© 1997 American Heart Association, Inc.
Articles |
PDGF Receptor Protein Tyrosine Kinase Expression in the Balloon-Injured Rat Carotid Artery
From the Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Mich.
Correspondence to Robert L. Panek, PhD, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co, 2800 Plymouth Rd, Ann Arbor, MI 48105.
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Abstract |
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Abstract Platelet-derived growth factor (PDGF) receptor gene expression has previously been demonstrated in balloon-injured rat carotid arteries to be regulated during repair of carotid injury. In the present study we showed that PDGF receptor protein expression and phosphorylation are changed over time after carotid artery injury. In control and 2-day-postinjury vessels, expression of PDGF
receptor protein was readily detectable, whereas PDGF ß
receptor expression appeared very low. Between 2 and 7 days postinjury,
a time interval previously shown to correspond with smooth muscle cell
migration followed by the appearance of a neointima, PDGF
receptor expression had increased only slightly, to roughly 35%
above control levels, and was maximal by day 7 postinjury, whereas PDGF
ß receptor expression had doubled. From 7 to 14 days after carotid
injury, intimal area was greatly increased and was associated with a
further increase in PDGF ß receptor protein expression and receptor
phosphorylation to a maximum between days 10 and 12. In
contrast, PDGF receptor expression had decreased slightly during
this time interval. Moreover, phosphorylation of PDGF
receptors was barely detectable and did not change over the time
course of injury. From 14 to 28 days after injury, intimal area was
increased only slightly, whereas PDGF ß receptor protein and
phosphorylation levels had diminished to roughly half
of the 10-day injury values. In addition, the increases in PDGF ß
receptor protein expression and tyrosine
phosphorylation observed over the time of injury were
also associated with a corresponding increase in the association of
phosphatidylinositol 3' kinase (PI-3 kinase) with
phosphorylated PDGF ß receptors. These findings show
that balloon injury to rat carotid arteries results in temporally
related changes in the expression of PDGF receptors and their state of
tyrosine phosphorylation. Furthermore, tyrosine
phosphorylation of PDGF ß receptors in the
balloon-injured rat carotid artery in vivo resulted in the association
of PI-3 kinase. These are important new findings, which add to our
knowledge concerning the role and activity of PDGF receptors in the
formation of a neointima.
Key Words: PDGF receptors • tyrosine phosphorylation • carotid artery injury • PI-3 kinase
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Introduction |
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Balloon catheter injury to the rat carotid artery triggers a sequence of events, including early platelet accumulation, proliferation of medial smooth muscle cells (SMCs), migration into the intima, and proliferation of intimal cells to form a thickened neointima. The formation of the neointima is a process that takes place over several weeks.1 Recent studies suggest proliferation and migration of vascular SMCs are controlled by distinct mechanisms. Platelet-derived growth factor (PDGF) released from adhering platelets may provide an initial stimulus to signal these cellular responses; however, lack of continued platelet interactions with the injured vessel wall at later times suggests involvement of other locally produced factors via autocrine/paracrine mechanisms.2 3 4 Basic fibroblast growth factor has been shown to be important in controlling medial cell replication in the balloon-injured rat carotid artery.5 PDGF has been shown to be involved in regulating SMC migration, with little effect on medial cell replication in this model.6 7 This does not, however, preclude PDGF's acting as a comitogen with other growth factors. Recent experiments have shown that SMC migration is essential to the development of neointimal thickening. When migration was inhibited in vivo in the injured rat carotid artery after administration of antiplatelet8 or anti-PDGF7 antibodies, neointima formation was markedly reduced. Conversely, when PDGF-BB was infused immediately after injury, neointimal formation was significantly increased.6
Coexpression of the PDGF and ß receptor mRNA with the mRNA for
the PDGF A and B chains at specific times and locations in the injured
rat carotid artery are observations that support a PDGF-dependent
mechanism of regulating arterial wound
repair.9 10 Since the biological functions of PDGF in vivo
could be regulated at the level of receptor density and
composition,11 we sought to determine whether expression
of PDGF receptor protein and its phosphorylation state
changes temporally after vessel wall injury.
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Methods |
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Rat Carotid Balloon Injury
Sprague-Dawley rats (350 to 400 g, Charles River Laboratories, Wilmington, Mass) were subjected to left common carotid artery injury by means of a 2F arterial embolectomy balloon catheter (Baxter Inc) introduced into the external branch as described previously (Clowes et al,1 1983). In brief, rats were anesthetized with tiletamine and zolazepam (20 mg/kg IM Telazol, Fort Dodge Laboratories), and the distal left common carotid and external carotid arteries were exposed through a midline neck incision. The embolectomy catheter was passed the length of the carotid artery three times, with the balloon distended sufficiently with saline to generate slight resistance. The external carotid was ligated after removal of the catheter and the wound closed. Animals were treated with antibiotics to prevent infection (30 000 U IM, Bicillin C-R, Wyeth Laboratories). For preparing sham rats, the left carotid and external carotid arteries were exposed and ligated as above but no incision was made into the vessels.
At intervals of 7, 14, and 28 days, rats were anesthetized and the vasculature was isolated for perfusion fixation. Carotid arteries were fixed by perfusion with a 10% buffered formalin solution (Tissue Path, Biochemical Sciences, Inc) via polyethylene tubing inserted into the ascending aorta through the left ventricle. The vena cava was cut for drainage, and the right and left carotid arteries were perfused at 100 mm Hg with normal saline by using a roller pump (Masterflex, model 7565, Cole-Parmer). When the saline perfusate cleared (approximately 3 to 5 minutes), the perfusate was switched to formalin for 10 minutes.
The left carotid arteries were removed from the aortic arch distal to the carotid bifurcation and stored in 10% formalin until they were prepared for histology. Cross sections were prepared for morphological assessment by cutting each carotid artery into four segments that were approximately equal in length. For morphological assessments, formalin-treated segments were dehydrated in a series of alcohols, embedded in paraffin blocks, cut into 5-µm cross sections, and then combo-trichrome stained for elastin, collagen, and SMCs.
To determine intimal and medial areas, cross sections of each segment were analyzed by a computerized image analysis system (PGT Imagist, Princeton Gamma-Tech, Inc). Segments from each of the four sections of each artery were evaluated. In general, intimal thickening in segments from the central region varied less in thickness than those taken near the aortic arch and carotid bifurcation. Thus, to obtain a single value of intimal thickening in each artery, the two central segments were averaged in each animal.
PDGF Receptor Protein Expression and Phosphorylation
Rats were killed at intervals of 2, 5, 7, 10, 12, 14, and 28
days after balloon catheter injury and left carotid arteries were
removed from the aortic arch to the carotid bifurcation and placed in
ice-cold PBS. Arteries were gently cleared of surrounding tissue, cut
into 10-mm segments, and opened lengthwise before snap freezing in
liquid nitrogen. Arteries were rapidly homogenized in 500
µL of 1% Triton X-100 buffer containing 50 mmol/L HEPES
(pH 7.5), 150 mmol/L NaCl, 10% glycerol, 1
mmol/L EDTA, 1 mmol/L EGTA, 10 mmol/L
sodium pyrophosphate, 30 mmol/L p-nitrophenyl
phosphate, 1 mmol/L sodium orthovanadate, 50
mmol/L sodium fluoride, aprotinin (10 µg/mL),
leupeptin (10 µg/mL), and 1 mmol/L PMSF at 4°C
for 30 seconds. The homogenates were transferred into
labeled microcentrifuge tubes. The tissue grinders were rinsed
with an additional 500 µL of the homogenization
buffer, combined with the original homogenates, and kept at
4°C for 15 minutes. Insoluble material was removed by
centrifugation at 4°C for 10 minutes at
10 000g. A 20-µL aliquot was removed for protein
analysis by the BCA protein assay (Pierce Chemical Co.) and 250
µg of protein was added per immunoprecipitation incubation to
normalize for protein loading. The PDGF receptors were
immunoprecipitated by incubating supernatants for 2 hours at 4°C with
anti-PDGF receptor polyclonal antibodies specific for either the
receptor isoform (SC-431, Santa Cruz Biotechnology, Inc) or ß
receptor isoform (06-498, Upstate Biotechnology, Inc). Both antibodies
have cross-reactivity with rodents. In separate experiments with
sham-operated rats, carotid arteries were harvested as above and both
PDGF and ß receptor isoforms were immunoprecipitated with an
anti-PDGF receptor polyclonal that recognizes both and ß subunits
(06-495, Upstate Biotechnology, Inc).12 After receptor
immunoprecipitation, the antibody-antigen complexes were
immobilized with protein A–Sepharose beads (Sigma Chemical
Co) overnight at 4°C. Immunoprecipitates were washed four times with
1 mL of 1% Triton X-100 buffer containing 50 mmol/L HEPES
(pH 7.5), 150 mmol/L NaCl, 10% glycerol, and 0.02% sodium
azide at 4°C. Sepharose complexes were boiled with 30 µL of Laemmli
sample buffer for 5 minutes, and the eluted proteins were separated on
an 8% to 16% polyacrylamide gel and electrophoretically
transferred onto nitrocellulose. To prevent nonspecific binding of
antibodies, the membrane was blocked in 3% nonfat dried milk in
PBS–0.2% Tween 20 (pH 7.5) for 2 hours at 27°C. Immunoprecipitated
PDGF or ß receptors were identified by incubating individual
nitrocellulose blots for 2 hours at 27°C with anti-PDGF receptor
polyclonal antibodies; receptor–specific isoform (SC-431) or ß
receptor–specific isoform (06-498, Upstate Biotechnology, Inc) diluted
1:1000 in blocking buffer. The phosphorylation state of
the PDGF receptors was detected by incubating the blocked
nitrocellulose blots for 2 hours at 27°C with an antiphosphotyrosine
monoclonal (Upstate Biotechnology, Inc; clone 4G10, 1 µg/mL in
blocking buffer). Detection of phosphatidylinositol 3' kinase (PI-3
kinase) complexed with immunoprecipitated PDGF ß receptors was
performed by incubating blots for 2 hours at 27°C with an anti-rat
PI-3 kinase polyclonal antibody (Upstate Biotechnology, Inc; 06-195,
diluted 1:1000 in blocking buffer), which recognizes the 85-kD subunit
of PI-3 kinase.13 After extensive washing with PBS–0.2%
Tween 20, the immunoblots were incubated with horseradish
peroxidase–labeled goat anti-rabbit IgG (1:5000) for 2 hours at 27°C
and washed as described. The proteins were visualized with an enhanced
chemiluminescence detection system according to the instructions of the
supplier (ECL, Amersham). The density of the protein bands was
determined by using NIH Image software (version 1.56).
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Results |
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By light microscopy, a neointima was evident 7 days after balloon injury (Fig 1
). Extensive
intimal thickening was observed by day 14, with little additional
thickening occurring over the next 14 days. Morphological measurements
at 7, 14, and 28 days postinjury are summarized in Fig 2. Measurable intimal thickening was
observed by day 7. By 14 days after injury, the intimal thickness
had increased fourfold (0.17±01 mm2), with only a
small additional increase in thickness by day 28 (0.20±05
mm2).
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Fig 3 shows immunoblots of
PDGF receptor protein expression and tyrosine
phosphorylation over time after carotid artery injury.
PDGF receptor protein expression was identified by anti-PDGF receptor
immunoprecipitation and Western blotting of carotid artery
homogenates with PDGF receptor antibodies directed against
either the receptor–specific isoform (3A) or ß
receptor–specific isoform (3C).
Tyrosine-phosphorylated PDGF receptors were identified
by antiphosphotyrosine Western blotting of immunoprecipitated PDGF
receptors (Fig 3B and 3D). Expression of PDGF receptor protein was
readily detectable (Fig 3A) and quantitatively similar (Fig 4) in control and 2-day-postinjury
vessels, whereas PDGF ß receptor expression was not readily observed.
Between 2 and 7 days postinjury, PDGF receptor expression had
increased only slightly, about 35% above control levels, and was
maximal by day 7 postinjury, whereas PDGF ß receptor expression had
increased twofold (Figs 3 and 4). From 7 to 14 days after carotid
injury, intimal area was greatly increased and was associated with a
further increase in PDGF ß receptor protein expression (Fig 3C), to a
maximum between days 10 and 12 (Fig 4). Paralleling the increase in
PDGF ß receptor expression was an increase in PDGF receptor tyrosine
phosphorylation. In contrast, PDGF receptor
expression had decreased slightly during this time interval (Fig 4).
Interestingly, tyrosine phosphorylation of PDGF
receptors was barely detectable and did not appear to change over the
time course of injury (Fig 3B). From 14 to 28 days after injury,
intimal area was increased only slightly, whereas PDGF ß receptor
protein had diminished to roughly half of the 10-day injury values
(Figs 3C and 4). PDGF ß receptor phosphorylation had
also diminished (Fig 3D), consistent with the decline in PDGF
ß receptor expression.
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To ensure that the time-dependent increases observed in PDGF receptor
protein expression and phosphorylation were not a
consequence of the trauma of surgical manipulation of the arteries,
left carotid vessels from a separate group of sham-operated rats were
harvested at 2, 5, 7, 10, 12, and 14 days postinjury. PDGF receptors
were immunoprecipitated with an antibody that recognized both and
ß isoforms, and tyrosine phosphorylation of total
PDGF receptors was examined. Fig 5 shows
that only a weak signal for the 190-kD
tyrosine-phosphorylated PDGF ß receptors was observed
compared with the corresponding time points of the injured vessels.
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Autophosphorylation of the PDGF ß receptor tyrosine
kinase by PDGF has been shown to promote cell migration via association
with PI-3 kinase. To determine whether this pathway may be involved in
PDGF-directed migration in vivo, we examined tissue extracts of injured
rat carotid arteries over time for PI-3 kinase association with the
190-kD phosphorylated PDGF ß receptor. Fig 6 shows the time-related increase in the
association of PI-3 kinase with PDGF receptors in injured carotid
artery homogenates, as identified by anti–PDGF ß
receptor immunoprecipitation followed by Western blotting with
antibodies to the 85-kD subunit of PI-3 kinase. The association of PDGF
ß receptors with PI-3 kinase in uninjured control and
2-day-post–balloon-injury arteries was shown by the appearance of a
weak band at 85 kD. From 2 to 7 days postinjury, there was a marked
increase in the association of the 85-kD subunit of PI-3 kinase with
PDGF receptors. Further increases in p85 PI-3 kinase were observed
between 7 and 10 days postinjury, with maximum increases observed
between 10 and 12 days postinjury (Fig 6). From 14 to 28 days
post–carotid injury, association of the 85-kD subunit of PI-3 kinase
with PDGF receptors was decreased (Fig 6) and paralleled the
decline in PDGF ß receptor expression and
phosphorylation during this time interval (Figs 3
and 4).
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Discussion |
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It has been suggested that vascular SMC proliferation and migration at sites of vessel wall injury may depend on growth factors produced locally by the vessel wall cells.14 15 16 17 18 A requirement for this process is that the SMCs of the injured arterial wall also express functional growth factor receptors to transduce the locally generated signals. The goal of these studies was to examine whether there is a temporal relationship between arterial injury and expression of PDGF receptor protein and level of phosphorylation. In normal (control) arteries and balloon catheter–injured vessels, we were able to detect expression of PDGF
and ß receptor protein. Expression of PDGF
receptor protein was observed to be considerably greater than that of
PDGF ß receptor protein in uninjured control and 2-day-postinjury
vessels. PDGF ß receptor protein was not readily detectable at these
time points; however, a weak signal for expression of the
phosphorylated PDGF ß receptor was observed,
indicating the presence of low levels of the ß receptor protein.
These data are consistent with the results of Majesky and
coworkers,9 who showed that uninjured and acutely (0.5 to
48 hours) injured rat carotid arteries contained mRNA for both PDGF
and ß receptors. Moreover, these investigators also showed that PDGF
ß receptor mRNA levels decreased markedly in the first 4 hours after
injury. Greater expression of PDGF receptor protein relative to the
PDGF ß receptor isoform in control and 2-day-postinjury arteries did
not result in increased PDGF receptor tyrosine
phosphorylation. There were no quantitative differences
in tyrosine phosphorylation between the PDGF and
ß receptors at these time points. These results indicate the presence
of a low level of PDGF receptor phosphorylation and
presumably activation of PDGF receptor tyrosine kinase function, which
depends on receptor autophosphorylation. Whether there
is sufficient PDGF receptor activity to influence the early injury
response in the rat carotid artery seems unlikely. In fact, previous
studies by Jawien et al6 showed that infusion of PDGF-BB
beginning immediately after carotid injury did not produce any
additional increase in the [3H]thymidine-labeling index
of medial SMCs (index of SMC proliferation) at 2 days after ballooning
than that produced by the injury alone. Instead, the release of
endogenous basic fibroblast growth factor from damaged
cells in the vessel wall has been shown to initiate early SMC
proliferation.5 20 This was demonstrated by administration
of a neutralizing antibody against basic fibroblast growth factor,
which caused a 90% reduction in medial SMC replication measured 2 days
after injury.5 Thus, the low levels of PDGF receptor
phosphorylation observed during the first 2 days after
injury in our studies support the notion that early medial SMC
proliferation is probably not a PDGF-driven process.
It has been suggested that migration of SMCs from the media to the
intima begins at around 2 to 3 days after balloon injury and may
continue until the appearance of a neointima at around day
7 postinjury.21 In the present studies, increases in
PDGF ß receptor expression (and to a lesser extent PDGF
receptors) and phosphorylation were observed from days
2 to 7 after balloon injury, which coincides with reported times for
SMC migration. Majesky et al9 also showed that PDGF ß
receptor mRNA increased from 2 to 7 days after rat carotid injury and
have suggested this increase is due to selectively increased amounts of
the PDGF ß receptor transcript in neointimal SMCs.
Moreover, there was no significant change in PDGF receptor mRNA
levels in the first 7 days after carotid injury.9 The
potential importance of migration in lesion formation has also been
highlighted by in vivo studies implicating PDGF in the
neointima that forms in the rat carotid artery within 2
weeks after balloon angioplasty. In vivo administration of anti-PDGF
antibody after balloon injury of the rat carotid decreased intimal
accumulation of SMCs by >40%, with no decrease in the
[3H]thymidine-labeling index in the neointima
or media.7 These studies, together with studies by Jawien
et al6 showing that PDGF-BB greatly increased the intimal
thickening and migration of SMCs from the media to the intima during
the first 7 days after injury, suggest that the effect of PDGF on
intimal thickening may result primarily from stimulation of SMC
migration from the media into the intima.
The signal-transduction pathways leading from PDGF receptor activation to stimulation of migration versus proliferation are not completely understood. Recent studies have shown that activation of the PDGF ß receptor results in motility responses in the forms of membrane ruffling and chemotaxis.23 The effects are manifested as a reorganization of actin filaments, the appearance of edge ruffles, and the subsequent chemotaxis of PDGF ß receptor–expressing cells.23 24 Recently, Wennstrom and coworkers23 showed that in porcine aortic endothelial cells, membrane ruffling and chemotaxis transduced by the PDGF ß receptor required the binding of p85, the src homology 2 (SH2)–containing regulatory subunit of PI-3 kinase, to phosphorylated tyrosine residues in the kinase insert of the PDGF ß receptor. To determine whether this pathway may be involved in PDGF-directed migration in vivo, we examined tissue extracts of injured rat carotid arteries over time for PI-3 kinase association with the phosphorylated PDGF ß receptor. In our studies, increased expression and phosphorylation of the PDGF ß receptor from 2 to 7 days after balloon injury coincided with an increase in the association of the p85 subunit of PI-3 kinase with the PDGF receptor. In addition, increases in PDGF receptor expression, phosphorylation, and association with PI-3 kinase were observed between 7 and 14 days postinjury, with maximal increases observed between 10 and 14 days.
Clowes and coworkers1 have shown that between 7 and 14 days after injury, neointimal thickening progresses, with SMC proliferation and extracellular matrix accumulation. PDGF has been implicated in stimulating intimal SMC replication and synthesis of collagen during this phase of injury repair.1 In contrast, medial SMC replication returns to basal rates. Furthermore, Majesky et al9 showed that PDGF ß receptor mRNA was almost fivefold higher in abundance in neointima than in media at these times. Similarly, Rubin et al25 showed that greater amounts of PDGF ß receptor protein are found in SMCs of human carotid atherosclerotic intima than normal artery.
Taken together, these results suggest that migration of SMCs from the media to the intima after rat carotid injury involves PDGF receptor activation and subsequent association with PI-3 kinase. In addition, there may be further involvement of PDGF receptor signaling in neointima formation during the 7- to 14-day injury repair period.
Recent studies have also shown that phosphoinositides
bind several actin-binding proteins, indicating that
phosphatidylinositol hydrolysis may be associated with the cytoskeletal
reorganization required for chemotaxis. PDGF-BB has been shown to
stimulate migration, phosphatidylinositol hydrolysis, diacylglycerol
formation, and intracellular calcium release in human aortic
SMCs.26 It was suggested that the mechanism for
PDGF-stimulated migration was via PDGF ß receptor activation and
association of phospholipase C
. We did not determine in these
studies whether PDGF receptors immunoprecipitated from injured rat
carotid arteries associate with phospholipase C, although redundant
signaling pathways from the PDGF receptor that lead to migration (or
proliferation) most likely exist.27
By 28 days postinjury, neointimal area had increased only slightly from the 14-day injury value, while medial area had decreased. In addition, PDGF receptor expression and phosphorylation had also declined as injury repair proceeded from 14 to 28 days. The increase in intimal area at this time may be due to further SMC synthesis and deposition of extracellular matrix stimulated by growth factors other than PDGF. Indeed, transforming growth factor-ß1 mRNA was shown to be increased in the neointima of 2-week-injured rat carotid arteries and was associated with increased fibronectin and collagen gene expression.28
Our findings demonstrate that changes in PDGF receptor protein expression and phosphorylation occur at specific times after carotid injury that coincide with specific phases of injury repair (ie, SMC migration and intima formation) previously reported for the rat carotid injury model. In particular, the increases in PDGF ß receptor expression coincide with increases in the PDGF-B chain observed in cells at the surface of the neointima, as demonstrated by Lindner and coworkers.10 It is not known whether PDGF ligand and receptor protein expression are upregulated in concert or are independent processes that combine to upregulate PDGF receptor phosphorylation. These results further support a role for PDGF in regulating these processes activated in response to vessel wall damage.
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Acknowledgments |
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The authors wish to thank Terry Major for initial help in excising tissues. We also thank Dr Michael Ryan for making histology illustrations and for helpful discussions.
Received July 26, 1996; accepted November 5, 1996.
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References |
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O. Leppanen, N. Janjic, M.-A. Carlsson, K. Pietras, M. Levin, C. Vargeese, L. S. Green, D. Bergqvist, A. Ostman, and C.-H. Heldin Intimal Hyperplasia Recurs After Removal of PDGF-AB and -BB Inhibition in the Rat Carotid Artery Injury Model Arterioscler. Thromb. Vasc. Biol., November 1, 2000; 20 (11): e89 - e95. [Abstract] [Full Text] [PDF]
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I. Fishbein, J. Waltenberger, S. Banai, L. Rabinovich, M. Chorny, A. Levitzki, A. Gazit, R. Huber, U. Mayr, S. D. Gertz, et al. Local Delivery of Platelet-Derived Growth Factor Receptor-Specific Tyrphostin Inhibits Neointimal Formation in Rats Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 667 - 676. [Abstract] [Full Text] [PDF]
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X. Xin, N. Yang, and J. E. Faber Platelet-Derived Growth Factor-BB Inhibits Rat alpha 1D-Adrenergic Receptor Gene Expression in Vascular Smooth Muscle Cells by Inducing AP-2-Like Protein Binding to alpha 1D Proximal Promoter Region Mol. Pharmacol., December 1, 1999; 56(6): 1152 - 1161. [Abstract] [Full Text]
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C.-H. Heldin and B. Westermark Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor Physiol Rev, October 1, 1999; 79(4): 1283 - 1316. [Abstract] [Full Text] [PDF]
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N. A. Giese, M. M. H. Marijianowski, O. McCook, A. Hancock, V. Ramakrishnan, L. J. Fretto, C. Chen, A. B. Kelly, J. A. Koziol, J. N. Wilcox, et al. The Role of Alpha and Beta Platelet-Derived Growth Factor Receptor in the Vascular Response to Injury in Nonhuman Primates Arterioscler. Thromb. Vasc. Biol., April 1, 1999; 19(4): 900 - 909. [Abstract] [Full Text] [PDF]
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