TSP and ligation of
v3-integrins.
transforming growth factor; receptors; vitronectin; extracellular matrix; angioplasty
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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TRANSFORMING
GROWTH FACTOR (TGF)-1 has been implicated in mediating
vascular repair after rat carotid artery injury. In this model of
angioplasty, TGF-1 mRNA increased early after balloon injury and
remained elevated for at least 2 wk (20, 33). Expression of TGF- type I receptors activin receptor-like kinase
(ALK)-5 and ALK-2 and type II receptor also increased after injury
(33). To delineate the functional importance of TGF-1,
early studies infused purified, recombinant TGF-1 into rats with a
preexisting neointima and found a significant increase in neointimal
smooth muscle cell (SMC) DNA synthesis. More recent studies inhibited TGF-1 effects and found that treatment with a neutralizing
anti-TGF- antibody (34) or recombinant soluble type II
TGF- receptor (30) significantly reduced the amount of
neointima that formed after injury.
TGF-1 has multiple and diverse effects on cultured SMC, including
the ability to profoundly inhibit or markedly stimulate proliferation.
We have been interested in the mechanisms by which TGF-1 stimulates
proliferation. In previous work, we (32) and others
(4, 18) found that proliferative responses to TGF-1 were partially mediated by autocrine production of platelet-derived growth factor (PDGF)-AA. We also found presumptive evidence that other
secondary factors were involved: 1) potent anti-PDGF-AA neutralizing antibodies inhibited only 10-40% of proliferative responses to TGF-1, 2) anti-PDGF-AA neutralizing
antibodies inhibited only 25% of the mitogenic activity in conditioned
media from TGF-1-treated SMC, and 3) TGF-1 stimulated
a proliferative response in a primary rat SMC line that did not express
PDGF- receptors and did not respond mitogenically to exogenous
PDGF-AA (32).
Thrombospondin-1 (TSP) is a multifunctional glycoprotein that has been
implicated in a variety of biological processes including vascular
repair and SMC proliferation. TSP is produced at high levels by SMC in
the vessel wall after vascular injury (22), and anti-TSP
antibodies reduced neointimal formation after rat carotid artery injury
(6). Majack et al. (17) showed that autocrine
TSP was functionally essential for SMC to proliferate in response to
serum, and subsequent studies (26, 31) showed that
exogenous TSP was a mitogen for human SMC. Because TSP is produced by
SMC in response to TGF-1 treatment (15, 18), we sought
to test the hypothesis that autocrine production of TSP plays an
essential role in proliferative responses of rat aortic SMC (RASMC) to
TGF-1.
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EXPERIMENTAL PROCEDURES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Reagents.
Reagents were obtained from various sources: recombinant TGF-1,
PDGF-AA, PDGF-BB, and TGF- neutralizing antibody (R&D Systems, Minneapolis, MN); TSP cDNA (American Type Culture Collection, Rockville, MD); rabbit anti-human TSP antiserum (Celsus Laboratories, Cincinnati, OH); F11 (PharminGen, San Diego, CA); A4.1, C6.7, AB-11,
and MBC200 (NeoMarkers, Freemont, CA); 10E5 (Dr. Marian Nakada,
Centocor, Malvern, PA); Gly-Arg-Gly-Asp-Ser (GRGDS),
Gly-Arg-Gly-Glu-Ser (GRGES), and Gly-Arg-Asp-Gly-Ser (GRDGS)
(GIBCO-BRL); and echistatin (Sigma). TSP was purified from recently
outdated human platelets using the method of Santoro and Frazier
(29) with minor modifications (31).
SMC culture, growth assays, Northern blotting, Western analysis, and c-Jun NH2-terminal kinase-1 assay. SMC from aortas of Sprague-Dawley rats were cultured, and [3H]thymidine incorporation and proliferation assays were performed as previously described (32). Immunoprecipitation and Western blotting were performed as previously described (28). Immunocomplex kinase assay for c-Jun NH2-terminal kinase (JNK)1 activity was performed as described by Rao and Runge (27).
Quantification of TSP levels in conditioned media.
RASMC were grown to confluence, growth arrested, and treated with
TGF-1 or vehicle. At the indicated time points, the medium was
carefully aspirated, and total protein concentration among the samples
was equalized. The samples were immunoprecipitated overnight with 1 µl of C6.7 antibody/sample at 4°C. Immune complexes were captured
by 1 h of incubation with protein A-G agarose (Pierce) at 4°C.
The samples were washed three times with isotonic saline, and the
immunocomplexes were eluted by boiling for 5 min in sample loading
buffer. The samples were separated on a 7.5% SDS-polyacrylamide gel
and transferred to nitrocellulose by electroblotting. Detection was done with anti-TSP antibody Ab-11 by use of the Supersignal chemiluminescence kit (Pierce).
Cell adhesion assay. RASMC were grown to confluence, growth arrested, and then exposed to antibodies for 72 h. The medium was aspirated, and PBS containing 0.5% crystal violet and 20% methanol was added. After incubation for 30 min at room temperature, the cells were washed three times in PBS and solubilized in 1% SDS. Cell binding was quantified by measuring absorbance at 540 nm in a Bio Kinetics model EL 340 plate reader.
Statistical analysis.
Results are presented as means ± SD. The data were analyzed by
ANOVA followed by the Newman-Keuls multiple-range test. P
value 
0.05 was considered statistically significant. Each
experiment was performed a minimum of three times.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Neutralizing antibodies to TSP block TGF-1- induced
proliferation of cultured RASMC.
A primary RASMC line that does not respond to PDGF-AA (32)
was used to enhance our ability to identify other secondary factors involved in responses to TGF-1.
1 (2.5 ng/ml) stimulated a proliferative response,
with cell number increasing 147 ± 11% (range 80-230%, n = 8) compared with vehicle-treated control. A
polyclonal neutralizing antiserum to TSP obtained by solid-phase
adsorption of serum from a pool of rabbits immunized with purified TSP
from human platelets inhibited 90% of the proliferative response to
TGF-1 (Fig. 1A). IgG from nonimmunized rabbits had no effect.
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1-induced proliferation (Fig. 1A). This concentration of C6.7 did not cause cell
detachment visible by light microscopy or detectable by cell adhesion
assays (Fig. 1B). Proliferative responses to TGF-1 were
not inhibited by monoclonal anti-TSP antibodies A4.1 or MBC200 (Fig.
1A). A4.1 recognizes an epitope in the
NH2-terminal one-half of the central stalklike region of
TSP and did not have an inhibitory effect on proliferative responses to
TGF-1, even at concentrations twice as high as that which blocked
50% of the proliferative response to serum (17). MBC200
recognizes an epitope in the heparin-binding domain of TSP and also did
not have an inhibitory effect. A monoclonal antibody against
IIb3-integrins (10E5), used as a control,
had no effect on TGF-1-induced proliferation.
Mitogenic activity in conditioned media from TGF-1-treated SMC
was inhibited by anti-TSP antibody.
TSP mRNA increased within 4 h and continued to increase for
24 h after exposure to TGF-1 (Fig.
2). To quantify the amount of secreted
TSP, RASMC were treated with vehicle or TGF-1, conditioned medium
was harvested, protein concentrations were equalized, and immunoprecipitation was performed with C6.7. This was followed by
Western analysis with anti-TSP antibody Ab-11. Levels of TSP in
conditioned medium were elevated 4 h after treatment with
TGF-1, peaked 24 h after treatment, and returned to baseline at
36 h (Fig. 3).
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1 secrete a mitogenic activity that is
transferable in conditioned medium (32). To determine
whether autocrine TSP contributed to this mitogenic activity, we
treated RASMC with TGF-1 or vehicle for 24 h and then removed
the conditioned medium. Anti-TGF- antibodies were added to
neutralize exogenous TGF-1, and the medium was transferred to
naïve, growth-arrested RASMC. We found that conditioned medium
from TGF-1-treated SMC stimulated a mitogenic response (as
determined by [3H]thymidine incorporation) that was 360%
of that observed with conditioned medium from vehicle-treated SMC (Fig.
4). Consistent with the hypothesis that
autocrine TSP was contributing to the mitogenic activity in conditioned
medium from TGF-1-treated SMC, we found that the mitogenic activity
in conditioned medium was partially inhibited by C6.7. Moreover,
exogenous TSP elicited a mitogenic response in cells treated with
conditioned medium from vehicle-treated, but not TGF-1-treated, SMC
(Fig. 4), demonstrating that the concentration of autocrine TSP in
conditioned medium from TGF-1-treated SMC was sufficiently high that
exogenous TSP was unable to stimulate an additive mitogenic effect.
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TSP stimulates [3H]thymidine incorporation by, and
proliferation of, RASMC.
By examining discrete 24-h windows of [3H]thymidine
incorporation, we previously found that maximal DNA synthesis in
response to TGF-1 occurs 48-72 h after treatment
(32). To determine the kinetics of mitogenic responses to
TSP, we examined DNA synthesis and cell proliferation in response to
treatment with TSP isolated from platelets. To exclude the possibility
that proliferative effects observed with platelet-derived TSP were due
to contamination by TGF-1, we used TSP preparations in which levels
of activated TGF-1 were <0.15 ng/ml. At this concentration,
TGF-1 has no effect on [3H]thymidine incorporation by,
or proliferation of, RASMC (32).
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TGF-1-induced proliferation of RASMC was inhibited by
v3-integrin antagonists.
TSP interacts with many cell surface proteins (reviewed in Ref.
23) including v3-integrins.
Because proliferative responses of human SMC to TSP were inhibited by
pretreatment with an anti-3 integrin monoclonal antibody
(31), we examined the effects of v3-integrin antagonists on
TGF-1-induced proliferation. F11 is a monoclonal
anti-3 integrin antibody active against rat proteins that blocks 3-integrin-mediated adherence of rat
osteoclasts to osteopontin, vitronectin, and fibronectin
(12) and inhibits osteopontin-induced migration of rat SMC
(35). We found that pretreatment with F11 inhibited
~60% of the proliferative response to TGF-1, whereas 10E5 had no
effect (Fig. 6). F11 had no effect on
cell adhesion (Fig. 1B).
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v3-integrins on
SMC with high specificity and has function-blocking activity
(16). Echistatin (100 nM), when added 1 h before
TGF-1, completely inhibited TGF-1-induced proliferation.
Pretreatment with RGD-containing peptides inhibited ~65% of the
proliferative response to TGF-1 (Fig. 6). Closely related peptides
in which one amino acid had been changed [i.e., RDG (Arg-Gly-Glu) and
RAD (Arg-Ala-Asp)] had no effect.
Autocrine TSP is necessary for TGF--induced activation of JNK1.
JNK1 is a member of the mitogen-activated protein (MAP) kinase
superfamily that is necessary for progression through G1
(24). Using an in vitro immunocomplex kinase assay with
glutathione S-transferase-c-jun as the
substrate, we found that JNK1 activity increased rapidly and
transiently after treatment with TSP (Fig. 7, A and B). Peak
effects were observed 15 min after TSP treatment, at which point JNK1
activity in TSP-treated SMC was 2.5-fold greater than in
vehicle-treated SMC. TSP-induced effects on JNK1 activation were
transient, with a return to baseline levels by 60 min.
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1 stimulated JNK1 activity but with a time course that was
delayed relative to TSP. Peak effects were observed 4 h after treatment (Fig. 7, C and D), with a return to
baseline within 8 h. C6.7, added 1 h before treatment with
TGF-1, blocked 70% of TGF-1-induced JNK1 activation as measured
at 4 h (Fig. 7, E and F). Pretreatment with
F11 inhibited TGF-1-induced JNK1 activation by 80%, whereas 10E5
had no effect.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Autocrine production of TSP was necessary for maximal
proliferative responses of RASMC to TGF-1. This conclusion is based on findings that 1) TGF-1-induced proliferation was
inhibited by anti-TSP antibodies, 2) levels of TSP protein
in conditioned media increased after treatment with TGF-1,
3) mitogenic activity in conditioned media from
TGF-1-treated SMC was partially inhibited by an anti-TSP antibody,
and 4) maximal mitogenic response to exogenous TSP occurred
~24 h earlier than maximal responses to TGF-1. These results,
together with prior studies (4, 18, 32), demonstrate that
autocrine PDGF-AA and autocrine TSP contribute to growth responses of
RASMC to TGF-1.
TGF-1 stimulated production and secretion of TSP, with peak
secretion of TSP occurring at 24 h. This time course is similar to
that reported by Majack et al. (18) and Janat and Liau
(15) in rat and rabbit SMC, respectively. In their
studies, Majack et al. (19) found that recombinant PDGF-AA
stimulated the production and secretion of TSP and that
TGF-1-induced expression of TSP was inhibited by cycloheximide. On
the basis of these findings, they postulated that TSP production in
response to TGF-1 required secretion of PDGF-AA (18).
Because the SMC used in the present studies were unresponsive to
PDGF-AA, our data demonstrate that cell lines exist in which autocrine
PDGF-AA is not a necessary intermediary for TGF-1-induced production
of TSP.
Proliferative responses to TGF-1 were inhibited by an
anti-3 integrin antibody, RGD peptides, and echistatin.
These results, together with prior studies showing that
TGF-1-treatment enhanced SMC expression of
3-integrins (5, 14) and that migratory responses of SMC to TGF-1 were inhibited by
anti-v3 integrin antibodies and RGD
peptides (5), strongly implicate
3-integrins in regulating SMC responses to TGF-1.
3-Integrins are highly expressed by SMC at sites of
vascular injury and mediate SMC proliferative responses to TSP and
-thrombin (31) as well as TGF-1.
Our findings that v3-integrin antagonists
and anti-TSP antibodies block TGF-1-induced proliferation are
suggestive that TSP interactions with
v3-integrins are necessary for RASMC
growth responses to TGF-1. Our results are similar to those of
Claisse et al. (8), who reported that TGF-1 stimulated
TSP production, that TSP mimicked the effects of TGF-1, and that
TGF-1 effects were inhibited by anti-TSP antibodies and
v3-integrin antagonists in thyroid
follicle cells. Definitive conclusions cannot be made, however, as SMC
secrete multiple other factors that bind
v3-integrins and express other
TSP-binding cell surface receptors.
TSP elicits a complex array of signals in SMC that influence cell cycle
events, including activation of extracellular signal-regulated kinase
(ERK)1/2 (11), tyrosine phosphorylation of focal adhesion kinase (FAK) (28), and activation of JNK1 (present
studies). Chen et al. (7) demonstrated that anti-TSP
antibody inhibited the activity of cyclin-dependent kinase-2 (cdk2) and
blocked S phase entry in serum-stimulated SMC. We recently showed that
heteromeric protein complexes involving
v3-integrins and FAK form after treatment
of human SMC with TSP (28); this mechanism could
potentially link TGF-1 and
v3-integrins. Further studies are needed
to determine the functional importance of these complexes and whether they directly mediate JNK1 activation, as has been observed in other
systems (24).
JNK1 is the prototypical member of the MAP kinase superfamily of JNKs
that modulate gene expression by translocating to the nucleus and
phosphorylating and activating the transcription factors c-Jun/activating protein (AP)-1 and activating transcription
factor (ATF)2 (13). AP-1, in turn, plays an important role
in c-jun transcription and cell proliferation and
differentiation. The time course of TGF-1-induced JNK1 activation in
RASMC was similar to that observed in hepatoma (HepG2) cells
(3), Madin-Darby canine kidney cells (2), and
293 cells (36), as the peak effect was observed 4 or more
hours after treatment. TGF-1-induced activation of JNK1 was delayed
relative to TSP and partially inhibited by C6.7, implicating autocrine
TSP in mediating JNK1 activation. The differing time courses of JNK1
activation (peak effect at 4 h) and TSP production (peak effect at
24 h) after TGF-1 treatment argue that mediators other than TSP
contribute to JNK1 activation and also that TSP has effects independent
of JNK1 activation. Our finding that TGF-1-induced JNK1 activation
was inhibited by F11 is consistent with recent studies
(24) that found integrin activation necessary for JNK1 activation.
TSP is a physiological activator of TGF-1 (9), and one
of the many functions of autocrine TSP may be to activate TGF-1. We
do not, however, believe that activation of TGF-1 by TSP is influencing our results for the following reasons: 1) we
used recombinant, activated TGF-1 at saturating concentrations (100 pM); 2) levels of latent TGF-1 secreted into the media by
quiescent RASMC (as measured using a commercially available ELISA
technique) were ~1% (1 pM) of the concentration of TGF-1 used in
these experiments; and 3) addition of 100 pM of recombinant
TGF-1 every day elicited the same mitogenic response as did a
one-time treatment with TGF-1 (25.3 ± 9.4-fold increase vs.
28.2 ± 6.5-fold increase in [3H]thymidine
incorporation, n = 3; P = not significant).
Studies in cultured cells have provided conflicting data regarding the
effects of TGF-1 on SMC proliferation. Several laboratories (1, 25) have demonstrated that TGF-1 can inhibit
proliferative responses of growth factor- or serum-stimulated SMC,
whereas other investigations (4, 18, 32) using different
primary lines of SMC have shown that TGF-1 stimulates proliferation.
Various etiologies have been suggested to explain differential SMC
growth responses to TGF-1, including cell-matrix interactions,
differential expression of TGF- receptors, and age-related changes.
McCaffrey et al. (21) recently reported that the
response of SMC to TGF-1 was determined by levels of type II TGF-
receptors. In particular, they found that TGF-1 inhibited growth
responses of normal human SMC but stimulated growth responses of cells
grown from human vascular lesions. Levels of the type II TGF-
receptor were decreased in lesion cells, and transfection of type II
receptors into these cells restored the growth inhibitory activity of
TGF-1.
In summary, results of the present studies demonstrate that levels of
soluble TSP were increased after treatment of quiescent SMC with
TGF-1, that endogenous and exogenous TSP stimulated mitogenesis of
RASMC, and that neutralizing antibodies to TSP inhibited
TGF-1-induced proliferation and JNK1 activation. Furthermore, v3-integrin antagonists also inhibited
TGF-1-induced proliferation and JNK1 activation. Our results support
the hypothesis that ligation of
v3-integrins by autocrine TSP plays an
important role in SMC responses to TGF-1.
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ACKNOWLEDGEMENTS |
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This study was supported in part by American Heart Association Texas Affiliate Grant-in-Aid (96G-631).
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. A. Stouffer, Sealy Center for Molecular Cardiology, Univ. of Texas Medical Branch, Galveston, TX 77555-1064 (E-mail: rastouff{at}utmb.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 15 October 1999; accepted in final form 8 June 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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