© 2000 American Heart Association, Inc.
Vascular Biology |
All-trans-Retinoic Acid Limits Restenosis After Balloon Angioplasty in the Focally Atherosclerotic Rabbit
A Favorable Effect on Vessel Remodeling
From the Cardiovascular Division, Department of Medicine (P.J.W., W.L.B., J.A.M. C.A.M., L.W.G., J.MS, G.G.B., E.R.P., M.R., I.J.S.) and the Department of Molecular Physiology and Cellular Biophysics (G.K.O.), University of Virginia Health Sciences Center, Charlottesville.
Correspondence to Ian J. Sarembock, MD, Cardiovascular Division, Department of Medicine, Box 158, University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail ijs4s{at}virginia.edu
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Abstract |
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Abstract—All-trans-retinoic acid (atRA) has potent in vitro effects on a number of processes involved in vascular injury and repair, such as modulating smooth muscle cell (SMC) proliferation and inducing SMC differentiation, and may play an important role in the in vivo response to vascular injury. We hypothesized that atRA would limit restenosis after balloon angioplasty through SMC-modulated changes in plaque size and vessel geometry. Balloon angioplasty was performed on rabbits with focal femoral atherosclerosis randomized to treatment with atRA or saline. At 28 days after balloon angioplasty, minimal luminal diameter was significantly larger in the atRA group (1.24±0.17 versus 1.12±0.22 mm, P=0.02). Histomorphometry confirmed a larger lumen area (0.51±0.20 versus 0.34±0.13 mm2, P=0.004) in the atRA group, with no difference in absolute plaque area. Internal elastic lamina and external elastic lamina areas were significantly larger in the atRA group (0.89±0.27 versus 0.66±0.24 mm2, P=0.001, and 1.29±0.38 versus 0.98±0.32 mm2, P=0.001, respectively). Vessel sections exhibited significantly more
-actin and desmin immunostaining
(P=0.01) in the atRA-treated group. No differences in
early cellular proliferation and collagen content were detected with
the use of bromodeoxyuridine. In this atherosclerotic model of vascular
injury, atRA limits restenosis after balloon angioplasty by
effects secondary to overall vessel segment enlargement at the
angioplasty site rather than by effects on plaque size or cellular
proliferation. Increased -actin and desmin
immunostaining suggest a possible role for phenotypic
modulation of SMCs in this favorable remodeling effect.
Key Words: retinoic acid • restenosis • remodeling • angioplasty • smooth muscle cells
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Introduction |
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Despite extensive investigation, the effectiveness of percutaneous transluminal coronary angioplasty remains limited by restenosis at the angioplasty site.1 2 3 Restenosis is thought to involve a complex interaction of biological processes initiated by arterial injury with resultant platelet deposition; thrombin generation; release of chemotactic, vasoactive, and mitogenic factors; migration and proliferation of smooth muscle cells (SMCs); and extracellular matrix synthesis. These processes combine to produce neointimal plaque growth and remodeling of vascular architecture resulting in variable degrees of arterial narrowing.4 5 6
All-trans-retinoic acid (atRA), a naturally occurring
metabolite of vitamin A, has potent in vitro effects on a number of
processes thought to be involved in the vascular response to injury.
For example, atRA has been shown to induce differentiation of
multipotential embryonal carcinoma cells to express multiple SMC
characteristics, including changes in cell morphology, responses to
contractile agonists, and expression of SMC-specific isoforms of
-actin and myosin heavy chain.7 Furthermore, atRA
induces cultured SMCs to assume a more differentiated contractile
phenotype, as assessed by -actin expression.8
By inducing SMCs to differentiate into a mature "contractile"
phenotype, atRA could potentially limit neointimal
formation and possibly hinder pathological vascular remodeling after
vascular injury by inhibiting the secretion of growth factors,
chemokines, and the elaboration of extracellular matrix by
"dedifferentiated" (-actin–negative) SMCs. Other studies
suggest that retinoids not only affect the phenotypic modulation of
SMCs but also inhibit cellular proliferation,9 increase
elastin synthesis,10 inhibit collagen
synthesis,11 and stimulate metalloproteinase
inhibitor production by fibroblasts,12
all of which may have important effects on matrix dynamics and
stability of the atherosclerotic plaque. Retinoids have a number of
other actions, including immunomodulatory actions,13
modification of cytokine-induced responses14
affecting nitric oxide production in macrophages and
cultured SMCs,15 16 and reduction of tissue factor/factor
VIIa–dependent arterial thrombus
formation.17 18 Finally, functional retinoid receptors
have been identified in cultured SMCs, and atRA has been shown to
inhibit SMC growth in vitro.19
In vitro, atRA differentiates leukemic promyelocytes into mature cells, and complete remission rates of 90% have been observed in phase 2 studies of patients with acute promyelocytic leukemia by use of atRA at doses of 1.0 to 1.5 mg/kg.20 21 22 To date, few in vivo studies have addressed the role of atRA in the response to arterial injury.23 On the basis of its effects on modulating SMC proliferation and differentiation, we hypothesized that atRA would limit restenosis after balloon angioplasty (BA) in the focally atherosclerotic rabbit either by changes in plaque size or by vessel geometry.
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Methods |
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Induction of Focal Femoral Atherosclerosis
Thirty-six male New Zealand White rabbits weighing 4.0±0.4 kg were anesthetized by intramuscular injection of ketamine (35 mg/kg) and xylazine (5 mg/kg). Bilateral focal atherosclerosis was induced in 1- to 2-cm femoral artery segments by air desiccation endothelial injury, followed by a 2% cholesterol/6% peanut oil diet for 28 days as described previously.24 25 The rabbits were housed according to Animal Welfare Act specifications, and all surgical procedures were performed using a sterile technique and general anesthesia.
Drug Administration
Twenty-six animals were randomly assigned to treatment with atRA
or placebo for 28 days. The atRA was administered at a dose of 25 mg in
1.5 mL of vegetable oil (
6 mg/kg per day) by oral intubation daily
for the 3 days before and for 28 days after BA (n=11). Control animals
(n=15) received vegetable oil alone by the same method. Blood samples
for serum atRA levels were obtained when the animals were euthanized.
Blood was stored in vacuum tubes shielded from light and
centrifuged within 2 hours. The serum fraction was isolated and
stored at -70°C. Samples were shipped on dry ice to the M.D.
Anderson Cancer Center, University of Texas, Houston, for
analysis by high-pressure liquid chromatography
(kindly provided by Dr Herbert A. Fritsche). This dose of atRA has been
shown to be of moderate teratogenicity in rabbits26 and
was slightly greater (3 to 4 times) than the dose used in human acute
promyelocytic leukemia.20 21 This regimen of atRA has been
shown to produce peak and trough atRA concentrations in rabbit serum of
100 and 5 ng/mL, respectively.26 All animals received
heparin (150 U/kg) by intravenous bolus immediately before
BA.
Balloon Angioplasty
After induction of anesthesia, the right carotid
artery was exposed through a midline neck incision. A 5F Berman
catheter (Arrow International, Inc) was inserted via an arteriotomy and
advanced into the descending aorta under fluoroscopic guidance.
Baseline angiography was performed by using a Siemens Optilux
angiographic system, and images were recorded on 35-mm
cineradiographic film with the use of 5 mL Hexabrix (39.3%
ioxaglate meglumine/19.6% ioxaglate sodium injection) diluted with 5
mL of sterile saline. A grid with 10-mm markings was used as an
internal calibration standard. BA was performed by use of a 0.014-in.
guidewire and a 2.5-mm balloon dilation catheter with three 60-second
10-atm inflations. The same protocol was repeated for the contralateral
femoral artery. The catheter and vascular sheath were then removed, the
carotid artery was ligated, and the wound was closed. Rabbits (n=26)
were maintained for 28 days after BA and fed normal rabbit chow. Final
angiography was performed with the left carotid artery and the
technique described above just before euthanasia.
Angiography
Angiograms were analyzed on a Sony coronary
angiography diagramming and reporting system. Minimum luminal diameter
(MLD) of the femoral artery segment was measured before BA, after BA,
and at 28 days in a blinded fashion by 2 observers. Intraobserver and
interobserver variability were 0.95 and 0.94, respectively. All images
were obtained in 1 angiographic plane and calibrated with a
grid.
Pressure Perfusion and Specimen Preparation
At 28 days after BA, final angiography was performed, and the
animals were euthanized by an overdose of sodium pentobarbital. The
distal aorta and iliofemoral segments were perfused at
physiological pressure (100 mm Hg and 22°C)
with 100 mL of 4% buffered paraformaldehyde. Segments
of the femoral artery (4 to 5 cm) were harvested bilaterally, and
the proximal and distal ends were marked with silk ligatures. The
specimens were postfixed in 4% buffered
paraformaldehyde and prepared for light microscopy.
Histopathology and Immunostaining
Each femoral artery segment was cut in cross section at 3- to
4-mm intervals, dehydrated in 70% ethanol and xylene, and embedded in
paraffin. Serial 5-µm sections from each 3- to 4-mm segment were
stained by use of the Movat technique. The section with the
greatest luminal narrowing was identified for each angioplasty site,
and quantitative histomorphometry was performed in a blinded fashion
with an Olympus AH-2, Vanox-S microscope in association with Mocha
image analysis software and a 486/80-based PC. The luminal
border, internal elastic lamina (IEL), and external elastic lamina
(EEL) were traced at the same magnification, and the image was
calibrated to a 1-mm grid. Overall vessel size was measured as the
total area bounded by the EEL. Plaque size was measured as the area
bounded by the IEL minus the lumen area.
Injury Score
Each femoral artery segment used for quantitative
histological evaluation was also evaluated for the
extent of injury by using a semiquantitative scale. The scoring system
was as follows: 0 indicates sections with IEL intact and media
compressed but not lacerated; 1, EL lacerated, with media compressed
but not lacerated; 2, IEL and media lacerated, with EEL intact; and 3,
large transluminal laceration involving the EEL.
SMC Characterization
The characterization of the "quiescent" contractile SMC
phenotype was assessed by -actin and desmin
immunostaining with the avidin-biotin-peroxidase method
(Vector Laboratories). Sections from all analyzed vessels were
stained with anti–SM–specific -actin antibody (clone HHF-35,
undiluted, Enzo Inc), and quantitative analysis was performed
in a blinded fashion by using the microscopic image analysis
system described above. Digitized images were analyzed for
areas of positive staining with Image-Pro software, version 3.0 (Media
Cybernetics). A color threshold mask for immunostaining
was defined to detect the brown color by sampling, and the same
threshold was applied to all the vessels. For each arterial
section, the area (mm2) of the intima and media
with -actin staining was determined. One adjacent section from each
vessel was also stained with anti-desmin antibody (clone 33, 1:80
dilution, BioGenex Laboratories), and semiquantitative analysis
was performed by a blinded observer using a 0 to 4 scaling system (0,
indicating absence of staining, to 4, indicating diffuse heavy
staining). Negative controls for desmin and -actin stains were
performed on vessel sections with omission of the primary antibody.
Serial vessel segments were analyzed for collagen content by
use of Sirius red staining (F3BA Sirius red, Cell Point), and polarized
microscopy and a semiquantitative scale were used as described
above.
Bromodeoxyuridine Labeling for Cellular Proliferation
Ten rabbits (n=5 for atRA, n=5 for controls) received 50 mg
bromodeoxyuridine (BrdU, Sigma Chemical Co) by subcutaneous injection
twice daily for 3 days after balloon dilatation to investigate the
effect of atRA on early cellular proliferation after BA. Vessels were
prepared as described above. Sections were stained for BrdU-positive
nuclei by use of a mouse monoclonal anti-BrdU antibody (Dako, Inc) and
an anti-mouse IgG "ABC" kit (Vector Laboratories).
BrdU-positive immunostaining in the intima and media
was analyzed by the image analysis system described
above. Analysis of each section was performed twice to assure
reproducibility. Cumulative BrdU incorporation is reported as total
number of BrdU-positive nuclei per millimeter.
Statistical Analysis
Data are reported as the number of femoral arteries in each
experimental group and expressed as the mean±SD. Angiographic and
histological differences between the 2 treatment groups
were analyzed by the Student t test. For
nonparametric data, such as the injury score and desmin
score, differences between the 2 treatment groups were detected by use
of a 2-tailed Mann-Whitney U test. A value of
P
0.05 was considered significant. Correlation of IEL and
EEL to plaque area of the atRA and control groups was performed by
regression analysis.
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Results |
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Drug Levels
At euthanasia, atRA concentrations in the blood were 44±30 ng/mL in the atRA-treated animals compared with 0 ng/mL in the control animals (P=0.004).
Angiography
The angiographic data are summarized in Figure 1
. MLD was similar in the 2 treatment
groups at baseline (pre-BA) and immediately after BA (post-BA). Vessels
with abrupt closure at the angioplasty site immediately after BA were
excluded from analysis (n=1 for atRA, n=4 for controls),
resulting in 21 vessels (from 11 rabbits) analyzed in the atRA
group and 26 (from 15 rabbits) in the control group. The MLD 28 days
after BA was significantly larger in the atRA group (1.24±0.17
mm, n=21) than in the control group (1.12±0.22 mm, n=26;
P=0.02). Upstream reference segments were similar in the
atRA and control groups at baseline, immediately after BA, and at
euthanasia (1.44±0.21 versus 1.38±0.19 mm, P=0.25;
1.44±0.25 versus 1.37±0.18 mm, P=0.30; and
1.32±0.23 versus 1.32±0.28 mm, P=0.97, respectively).
In addition, no significant differences were present in the
angiographic MLD of the reference segments within the respective
treatment groups at the various time points (pre-BA, post-BA, and at 28
days).
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Histomorphometry
Results of planimetric analysis are illustrated in Figure 2. Histomorphometry confirmed a larger
lumen area in the atRA group than in the control group (0.51±0.20
versus 0.34±0.13 mm2, P=0.004).
Absolute plaque area was similar in the atRA and control groups
(0.38±0.19 versus 0.32± 0.14 mm2,
P=0.15). The IEL and EEL areas were significantly larger at
the angioplasty site in the atRA group than in the control group
(0.89±0.27 versus 0.66±0.24 mm2,
P=0.001, and 1.29±0.38 versus 0.98±0.32
mm2, P=0.001, respectively). Figure 3 demonstrates the correlation of IEL
area (panel A) and EEL area (panel B) to plaque area (in
mm2) in the atRA and control groups (atRA group,
IEL=0.96x plaque area+0.53, P=0.001; control group,
IEL=0.50xplaque area+0.18, P=0.0001; atRA group,
EEL=0.53xplaque area+0.71, P=0.0001; and control group,
EEL=0.9xplaque area+0.37, P=0.0001). At similar plaque
areas, both IEL and EEL areas were greater in the atRA group,
demonstrating an effect on favorable remodeling to a larger vessel
size, which translates into a larger lumen size as measured by both
angiography and histomorphometry. Vessel injury scores were not
statistically different between atRA-treated and control animals
(1.3±1.2 versus 0.83±0.92, respectively).
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Cellular Proliferation
Cellular proliferation, as measured by cumulative BrdU
incorporation at 72 hours post-BA, was similar in the atRA (n=10
vessels) and control (n=10 vessels) groups. The mean number of
BrdU-positive cells was 799±371 cells/mm2 in the
atRA group versus 988±465 cells/mm2 in the
control group (P=0.39).
-Actin, Desmin, and Collagen Staining
Results of the -actin and desmin staining are depicted in
Figure 4, and representative photomicrographs are shown in Figure 5. Vessel sections in the atRA-treated
group exhibited significantly more -actin staining than did the
control group (0.23±0.11 versus 0.15±0.06
mm2, P=0.01). Similarly, desmin
immunostaining by qualitative scoring was higher in the
atRA group than the control group (mean desmin score, 1.90±0.76 versus
1.35±0.55, P=0.01). Collagen staining was similar in the 2
groups (qualitative score, 0.39±0.13 versus 0.39±0.14
mm2).
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Discussion |
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The results of the present study performed in the double-injured focally atherosclerotic rabbit demonstrate that both angiographic and histological lumen areas were larger at 28 days after BA in atRA-treated animals compared with control animals. This effect on lumen size was secondary to a larger overall vessel size at the angioplasty site rather than the result of a smaller plaque area or an inhibition of early cellular proliferation.
Although strategies to limit restenosis have focused on
inhibition of SMC proliferation and/or thrombosis,27 28 29 30 31 32
more recent observations suggest that changes in overall vessel size at
the injury site may contribute to restenosis. "Unfavorable"
or negative vascular remodeling, defined as a decrease in EEL area, has
been reported by serial intravascular ultrasound studies to contribute
to the late luminal narrowing associated with restenosis in
humans.33 34 The determinants of vascular remodeling to an
overall smaller vessel size after arterial injury remain
poorly understood. Coronary stenting provides a mechanical
strategy to potentially reduce this problem.35 Recently,
prolonged pretreatment with the antioxidant probucol was shown to
reduce restenosis in humans, primarily through improved
vascular remodeling after angioplasty.36 The authors
speculated that the antioxidant effects of probucol may have modified
vascular remodeling through decreased SMC activation, migration, and
proliferation, resulting in limited matrix degradation and new collagen
deposition. Our data suggest that atRA may also favorably affect
vascular remodeling after vessel injury. The cellular and molecular
mechanisms involved in this effect on vascular dimensions are unknown.
Our observation that atRA did not alter cumulative BrdU incorporation
at 3 days after BA provides evidence that the in vivo effect on lumen
size is not predominantly due to inhibition of early cellular
proliferation. Previous studies in our laboratory have suggested that
the peak SMC proliferation occurs 3 days after BA, with return of
cellular proliferation to baseline at 7 days.37 The
finding of similar rates of proliferation in the treatment and control
groups is contrary to observations in cell culture, where atRA has been
shown to inhibit proliferation of SMCs.9 19 38 Additional
studies are necessary to determine whether this apparent contradiction
may be due to species differences or different behavior of SMCs in
culture versus SMCs in vivo after vascular injury. In addition, other
mediators of SMC proliferation in vivo may not be affected by atRA. It
is also possible that inhibition of SMC mitogenesis is only seen at
higher doses than we used in vivo. Our dose of 6 mg/kg per day is 3
to 4 times the dose used in human clinical trials in acute
promyelocytic leukemia.20 21 22 In vitro, atRA inhibits
platelet-derived growth factor–stimulated
[3H]thymidine uptake in a dose-dependent
manner, being maximal at 2x10-6
mol/L.19
Another possible mechanism by which atRA produces its favorable effect on remodeling might be by altering the elastic properties of the vessel wall and/or affecting vascular tone.9 In the present study, the luminal dimensions of the reference segments upstream from the angioplasty site were similar in both the atRA and control groups when examined by serial angiography, arguing against a generalized increase in vessel caliber through modulation of vascular tone, vessel elasticity, or blood pressure. Retinoids may also modulate collagen and elastin production at the angioplasty site in response to injury, resulting in a favorable effect on the healing response.9 10 11 However, our data did not demonstrate a difference in total vessel collagen content as measured by Sirius red staining, arguing against a significant effect on collagen metabolism.
A further interesting possibility is that atRA has important effects on
the manifestation of SMC phenotype in vivo. The
maintenance of SMCs in a "quiescent" phenotype
might in part explain the favorable effect we observed on overall
vessel size of the injured segment. There is extensive evidence showing
that phenotypic modulation of SMCs is important in the response to
arterial injury. Phenotypic modulation involves conversion
of SMCs from a quiescent, differentiated, "contractile"
phenotype to a less differentiated "secretory"
phenotype characterized by an increase in growth responsiveness
and enhanced secretion of extracellular matrix proteins.39
atRA has been shown in a variety of cell culture experiments to impact
a variety of these processes, ultimately promoting SMC phenotypic
differentiation, resulting in increased collagen and metalloproteinase
inhibitor production, which may then permit
favorable enlargement of the injured segment.7 8 9 10 11 12 13 14 In
support of this hypothesis, in the atRA-treated group, we observed
significantly more -actin and desmin staining: proteins were
expressed to a greater degree by cells in the quiescent
"contractile" phenotype. Our observations, however, do not
establish a causal relation or chronicle the time course of SMC
-actin and desmin expression after injury. We believe that this
would be an interesting focus for future studies of the potential
beneficial effects of atRA on arterial repair.
The present study analyzed the effects of atRA on restenosis in this model by using both an in vivo method (angiography) and an in vitro method (histomorphometry). Despite perfusion with paraformaldehyde at physiological pressure, vessel shrinkage does occur during dehydration and processing before paraffin embedding. All vessels in the atRA and control groups are subject to this. A discrepancy between the angiographic MLD and the histomorphometry clearly exists. However, the directional changes in lumen size by both measures (1 in vivo and 1 in vitro) are concordant. Therefore, we assert that conclusions drawn on these data are valid. A further limitation of the present study was the fixed dose used in the experiment. The dose chosen was slightly higher than that used in human trials of atRA in the treatment of acute promyelocytic leukemia and was a dose shown to be of moderate teratogenicity in rabbits. A complete dose-response study of the drug is beyond the scope of the present investigation.
In conclusion, atRA resulted in a larger luminal diameter 28 days after
BA, as determined by both angiography and histomorphometry in the
hypercholesterolemic, focally atherosclerotic rabbit
model of restenosis. The larger luminal diameter was secondary
to an overall larger vessel size of the injured segment without a
demonstrable effect on plaque size or early cellular proliferation.
atRA resulted in no difference in early cellular proliferation or
vessel collagen content but did result in higher -actin and desmin
staining, suggesting a role of phenotypic modulation in producing the
favorable vessel enlargement after vascular injury.
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Acknowledgments |
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This study was supported in part by an American Heart Association National Grant-in-Aid (No. 95009480 to Dr Sarembock). We thank the members of the vivarium staff of the Department of Comparative Medicine at the University of Virginia for their excellent animal care, Dr Ariel Gomez for use of the image analysis system, Dr Herbert A. Fritsche for analysis of retinoic acid levels, John J. Kim for his expert technical assistance, and Dr S. David Gertz for his helpful review of the manuscript.
Received February 11, 1999; accepted August 23, 1999.
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