© 2000 American Heart Association, Inc.
Molecular Medicine |
Role of the JAK/STAT Pathway in Rat Carotid Artery Remodeling After Vascular Injury
From the Cardiovascular Research Institute (Y.S., H.K., R.S., T.N., T.I.), Kurume University, and Internal Medicine III, Kurume University School of Medicine (Y.S., H.K., R.S., T.N., T.I.), and Department of Molecular Genetics, Institute of Life Science (H.Y., A.Y.), Kurume University, Kurume, Japan.
Correspondence to Hisashi Kai, MD, PhD, The Cardiovascular Research Institute, Kurume University, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. E-mail naikai{at}med.kurume-u.ac.jp
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Abstract—In cultured vascular smooth muscle cells (VSMCs), Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are expressed constitutively and play a role in angiotensin II (Ang II)–induced intracellular signaling and proliferation. However, little is known regarding the relevance of these proteins to the process of vascular remodeling. The role of JAK and STAT proteins in vascular remodeling and their functional coupling with Ang II were examined in balloon-injured rat carotid artery. Immunoreactive Jak2, Tyk2, Stat1, and Stat3 were not detected in the intact artery. Immunohistostaining showed transient expressions of these JAKs and STATs in medial and neointimal VSMCs at days 2 and 5, respectively, with a peak at day 7 in both layers. The expressions declined to insignificant levels by day 14. Ang II type 1 receptors (AT1s) were coexpressed in the medial and neointimal VSMCs expressing Jak2 and Stat3. The Jak2 and Stat3 inductions in the injured artery were accompanied by constitutive Jak2 and Stat3 phosphorylations, which were enhanced by ex vivo Ang II stimulation via AT1. Additionally, a Jak2 inhibitor, AG490, blocked the Ang II–induced Stat3 phosphorylation. Furthermore, local treatment with AG490 inhibited constitutive Stat3 phosphorylation and neointimal VSMC replication and subsequently reduced neointima formation in the injured artery. In conclusion, JAK and STAT proteins were inducible in medial and neointimal VSMCs after vascular injury and were functionally coupled to AT1. The inductions of JAKs and STATs would be involved in the mechanisms of neointima formation after vascular injury. (Circ Res. 2000;87:12-18.)
Key Words: signal transduction • remodeling • arteries • muscle, smooth • angiotensin
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Introduction |
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The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway was initially recognized as the primary mediator of intracellular signaling induced by interferon in hematopoietic and immune cells. However, it is now well known that JAK and STAT proteins transmit the intracellular signaling elicited by various kinds of cytokines and growth factors in a wide variety of cell types.1 2 In cultured rat vascular smooth muscle cells (VSMCs), it has been demonstrated that JAK and STAT proteins are constitutively expressed and directly coupled to angiotensin II (Ang II) type 1 receptor (AT1). Ang II directly stimulates tyrosine phosphorylation and activation of Jak2 and Tyk2, which in turn tyrosine phosphorylate and activate Stat1, Stat2, and Stat3.3 Activated Stat3 and Stat1 form homo- and heterodimer cis-inducible factor complexes that translocate to the nucleus, where they bind to the cis-inducing element, resulting in the activation of transcription of early growth response genes.2 4 Furthermore, Ang II–induced proliferation of cultured VSMCs is inhibited by either pretreatment with Jak2-specific inhibitor AG490 or electroporation of anti-Stat1 or anti-Stat3 antibody, which suggests that Stat1 and Stat3 play an essential role in Ang II–induced proliferation of cultured VSMCs via Jak2 activation.5 However, no information is available on the expression of JAKs and STATs in VSMCs in vivo under physiological and pathological conditions, and little is known about the significance of the JAK/STAT pathway in VSMCs in vivo.
Neointima formation of rat carotid artery after balloon injury is the most well-studied model of vascular remodeling, especially accompanied with VSMC proliferation. Endothelial denudation and vascular injury trigger medial VSMC replication and migration into the intima and their proliferation associated with extracellular matrix production in the neointima.6 Several cytokines and growth factors released by activated platelets, infiltrating cells, and damaged vascular cells are thought to play a role in the process that leads to neointima formation in response to vascular injury.7 8 9 However, it remains poorly understood how the various components initiate and sustain VSMC proliferation resulting in neointima formation. Currently, the tissue renin-angiotensin system has been implicated in the mechanism of neointima formation in this model. Angiotensin-converting enzyme inhibitors or AT1 antagonists prevented the injury-induced neointima formation.10 11 Furthermore, Ang II stimulates VSMC proliferation in the injured artery.8 12 Moreover, gene expressions of most components of the renin-angiotensin system, including renin, angiotensinogen, angiotensin-converting enzyme, and AT1, are transiently induced in the neointima after vascular injury.13 14 15 16 These findings underscore the likelihood that Ang II is one of the potent contributors to neointima formation in this model.
Accordingly, we investigated not only the expression of JAKs and STATs in quiescent VSMCs in the rat intact carotid artery but also the temporal and spatial changes in JAK and STAT expressions in medial and neointimal VSMCs after balloon injury. Furthermore, functional coupling of JAK and STAT proteins in response to ex vivo Ang II stimulation was examined in the injured artery. We also investigated the effects of local AG490 treatment on the injury-induced neointima formation.
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Materials and Methods |
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Vascular Injury Model
All procedures were approved by the institutional animal use and care committee and conducted in conformity with institutional guidelines. Male Sprague-Dawley rats were anesthetized by sodium pentobarbital (50 mg/kg), and then balloon injury of the left carotid artery was performed as described previously.17
Morphometry and Immunohistostaining Study
After rats (n=5) were killed with an overdose of pentobarbital,
the carotid artery was perfusion-fixed at 100 mm Hg, excised, and
embedded in paraffin. Serial sections of the transverse
arterial rings were subjected to morphometry for assessing
the intima/media area ratio (I/M ratio) and to immunohistostaining
using a denoted primary antibody and a commercially available detection
system (DAKO). An anti-AT1 polyclonal
antibody18 19 was a gift of Dr H. Rakugi (Osaka
University).
Immunoblotting Study
Protein sample was extracted from the homogenates of
the carotid artery (n=3), separated by 10% SDS-PAGE, and blotted onto
polyvinylidene difluoride membrane, as described
elsewhere.20 Blots were probed with a denoted primary
antibody, and the signals were analyzed by the
chemifluorescence detection system and the laser digital
analyzer (FluorImager, Amersham Pharmacia Biotech).
Jak2 and Stat3 Phosphorylation in the
Balloon-Injured Artery
At day 7, the injured artery was excised and cut into strips.
The arterial strips were equilibrated in HBSS for 60
minutes (37°C) in the presence of 100 nmol/L candesartan (Takeda
Chemical Industries) or vehicle. Ang II (1 µmol/L, Sigma) or
vehicle was applied to the strips for 20 minutes (37°C), and the
strips were immediately frozen in dry ice/acetone (n=5). In some
experiments, the arterial strips were incubated in HBSS for
16 hours (37°C) with 10 µmol/L AG490 (Calbiochem) or vehicle,
and then Ang II was applied to the strips (n=5).
Phosphorylated Stat3 was detected by
immunoblotting using phosphospecific Stat3 antibody.
Jak2 phosphorylation was assessed on the basis of
anti-Jak2 immunoprecipitation followed by anti-phosphotyrosine
immunoblotting, as described previously.3
Immunoreactive bands were quantified by FluorImager, and the signal
intensity of phosphorylated Jak2 and Stat3 was
normalized by that of total Jak2 and Stat3, respectively.
Local Treatment With AG490 of the Balloon-Injured Artery
AG490 was dissolved in 25% pluronic F127 gel (Sigma) with the
final concentrations of 0.5, 1, or 2 mg/mL. At the time of balloon
injury (n=5), gel containing AG490 or vehicle was applied around the
middle segment (2 cm in length) of the injured carotid artery (1 mL per
1-cm length of the artery segment), as previously
described.21 As a control experiment, 2 mg/mL AG490 was
applied around the sham-operated carotid artery.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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After balloon injury, the neointima was first seen in the denuded left carotid artery at day 5, and then a transient burst phase of VSMC proliferation was observed during days 5 to 14. At day 14, the neointimal area peaked, with an I/M ratio of 1.87±0.24 (0.03±0.01 in the sham-operated rats, P<0.01).
Transient Induction of JAK and STAT Expression
Immunoblotting demonstrated that Jak2, Tyk2,
Stat1, and Stat3 proteins were not expressed in the intact rat carotid
artery (Figure 1
). In balloon-injured
artery, expression of these JAKs and STATs was transiently observed at
day 7 and decreased to insignificant levels at day 14.
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Immunohistostaining was performed to investigate the temporal and
spatial changes in the expression of JAK and STAT proteins in intact
and balloon-injured carotid arteries (Table). Immunoreactive Jak2 and
Stat3 were not detectable in medical VSMCs in the intact carotid artery
(Figure 2). Transient expression of Jak2
and Stat3 was observed after vascular injury. In medial VSMCs,
immunoreactive Jak2 and Stat3 were observed beginning at day 2 and
peaked at days 5 to 7. Proliferating neointimal VSMCs
showed immunoreactivities of Jak2 and Stat3 at day 5, and the Jak2 and
Stat3 expressions peaked at day 7. Jak2 and Stat3 were scarcely found
in both layers at day 14. Transient Tyk2 and Stat1 expressions were
detected in a time course and distribution similar to those of Jak2 and
Stat3 (data not shown). The transient induction of JAKs and STATs was
not observed in either sham-operated carotid artery or right carotid
artery of the injured rats. The cells expressing Jak2 and Stat3 in the
media and neointima were identified as VSMCs on the basis
of coimmunostaining with a VSMC marker, 
-smooth
muscle actin (data not shown).
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Coexpression of AT1 with Jak2 and Stat3
Temporal and spatial changes of AT1
expression were examined in balloon-injured artery (Figure 3A) because AT1 is
the upstream molecule that activates the JAK/STAT pathway in
cultured VSMCs.3 5 The baseline AT1
expression was observed constitutively in medial VSMCs in the intact
artery. Vascular injury triggered a transient increase in
AT1 expression in medial and
neointimal VSMCs at days 2 and 5, respectively, with a peak
at day 7 in both layers. The AT1 expression
returned to control level in both layers by days 14 to 28. These
temporal changes of AT1 expression were in accord
with earlier studies.13 16 Immunohistostaining for
AT1, Jak2, or Stat3 was performed using serial
tissue sections at day 7 when all of these proteins showed the maximum
expression. AT1 was coexpressed in the VSMCs,
which showed strong immunoreactivities against both Jak2 and Stat3
(Figure 3B).
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Phenotype Transition of VSMCs After Balloon Injury
To determine the relation of the phenotype transition of
VSMCs to the transient expression of JAK and STAT proteins after
vascular injury, immunohistostaining against the
phenotype-specific smooth muscle myosin heavy chain (MHC)
isoforms SM2 and SMemb was performed using serial sections
(Table
). The media of the intact carotid artery consisted of
SM2+ VSMCs, suggesting that these VSMCs were of
the differentiated and contractile phenotype. After balloon
injury, the most medial VSMCs were SM2+
throughout the observation period, whereas SMemb+
cells, indicative of the dedifferentiated and proliferative
phenotype, were transiently found at days 2 to 7, but were not
observed at day 14. In the neointima,
SMemb+ VSMCs were exclusively observed from days
5 to 14, although SM2+ cells were scarcely
found.
Jak2 and Stat3 Phosphorylations
Immunoblotting studies showed that a transient
Stat3 induction was accompanied with constitutive
phosphorylation in balloon-injured artery (Figure 4A). The constitutive Stat3
phosphorylation was detected in the injured artery
after day 5, peaked at day 7, and declined to insignificant levels at
day 14. To determine functional coupling of the inducible Jak2, Stat3,
and AT1, balloon-injured arterial
strips were stimulated by Ang II ex vivo, and then Jak2 and Stat3
phosphorylation levels were investigated on the basis
of immunoblotting. Signal of
phosphorylated Jak2 or Stat3 was not detected in the
strips of the intact artery, irrespective of ex vivo Ang II stimulation
(data not shown). Constitutive Jak2 and Stat3
phosphorylations were found in balloon-injured artery
at day 7. The Jak2 and Stat3 phosphorylations were
markedly enhanced by ex vivo Ang II stimulation (Figure 4B). The
Ang II–induced Jak2 and Stat3 phosphorylations were
blocked by an AT1-specific inhibitor,
candesartan, although candesartan did not have significant effects on
the constitutive Jak2 and Stat3 phosphorylations.
Furthermore, the Ang II–induced Stat3 phosphorylation
was significantly reduced by ex vivo pretreatment with AG490, a
specific Jak2 inhibitor, whereas the constitutive Stat3
phosphorylation was not affected by the ex vivo AG490
pretreatment (Figure 4C).
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Effects of Local Treatment With AG490 on Neointima
Formation
To determine the role of JAK/STAT proteins in VSMC regulation in
vivo, we studied the effects of periadventitial treatment with AG490
dissolved in pluronic F127 gel, a sustained release polymer, on
neointima formation. There were no apparent differences in
body weight or other systemic conditions between controls and
AG490-treated rats. Inflammation or necrosis was not found in the
AG490-treated artery, irrespectively of vascular injury, during the
observation period. Additionally, locally applied AG490 showed neither
macroscopic nor microscopic changes in the sham-operated artery over
the course of this study. At day 14, neointima formation
after balloon injury was reduced by the AG490 treatment, and the
inhibitory effect of AG490 was dose dependent (Figure 5). The I/M ratio of the injured artery
was reduced by 65% in the AG490-treated rats versus the
vehicle-treated rats (P<0.01, Figure 5B). The
vehicle treatment had no effect on the I/M ratio at day 14
(1.75±0.14).
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Effects of AG490 on neointimal VSMC replication were
evaluated at day 7 on the basis of immunohistostaining for
proliferating cell nuclear antigen (PCNA), a marker of cell replication
in vivo (Figure 6A), because preliminary
experiments showed that balloon injury induced a transient increase in
the PCNA+ neointimal VSMCs after day
5 with a peak at day 7, declining to lower levels at day 14. Local
treatment with AG490 reduced the number of PCNA+
neointimal VSMCs at day 7 by 60% and the I/M ratio at day
7 by 57%, as compared with vehicle treatment (Figure 6B, P<0.05). Furthermore, at day 7, the constitutive Stat3
phosphorylation in the injured artery was remarkably
inhibited by the local AG490 treatment (Figure 6C, P<0.01).
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Discussion |
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The present study demonstrated for the first time that JAK (Jak2, Tyk2) and STAT (Stat1, Stat3) proteins were below detection levels in in vivo VSMCs of the rat intact carotid artery and were transiently expressed in medial and neointimal VSMCs during the process of neointima formation after balloon injury. The Jak2 and Stat3 inductions in the injured artery were accompanied by the constitutive Jak2 and Stat3 phosphorylations, which were enhanced by ex vivo Ang II stimulation via AT1. AG490 inhibited the ex vivo Ang II–induced Stat3 phosphorylation. Furthermore, local treatment with AG490 not only inhibited the constitutive Stat3 phosphorylation and VSMC replication but also reduced neointima formation after vascular injury.
The processes of vascular remodeling after balloon injury in rats can
be divided into the following 4 phases.6 The first phase
is the burst of medial VSMC proliferation that peaks within a few days
after injury. The second phase involves VSMC migration into the intima,
beginning at days 4 to 5. The third phase refers to the sustained VSMC
proliferation in the neointima, with cell numbers reaching
a maximum at day 14. The fourth phase is characterized by extracellular
matrix deposition. Nevertheless, very little is known about
intracellular signal events after vascular injury. Recently,
involvement of the extracellular signal–regulated kinase (ERK)-1/ERK2
pathway, which is commonly related to cell growth in response to growth
factors, has been suggested in vascular remodeling of rat
balloon-injured artery.21 However, despite the constant
ERK1/ERK2 expression levels, an ERK kinase inhibitor
reduces medial VSMC replication but does not affect
neointimal VSMC proliferation.21 Thus,
although ERK1/ERK2 activation may induce medial VSMC replication in the
first phase in response to vascular injury, an alternative signaling
pathway must be involved in neointima formation in the
second and third phases. As shown in Figure 2 and the
Table, JAKs and STATs were inducible simultaneously
in medial and neointimal VSMCs, beginning in the first
phase, reaching the maximum in the second and third phases. Inducible
Jak2 and Stat3 were accompanied by constitutive
phosphorylation in the injured artery (Figure 4). Moreover, local treatment with AG490 inhibited constitutive
Stat3 phosphorylation and neointimal VSMC
replication in the injured artery (Figure 6). Because the size
of the neointimal lesion is mainly dependent on VSMC
accumulation, inhibition of VSMC replication by AG490 was considered to
reduce neointima formation. As expected, AG490 reduced
neointima formation (Figures 5 and 6). Taken
together, constitutive Stat3 phosphorylation at day 7
is dependent on Jak2 activation in the injured artery, and it is
suggested that induction and activation of the JAK/STAT pathway play a
role in the mechanisms underlying neointima formation after
balloon injury via VSMC replication. However, we do not deny the
possibility that additional signaling pathways are involved in the
mechanism of neointima formation, because the
inhibitory effects of AG490 on VSMC replication and
neointima formation were partial.
The present study suggests that Jak2 and Stat3, as well as
AT1, are not only coexpressed but also coupled
functionally in the vascular remodeling process, given that candesartan
blocked the Jak2 and Stat3 phosphorylations induced by
ex vivo Ang II stimulation and the Ang II–induced Stat3
phosphorylation was dramatically reversed by AG490
(Figure 4). The rationale for testing the functional coupling of
Jak2 and Stat3 by applying Ang II to the injured artery derives from
the evidence that activation of Jak2 and Stat3 is involved in the Ang
II–mediated proliferation in cultured VSMCs5 and that
AT1 was coexpressed with Jak2 and Stat3 in VSMCs
of the injured artery (Figure 3). Moreover, it is well known
that components of the tissue renin-angiotensin system as
well as AT1 are upregulated in response to
vascular injury.13 14 15 16 Taken together, it seems likely
that Ang II is one of the in vivo ligands that activate the
inducible JAK/STAT pathway and induce the constitutive Jak2 and Stat3
phosphorylation in the injured artery. However, we do
not necessarily consider Ang II to be the only essential agonist
coupling to inducible JAKs and STATs in balloon-injured artery. Several
cytokines and growth factors, including basic fibroblast growth
factor and platelet-derived growth factor, are also considered to
be candidates responsible for VSMC migration and/or proliferation after
vascular injury.7 8 9 These agonists also can
activate the intracellular signaling pathways utilizing JAK and
STAT proteins.2 An expected finding was that Jak2 and
Stat3 were already somewhat phosphorylated in the
injured artery. Thus, the constitutive Jak2 and Stat3
phosphorylation in the injured artery may reflect the
phosphorylation induced by these agonists or hitherto
unidentified factors produced in the vessel wall in response to
vascular injury, which is possibly related to neointima
formation.
Molecular mechanisms of transient inductions of JAKs and STATs are
currently unknown. Phenotypic modulation of VSMCs from the
differentiated state to the dedifferentiated state is suggested to be
involved in the pathogenesis of neointima formation after
vascular injury. The induction of expressions of several proteins was
indeed observed during the phenotype transition.22
Thus, transient JAK and STAT expressions were possibly related to the
VSMC phenotype transition. To address this issue, we did
immunostaining for the phenotype-specific MHC
isoforms, SM2 and SMemb, for assessing VSMC phenotypes;
expression of SM2, a marker of differentiated VSMCs, and SMemb, a
marker of undifferentiated VSMCs, have been reported to be
downregulated and upregulated in neointimal VSMCs after
injury, respectively.23 As shown in the Table, time
course of the VSMC phenotypic transition, however, was not in accord
with those of JAK and STAT expressions. Thus, it is suggested that
transient expressions of JAKs and STATs are not necessarily associated
with the phenotype transition. Recent studies documented
transient inductions of JAKs and STATs in the nerve system after neural
damages.24 25 Additionally, the JAK/STAT pathway,
especially the Stat3-mediated pathway, induces the expression of a
variety of genes that dramatically increase with tissue injury and
inflammation.2 Taken together, it is possible that
induction of JAKs and STATs could be a ubiquitous response to tissue
injury. It is important to clarify the molecular mechanisms triggering
and modulating JAK and STAT expression in vascular remodeling in future
studies.
Limitations
Recent studies have demonstrated that a single periadventitial
administration of various drugs from pluronic F127 gel, a
sustained-release polymer, is an effective means of delivering drug
locally and limiting neointima formation in rat models, but
little is known regarding the pharmacodynamics of delivered
drugs.26 27 28 Currently, neither labeled compound nor
quantitative assay technique is available for direct measurements of
tissue AG490 concentrations. Moreover, no data are available regarding
the in vivo degradation rate of AG490. Therefore, the kinetics of AG490
released from pluronic gel matrix and the intramural AG490
concentrations remain to be elucidated. However, locally applied AG490
showed neither macroscopic nor microscopic changes in sham-operated
artery during the observation period. Thus, it seemed unlikely that the
observed effects of local AG490 treatment on neointima
formation were attributable to the toxic effects of the drug.
In conclusion, it is suggested that inductions of JAKs and STATs may be involved in the mechanisms of neointimal formation after balloon injury, especially in the second and third phases of the tissue response. Modulation of JAK and STAT expressions may be a regulatory mechanism of cellular responses to the agonists that activate the pathway, given that the enrichment of the components of the signaling cascade could be of crucial importance in effective signaling through the pathway. Finally, the present study may provide insight into a possible treatment strategy for the prevention of the progression of atherosclerosis and restenosis after angioplasty, especially after stent implantation.
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Acknowledgments |
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This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of the Education, Science, Sports and Culture of Japan and by a grant from the Kimura Memorial Foundation. We thank Dr Hiromi Rakugi for kindly providing the anti-AT1 antibody and Kaoru Moriyama for technical assistance.
Received May 9, 2000; accepted May 15, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
- Schindler C. Transcriptional responses to polypeptide ligands: the Jak-STAT pathway. Annu Rev Biochem. 1995;64:621–651.[Medline] [Order article via Infotrieve]
- Ihle JN. STATs: signal transducers and activators of transcription. Cell. 1996;84:331–334.[Medline] [Order article via Infotrieve]
- Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature. 1995;375:247–250.[Medline] [Order article via Infotrieve]
- Schieffer B, Bernstein KE, Marrero MB. The role of tyrosine phosphorylation in angiotensin II mediated intracellular signaling and cell growth. J Mol Med. 1996;74:85–91.[Medline] [Order article via Infotrieve]
-
Marrero MB, Schieffer B, Li B, Sun J, Harp JB, Ling
BN. Role of Janus kinase/signal transducer and activator of
transcription and mitogen-activated protein kinase cascades in
angiotensin II- and platelet-derived growth
factor-induced vascular smooth muscle cell proliferation. J
Biol Chem. 1997;272:24684–24690.
[Abstract/Free Full Text] - Schwartz SM, Reidy MA, O’Brien ERM. Assessment of factors important in atherosclerotic occlusion and restenosis. Thromb Haemost. 1995;74:541–551.[Medline] [Order article via Infotrieve]
- Majesky MW, Reidy MA, Bowen-Pope DF, Hart CE, Wilcox JN, Schwartz SM. PDGF ligand and receptor gene expression during repair of arterial injury. J Biol Chem. 1990;111:2149–2158.
-
Daemen MJAP, Lombardi DM, Bosman FT, Schwartz SM.
Angiotensin II induces smooth muscle proliferation in the
normal and injured rat arterial wall. Circ Res. 1991;68:450–456.
[Abstract/Free Full Text] -
Lindner VD, Reidy MA. Proliferation of smooth muscle
cells after vascular injury is inhibited by an antibody against basic
fibroblast growth factor. Proc Natl Acad Sci U S A. 1991;88:3739–3743.
[Abstract/Free Full Text] -
Powell J, Clozel J, Muller R, Kuhn H, Hefti F, Hosang
M, Baumgartner HR. Inhibitors of
angiotensin-converting enzyme prevent myointimal
proliferation after vascular injury. Science. 1989;245:186–188.
[Abstract/Free Full Text] - Prescott M, Webb RL, Reidy MA. ACE inhibitors versus AII, AT1 receptor antagonist: effects on smooth muscle cell migration and proliferation after balloon catheter injury. Am J Pathol. 1991;139:1291–1296.[Abstract]
- Powell JS, Muller RKM, Rouge M, Kuhn H, Hefti F, Baumgartner HR. The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition. J Cardiovasc Pharmacol. 1990;16:S42–S49.
-
Iwai N, Izumi M, Inagami T, Kinoshita M.
Induction of renin in medial smooth muscle cells by balloon injury.
Hypertension. 1997;29:1044–1050.
[Abstract/Free Full Text] - Rakugi H, Jacob HJ, Krieger JE, Ingelfinger JR, Pratt RE. Vascular injury induces angiotensinogen gene expression in the media and neointima. Circulation. 1993;90:1707–1712.
- Rakugi H, Kim DK, Krieger JE, Wang DS, Dzau VJ, Pratt RE. Induction of angiotensin converting enzyme in the neointima after vascular injury: possible role in restenosis. J Clin Invest. 1994;93:339–346.
- Viswanathan SM, Stromberg C, Seltzer A, Saavedra JM. Balloon angioplasty enhances the expression of angiotensin II AT1 receptors in neointima of rat aorta. J Clin Invest. 1992;90:1707–1712.
-
Yasukawa H, Imaizumi T, Matsuoka H, Nakashima A,
Morimatsu M. Inhibition of intimal hyperplasia after balloon injury by
antibodies to ICAM-1. Circulation. 1997;95:1515–1522.
[Abstract/Free Full Text] - Rakugi H, Okamura A, Kamide K, Ohishi M, Sasamura H, Morishita R, Higaki J, Ogihara T. Recognition of tissue- and subtype-specific modulation of angiotensin II receptors using antibodies against AT1 and AT2 receptors. Hypertens Res. 1997;20:51–55.[Medline] [Order article via Infotrieve]
-
Katoh M, Egashira K, Usui M, Ichiki T, Tomita H,
Shimokawa H, Rakugi H, Takeshita A. Cardiac angiotensin II
receptors are upregulated by long-term inhibition of nitric oxide
synthesis in rats. Circ Res. 1998;83:743–751.
[Abstract/Free Full Text] -
Kai H, Griendling KK, Lassègue B, Fukui T,
Minieri CA, Alexander RW. Prolonged exposure to agonist results in a
reduction in the levels of the
Gq/G11 -subunit in
cultured vascular smooth muscle cells. Mol Pharmacol. 1996;49:96–104.[Abstract]
-
Koyama H, Olson NE, Dastvan FF, Reidy MA. Cell
replication in the arterial wall: activation of signaling
pathway following in vivo injury. Circ Res. 1998;82:713–721.
[Abstract/Free Full Text] -
Owens GK. Regulation of differentiation of vascular
smooth muscle cells. Physiol Rev. 1995;75:487–517.
[Abstract/Free Full Text] - Okamoto E, Suzuki T, Aikawa M, Imataka K, Fujii J, Kuro-o M, Nakahara K, Hasegawa K, Yazaki Y, Nagai R. Diversity of the synthetic-state smooth muscle cells proliferating in mechanically and hemodynamically injured rabbit arteries. Lab Invest. 1996;74:120–128.[Medline] [Order article via Infotrieve]
- Planas AM, Soriano MA, Berruezo M, Justicia C, Estrada A, Pitarch S, Ferrer I. Induction of Stat 3, a signal transducer and transcription factor, in reactive microglia following transient focal cerebral ischemia. Eur J Neurosci. 1996;8:2612–2618.[Medline] [Order article via Infotrieve]
- Yao GL, Kato H, Khalil M, Kiryu S, Kiyama H. Selective upregulation of cytokine receptor subchain and their intracellular signalling molecules after peripheral nerve injury. Eur J Neurosci. 1997;9:1047–1054.[Medline] [Order article via Infotrieve]
- Indolfi C, Avvedimento EV, DiLorenzo E, Esposito G, Rapacciuolo A, Giuliano P, Grieco D, Cavuto L, Stingone AM, Ciullo I, Condorelli G, Chiariello M. Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury. Nat Med. 1997;3:775–779.[Medline] [Order article via Infotrieve]
- Ishizaka N, Taguchi J, Kimura Y, Ikari Y, Aizawa T, Togo M, Miki K, Ohno M. Effects of a single local administration of cilostazol on neointimal formation in balloon-injured rat carotid artery. Atherosclerosis. 1999;142:41–46.[Medline] [Order article via Infotrieve]
-
Hu Y, Zou Y, Dietrich H, Wick G, Xu Q. Inhibition of
neointima hyperplasia of mouse vein grafts by local applied
suramin. Circulation. 1999;100:861–868.
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 A. K. L. Banes-Berceli, P. Ketsawatsomkron, S. Ogbi, B. Patel, D. M. Pollock, and M. B. Marrero Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1291 - H1299. [Abstract] [Full Text] [PDF]
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D. Torella, A. Curcio, C. Gasparri, V. Galuppo, D. D. Serio, F. C. Surace, A. L. Cavaliere, A. Leone, C. Coppola, G. M. Ellison, et al. Fludarabine prevents smooth muscle proliferation in vitro and neointimal hyperplasia in vivo through specific inhibition of STAT-1 activation Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2935 - H2943. [Abstract] [Full Text] [PDF]
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|
 K. Srivastava, V. Kundumani-Sridharan, B. Zhang, A. K. Bajpai, and G. N. Rao 15(S)-Hydroxyeicosatetraenoic Acid-Induced Angiogenesis Requires STAT3-Dependent Expression of VEGF Cancer Res., May 1, 2007; 67(9): 4328 - 4336. [Abstract] [Full Text] [PDF]
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 K. Kusaba, H. Kai, M. Koga, N. Takayama, A. Ikeda, H. Yasukawa, Y. Seki, K. Egashira, and T. Imaizumi Inhibition of Intrinsic Interferon-{gamma} Function Prevents Neointima Formation After Balloon Injury Hypertension, April 1, 2007; 49(4): 909 - 915. [Abstract] [Full Text] [PDF]
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 S.-F. Yan, E. Harja, M. Andrassy, T. Fujita, and A. M. Schmidt Protein Kinase C {beta}/Early Growth Response-1 Pathway: A Key Player in Ischemia, Atherosclerosis, and Restenosis J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A47 - A55. [Abstract] [Full Text] [PDF]
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H. Cao, N. Dronadula, F. Rizvi, Q. Li, K. Srivastava, W. T. Gerthoffer, and G. N. Rao Novel Role for STAT-5B in the Regulation of Hsp27-FGF-2 Axis Facilitating Thrombin-Induced Vascular Smooth Muscle Cell Growth and Motility Circ. Res., April 14, 2006; 98(7): 913 - 922. [Abstract] [Full Text] [PDF]
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 W. KIM, B. I. HUDSON, B. MOSER, J. GUO, L. L. RONG, Y. LU, W. QU, E. LALLA, S. LERNER, Y. CHEN, et al. Receptor for Advanced Glycation End Products and Its Ligands: A Journey from the Complications of Diabetes to Its Pathogenesis Ann. N.Y. Acad. Sci., June 1, 2005; 1043(1): 553 - 561. [Abstract] [Full Text] [PDF]
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M. Andrassy, D. Belov, E. Harja, Y. S. Zou, M. Leitges, H. A. Katus, P. P. Nawroth, S. D. Yan, A. M. Schmidt, and S.-F. Yan Central Role of PKC{beta} in Neointimal Expansion Triggered by Acute Arterial Injury Circ. Res., March 4, 2005; 96(4): 476 - 483. [Abstract] [Full Text] [PDF]
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 T. A. Wallace, D. VonDerLinden, K. He, S. J. Frank, and P. P. Sayeski Microarray analyses identify JAK2 tyrosine kinase as a key mediator of ligand-independent gene expression Am J Physiol Cell Physiol, October 1, 2004; 287(4): C981 - C991. [Abstract] [Full Text] [PDF]
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S. F. Yan, R. Ramasamy, Y. Naka, and A. M. Schmidt Glycation, Inflammation, and RAGE: A Scaffold for the Macrovascular Complications of Diabetes and Beyond Circ. Res., December 12, 2003; 93(12): 1159 - 1169. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 T. Tokunou, R. Shibata, H. Kai, T. Ichiki, T. Morisaki, K. Fukuyama, H. Ono, N. Iino, S. Masuda, H. Shimokawa, et al. Apoptosis Induced by Inhibition of Cyclic AMP Response Element-Binding Protein in Vascular Smooth Muscle Cells Circulation, September 9, 2003; 108(10): 1246 - 1252. [Abstract] [Full Text] [PDF]
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|
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 G. D. Frank, S. Saito, E. D. Motley, T. Sasaki, M. Ohba, T. Kuroki, T. Inagami, and S. Eguchi Requirement of Ca2+ and PKC{delta} for Janus Kinase 2 Activation by Angiotensin II: Involvement of PYK2 Mol. Endocrinol., February 1, 2002; 16(2): 367 - 377. [Abstract] [Full Text] [PDF]
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H. Kai, F. Kuwahara, K. Tokuda, R. Shibata, K. Kusaba, H. Niiyama, N. Tahara, T. Nagata, and T. Imaizumi Coexistence of Hypercholesterolemia and Hypertension Impairs Adventitial Vascularization Hypertension, February 1, 2002; 39(2): 455 - 459. [Abstract] [Full Text] [PDF]
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