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Vß3 Antagonists Inhibit Insulin-Like Growth Factor-I-Stimulated Smooth Muscle Cell Migration and Replication1
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and Monsanto/Searle Discovery Research, Chesterfield, Missouri 63198
Address all correspondence and requests for reprints to: David R. Clemmons, M.D., Division of Endocrinology, University of North Carolina School of Medicine, CB No. 7170, Chapel Hill, North Carolina 27599-7170. E-mail: dpm{at}med.unc.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Vß3 integrin has been shown to be
necessary for IGF-I to stimulate maximal increases in both processes,
we determined whether synthetic Vß3 antagonists could inhibit
IGF-I-stimulated actions on this cell type. Low-molecular-weight
compounds that had been selected based on their ability to compete with
vitronectin for binding to purified human Vß3 in
vitro were analyzed for their ability to compete with
125I-kistrin (a known ligand for porcine Vß3) for
binding to porcine Vß3. Nine compounds were screened, and five
were found to be potent competitive inhibitors. The most potent
compound, SC-69000, resulted in 88% competition at 10-7
M and was nearly equipotent with echistatin. The compounds
that were the most potent inhibitors of kistrin binding were tested for
their capacity to inhibit the cell migration response to IGF-I. Three
compounds caused between 81–88% inhibition of IGF-I-stimulated
migration at 10-7 M. To determine whether
these compounds could inhibit other IGF-I-stimulated actions, their
ability to inhibit IGF-I-stimulated [3H]-thymidine
incorporation into DNA was analyzed. The four compounds that were the
most potent inhibitors of cell migration also inhibited
IGF-I-stimulated DNA replication. IGF-I stimulates the synthesis of IGF
binding protein-5 by these cells. Preincubation with the four
most active compounds also resulted in significant inhibition of the
ability of IGF-I to stimulate IGF binding protein-5 synthesis. Vß3
occupancy by the ligand vitronectin has been shown to enhance the
capacity of IGF-I to activate its receptor tyrosine kinase. The four
most active compounds were shown to inhibit IGF-I-stimulated IGF-I
receptor autophosphorylation. These findings suggest that blockade of
ligand occupancy of the Vß3 integrin globally inhibits several
IGF-I-stimulated biologic actions and that synthetic inhibitors are
very active in this regard. Because these compounds can be administered
to whole animals, they should be very useful in determining whether
blocking Vß3 occupancy in vivo results
in alteration in responsiveness to IGF-I. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vß3 by
vitronectin or fibronectin results in the potentiation of IGF-I
responsiveness (7, 8). This has been shown to modulate IGF-I
stimulation of DNA synthesis, cell migration, and IGFBP-5 synthesis, a
gene whose transcription is specifically induced by IGF-I (9). The
addition of an Vß3 antagonist, such as echistatin, to SMC
cultures, abrogates the ability of IGF-I to stimulate cell migration
(7) and both DNA and IGFBP-5 synthesis (8, 10). Similarly, increasing
ligand occupancy of Vß3 by plating cells on vitronectin results in
enhancement in the ability of IGF-I to stimulate DNA synthesis or
IGFBP-5 synthesis, and these responses can also be attenuated by
echistatin (8). Based on these responses, we developed a system for
measuring binding of nonpeptidyl, low molecular weight Vß3
antagonists to SMC surfaces, and we screened these molecules for their
ability to compete with 125I kistrin [a disintegrin that
binds to Vß3 (7)] for binding to porcine Vß3. Based on the
results of competitive binding studies, we selected several of these
molecules and determined their ability to inhibit IGF-I-stimulated
biologic actions in this cell type. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vß3 antagonists were prepared
as described previously (13). Echistatin was purchased from Sigma Chemical Co. (St. Louis, MO). Kistrin was a gift from Dr.
Robert Lazarus, Genentech, Inc., and had been purified by
a previously described method (14). 125I was purchased from
Amersham Pharmacia Biotech (Arlington Heights, IL). The
antiphosphotyrosine antibody (PY 20) was purchased from
Transduction Laboratories, Inc. (Lexington, KY).
Methods
Cell culture. Porcine aortic SMC were isolated from thoracic
aorta of young pigs (3 weeks old) and maintained in DMEM supplemented
with 10% FBS, penicillin (100 U/ml), and streptomycin (100 µg/ml),
as described previously (12). To measure DNA synthesis, the cells were
plated at a density of 2.5 x 104 cells per
cm2 in 96-well test plates (Falcon, Division of
Becton Dickinson and Co., Franklin, NJ) and grown for 5
days, until they reached confluence. The cultures were rinsed once with
DMEM without FBS, and increasing concentrations of IGF-I (0–100 ng/ml)
were added to triplicate cultures in 0.2 ml DME supplemented with 0.2%
human platelet-poor plasma and [3H]-thymidine (0.5
µCi/well) (15). Duplicate wells received echistatin
(10-7 M) or the test compounds using
concentrations between 10-8 and 10-6
M. At the end of the 36-h incubation period, the plates
were placed on ice, washed twice with PBS, and incubated with 5% TCA
for 10 min. The TCA precipitates were solubilized by adding 0.1 ml of
1% SDS, 0.1 NaOH, and the amount of [3H]-thymidine that
had been incorporated was measured by scintillation counting.
Cell migration assays. Porcine smooth muscle cells
(pSMCs) were grown to confluence in 6-well plates (Falcon 3004).
The confluent, monolayer cultures were maintained at high density for 6
days before initiation of the experiment. They were wounded with a
single edge razor blade, as described by Jones et al. (7).
The plate was rinsed once with 1.0 ml DMEM containing 0.2% FBS, then
IGF-I (100 ng/ml) and the Vß3 antagonists
(10-8–10-6 M) were added.
Immediately after wounding, the areas that were to be counted were
scored, and 1-mm regions with a continuous wound edge were selected.
After a 48-h incubation, the cells were fixed and stained with
methylene blue, then the number of cells that migrated across the wound
area was determined. Each data point represents the mean of 7–10 1-mm
regions.
IGFBP-5 synthesis. pSMCs were grown to subconfluence in
24-well plates. The cultures were washed three times with serum-free
DME and incubated for 14 h with low methionine (10-6
M) DMEM containing 1% BSA. At that time, IGF-I (0–100
ng/ml) was added to the plates in the presence or absence of the
Vß3 antagonists (10-6 M) and 50 µCi/ml
of 35S methionine. The media were collected, and the
insoluble material was removed by centrifugation at 13,000 x
g for 10 min. Aliquots of media (50 µl) were incubated
with anti-IGFBP-5 antiserum (1:1000 dilution) for 14 h at 4 C. The
complexes were precipitated by adding protein-A Sepharose, as
previously described (9). The pellets were washed four times, and the
proteins were resuspended in 0.2 ml Laemmli sample buffer. The
samples were separated by SDS-PAGE (12.5% gel). The amount of
35S methionine-labeled IGFBP-5 that was precipitated was
determined by incubating the gels with an enhancing solution (Amplify,
Amersham Pharmacia Biotech), followed by autoradiography.
Band intensity was determined in a PhosphorImager, and the results were
analyzed using Image Quant software (Molecular Dynamics, Inc., Sunnyvale, CA), as described previously (9).
IGF-I receptor phosphorylation. To determine whether these compounds could inhibit the capacity of IGF-I to stimulate IGF-I receptor phosphorylation, they (10-6 M) were added to pSMC cultures that had been grown to confluence in 10-cm dishes. After 14 h at 37 C, the cell monolayers were washed with serum-free DMEM and exposed to IGF-I (100 ng/ml) or IGF-I plus test compounds for 10 min. The monolayers were lysed by adding 1.0 ml of 1% NP-40/0.25% sodium deoxycholate/1.0 mM EGTA/150 mM NaCl/50 mM Tris/HC4 (pH 7.5), 1 mM sodium vanadate/1.0 mM NaF/1.0 mM phenylmethylsulfonylflouride/1 µg/ml pepstatin, 1.0 µg/ml leupeptin, and 1.0 µg/ml aprotinin. The cell lysates were incubated with a 1:500 dilution of anti-IGF-I receptor antiserum for 14 h at 4 C; then the immune complexes were precipitated with protein-A Sepharose, as described previously (16). The precipitates were analyzed by SDS-PAGE, followed by immunoblotting for phosphotyrosine using a 1:1000 dilution of the antiphosphotyrosine antiserum (PY 20), and the immune complexes were detected by chemiluminescence. The ability of each compound to inhibit phosphorylation was quantified by phosphor-Image analysis, as described previously (10).
Purification of vitronectin and Vß3. Human vitronectin
was purified from fresh frozen plasma and biotinylated as described
previously (17). Vß3 was purified from human placenta, as
described previously (18). The material was proven to be homogenous by
amino acid sequencing of both the V- and ß3 subunits. Serial
dilutions of the test compounds were incubated with 1 nM
biotinylated vitronectin and washed twice, and the bound vitronectin
was determined using a microplate reader, as previously described
(13).
Statistical analysis
Students t test was used to compare the differences
between control and test groups.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vß3 integrin. A small amount of material also
cross-links to what seems to be a ß1 integrin, but this is less than
10% of the total binding (7). Competitive binding assays showed that
several of the synthetic compounds competed with 125I
kistrin for binding to Vß3 on the pSMC surface (Table 1
). One compound in particular, termed
SC-69000, was equipotent with echistatin in competing for binding to
this receptor. This compound was also a potent inhibitor of vitronectin
binding to purified Vß3 because it has an IC50
of 0.56 nM. This suggests that SC-69000 is a good mimic of
the echistatin structure that is required for porcine Vß3
recognition and that it would be useful as a competitive antagonist.
Several other compounds that were tested were also highly active in
terms of inhibiting 125I kistrin binding, and these are
listed in Table 1. The most potent were SC-74758, SC-75369, SC-68552,
and SC-65811. The IC50 values for vitronectin binding to
purified Vß3 were 0.34, 1.42, 0.51, and 0.79 nM,
respectively. The structures of some of the test compounds are shown in
Fig. 1.
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Vß3 would inhibit cell migration,
IGF-I-stimulated cultures were also exposed to 10-8 or
10-7 M concentrations of each of the test
compounds. As shown in Table 2, the five
compounds that had the greatest effect on inhibiting kistrin binding
were active in inhibiting IGF-I-stimulated migration. Each of the five
compounds was a potent inhibitor of binding and inhibited
IGF-I-stimulated migration by at least 70% at 10-7
M. Three other compounds that were tested and had
intermediate levels of activity included SC-68713, SC-57220,
and SC-56631 (Table 2). SC-64258, the test compound that had no
activity in the binding assay, also had no capacity to inhibit
IGF-I-stimulated pSMC migration. SC-64258 does not inhibit vitronectin
binding to purified Vß3 (IC50 = 28,700
nM). It was included in the study as a negative control.
None of the compounds that were tested caused cell detachment. To
determine their specificity, cell migration was also stimulated by
platelet-derived growth factor (PDGF). When added at 10-7
M, none of the compounds that were potent inhibitors of
IGF-I-mediated cell migration caused more than 28% inhibition of
migration that was stimulated by PDGF (data not shown).
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IIBß3; however,
that receptor is not expressed on the SMC surface. Because we have
previously shown that 125I kistrin bound to unknown ß1
integrin (7), we cross-linked 125I kistrin to the pSMC
cultures in the presence and absence of an excess of that compound.
SC-57220 inhibited cross-linking to this ß1 integrin at
10-6 M (data not shown). This
suggests that, although Vß3 is the predominant integrin expressed
on porcine SMC, the Vß1 integrin also binds SC-57220, and this
inhibition of ligand occupancy of a Vß1 contributes to its ability
to inhibit IGF-I-stimulated migration.
To further determine the physiologic significance of inhibiting IGF-I
action in this cell type, the compounds that were the most potent
inhibitors of cell migration and kistrin binding were also tested for
their ability to inhibit the [3H]-thymidine incorporation
response to IGF-I. As shown in Fig. 2, several of the compounds were potent inhibitors of IGF-I-stimulated
pSMC DNA synthesis. There did not seem to be major discrepancies
between their activity in this assay and their ability to inhibit cell
migration, although none inhibited [3H]-thymidine
incorporation as potently as they did cell migration. This is probably
because the basal medium contains other mitogens that are secreted by
the cells, or are present in 0.2% platelet-poor plasma, that
can stimulate DNA synthesis independently of IGF-I or that the DNA
synthesis response to IGF-I is less dependent upon costimulation of
Vß3, compared with cell migration.
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). Phosphor-image analysis showed that
SC-75369, SC-65811, and SC-69000 inhibited IGF-I-stimulated IGFBP-5
synthesis by 59, 70, and 86%, respectively, whereas SC-74758 and
SC-68552 were less active (Table 3). This suggests that
the stimulation of synthesis of this protein is a good marker of IGF-I
action and that optimum stimulation of its synthesis by IGF-I requires
Vß3 occupancy.
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Vß3 has also been shown to alter
the signal transduction response to IGF-I (10). Therefore, the five
most active compounds were tested for their ability to inhibit
IGF-I-stimulated receptor tyrosine phosphorylation. The cultures were
exposed to the test compounds for 14 h, then stimulated with IGF-I
for 10 min, and phosphorylation of the ß-subunit of the receptor was
analyzed. The compounds 69000 and 65811 were the most active, and they
inhibited tyrosine phosphorylation of the ß-subunit of the IGF-I
receptor by 69 and 60%, respectively (Fig. 4 and Table 4). Echistatin induced an
83% inhibition in the same experiment. These changes are not
attributable to a reduction in IGF-I receptor number, because we have
shown previously that exposure of these cells to similar concentrations
of echistatin for 14–48 h does not alter IGF-I receptor binding (7, 10).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vß3 is necessary for optimum IGF-I stimulation of pSMC DNA and
protein synthesis, cell migration, and stimulation of IGFBP-5 synthesis
(7, 8, 10). These studies expand those findings to show that synthetic
Vß3 antagonists also inhibit these processes in cultured porcine
SMC. Importantly, their capacity to inhibit these processes correlates
with their ability to inhibit the binding of radiolabeled kistrin to
Vß3 on pSMC surfaces. The compounds with high affinity for the
human Vß3 receptor, as determined by their ability to inhibit the
vitronectin binding to purified human Vß3, were extremely active
in these test systems. These compounds were potent inhibitors of
kistrin binding to the pSMC surface and of IGF-I-stimulated pSMC
migration. In general, the capacity of these compounds to inhibit
IGF-I-stimulated cell migration correlated with their ability to
inhibit kistrin binding and their relative affinities for purified
Vß3 integrin. For example, SC-68511, SC-69000, and SC-75369 were
the most potent inhibitors of kistrin binding and cell migration.
However, there were exceptions, because SC-57220 significantly
inhibited migration but was a relatively weak inhibitor of kistrin
binding. Therefore, we conclude that these compounds are inhibiting
IGF-I-stimulated migration predominantly by blocking ligand occupancy
of the Vß3 integrin.
Although cross-linking studies show that kistrin binds principally to
Vß3, after affinity labeling, approximately 10% of the
radiolabeled material associates with a ß1 integrin, possibly
Vß1 (7). One of these compounds, SC-57220, inhibited migration but
was minimally competitive with kistrin for binding to pSMC surfaces.
However, it did inhibit the binding of [125I]-kistrin to
a ß1 integrin. This suggests that the Vß1 integrin may also be
involved in mediating the IGF-I-stimulated migration and that the
effects on SMC of the compounds such as SC-57220 that were weak
competitors of kistring binding may be mediated through this ß1
integrin.
Although these compounds are potent inhibitors of cell migration, they do not seem to interfere with cell attachment. This suggests that the capacity of SMC to adhere to extracellular matrix is not influenced by IGF-I. In previous studies, we have found no enhancement of SMC attachment when IGF-I is added to the incubation medium (7).
In previous studies, we have shown that IGF-I binding to its receptor
results in increased affinity of Vß3 for ligands (7).
Additionally, occupancy of Vß3 is required for optimum
stimulation, by IGF-I, of several steps in the IGF-I signaling cascade
that are linked to receptor binding (8, 10). This seems to be mediated
through enhancement of IGF-I-stimulated phosphorylation of its
receptor. Vß3 antagonists, such as echistatin, potently inhibit
the ability of IGF-I to stimulate receptor autophosphorylation and
phosphorylation of the downstream targets, IRS-1 and PI-3 kinase.
Phosphorylation of these substrates has been shown to be linked to
several physiologic functions that are enhanced by IGF-I
(20).
The compounds that were potent inhibitors of cell migration also
inhibited activation of IGF-I receptor tyrosine kinase activity,
implying that (like echistatin) they will also inhibit IGF-I-stimulated
phosphorylation of IRS-1 and PI-3 kinase. In other studies, we have
shown that PI-3 kinase activation is required for IGF-I-stimulated
migration, and this is the major signaling pathway that mediates this
effect (Y. Imai and D. R. Clemmons, our unpublished data). This
suggests that inhibiting PI-3 kinase activation is linked to the
inhibition of cell migration that is induced by inhibiting ligand
occupancy of Vß3.
In these studies, we also analyzed the ability of IGF-I to specifically
induce synthesis of IGFBP-5. The Vß3 antagonists were potent
inhibitors of induction of IGFBP-5 synthesis. We have shown that
stimulation of IGFBP-5 synthesis by IGF-I is specific for this growth
factor (9). Because we have previously shown that plating cells on
vitronectin is a potent stimulant of IGFBP-5 synthesis (8), this
suggests that occupancy of Vß3 is necessary for optimal
stimulation of IGFBP-5 synthesis. The results also suggest that
analysis of IGFBP-5 expression may be an excellent marker for detecting
IGF-I bioactivity in tissues that contain SMCs in vivo
(8).
Whether these compounds have additional effects over and above that of
inhibiting IGF-I signaling was not specifically addressed in these
studies; however, the ability of PDGF to stimulate SMC migration and/or
DNA synthesis was only minimally affected by the addition of these
compounds, suggesting that this growth factor does not work principally
through a Vß3 cooperativity and that these compounds are not
inhibiting other important matrix protein-integrin reactions that are
necessary for PDGF to induce signaling (21). PDGF has been shown to use
2ß1 to facilitate SMC migration, and these compounds do not
inhibit binding to that integrin (20). Additionally, the basal rate of
cell migration and [3H]-thymidine incorporation was not
affected by these compounds when added at 10-7
M. Therefore, when these compounds are used at that
concentration, their effects seem to be relatively specific for
analyzing the interaction between Vß3 occupancy and IGF-I
signaling.
These compounds may be very useful tools to study the role of Vß3
in neointima or lesion formation in vivo. Neointimal cells
have been shown to have abundant Vß3 receptors, and ligands that
bind to that receptor (such as vitronectin, thrombospondin, and
osteopontin) are also increased in abundance during neointima formation
(22, 23, 24, 25). In addition, they may be useful tools to probe the role of
IGF-I in neointima formation and vascular remodeling, because less
specific compounds that block ligand occupancy of Vß3 have been
shown to inhibit neointima formation in vascular injury model systems
(26, 27). Furthermore, a chimeric monoclonal antibody Fab fragment
(C7E3), directed against ß3-containing integrins (including
Vß3), shows marked inhibition of restenosis that occurs after
balloon angioplasty in humans (28).
After balloon denudation of arteries, there is a major increase in
IGF-I synthesis locally, and this wave of IGF-I synthesis is believed
to be important in terms of development of atherosclerotic lesions (29, 30). In addition, a form of IGFBP (IGFBP-4) that is inhibitory to
several IGF-I actions in vitro and in vivo (31, 32) has been shown to alter IGF-I actions in blood vessels in
vivo. Wang et al. (33) demonstrated that forced
overexpression of IGFBP-4 in blood vessels of transgenic animals
results in SMC hypoplasia. This finding suggests that IGF-I is
necessary for normal SMC growth and matrix protein synthesis within
arteries and that inhibition of IGF-I action may inhibit those SMC
functions. Because the specific, anti-ß3 antibody (ReoPro) has been
shown to reduce lesion development that occurs after angioplasty (28),
our findings suggest that a potential mechanism accounting for part of
its effect is blocking Vß3-mediated enhancement of
IGF-I-stimulated actions. Thus, it will be of importance to determine
whether directly inhibiting IGF-I receptor-mediated SMC functions
alters the ability of Vß3 antagonists to attenuate these
processes. The availability of these compounds should enable
investigators to test this hypothesis by determining their effects on
lesion formation in vivo.
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Acknowledgments |
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Footnotes |
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Received January 26, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vß3 integrin is necessary for smooth
muscle cell to migrate in response to insulin-like growth factor I.
Proc Natl Acad Sci USA 93:2482–2487Vß3 integrin inhibits IGF-I signaling in vascular smooth
muscle cells. Proc Natl Acad Sci USA 95:11217–11222Vß3 integrin inhibits bone resorption and
prevents osteoporosis in vivo. J Clin Invest 99:2284–2292[Medline]
1ß1 and 2ß1 integrin receptors by human
vascular smooth muscle cells. 2ß1 integrin is required for
chemotaxis across type I collagen-coated membranes. Am J Pathol 145:1070–1081[Abstract]
Vß3 and glycoproteins IIb-IIIa and
anti-fibrinogen. J Biol Chem 265:12267–12271Vß3 integrin with a small peptide antagonist Gpen
GRGDSPCA. J Vasc Surg 19:125–134[Medline]
actin-IGFBP-4 fusion gene induces smooth muscle hypoplasia.
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