Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:208-213
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:208.)
© 2001 American Heart Association, Inc.
Low Blood Flow After Angioplasty Augments Mechanisms of Restenosis
Inward Vessel Remodeling, Cell Migration, and Activity of Genes Regulating Migration
Michael R. Ward;
Philip S. Tsao;
Alex Agrotis;
Rodney J. Dilley;
Garry L. Jennings;
Alex Bobik
From the Cell Biology Laboratory, Baker Medical Research Institute, and
Alfred Baker Medical Unit (M.R.W., A.A., R.J.D., G.L.J., A.B.), Alfred
Hospital, Prahran, Victoria, Australia, and the Department of Cardiovascular
Medicine (M.R.W., P.S.T.), Stanford University, Stanford, Calif.
Correspondence to Dr Michael Ward, MBBS, PhD, Department of Cardiology, Royal North Shore Hospital, St Leonards NSW 2065, Australia. E-mail mrward{at}doh.health.nsw.gov.au
 |
Abstract
|
|---|
AbstractThe
predominant cause of restenosis after angioplasty
is now
thought to be inward remodeling, but the mechanisms responsible
are
unknown. Remodeling in normal vessels is regulated by the
endothelium
in response to altered shear stress.
Although the endothelium
is often damaged by
angioplasty, restenosis rates after angioplasty
have been
correlated with impaired coronary flow. Thus, we examined
how
increases or decreases in blood flow through balloon catheterinjured
rat
carotid arteries affect vessel morphometry (4, 10, and 28 days),
cell
migration (4 days), and levels of promigratory mRNAs (2 and
10
days). After 28 days, the luminal area in vessels with low
blood
flow was significantly less than in those with normal
and high blood
flow (0.17±0.01 [low] versus 0.24±0.06
[normal] versus 0.30±0.02
[high] mm
2,
P<0.01), predominantly
because
of accentuated inward remodeling (or reduced area within
the external
elastic lamina; 0.42±0.02 [low] versus 0.54±0.07
[normal] versus
0.53±0.04 [high] mm
2,
P<0.05). Low
flow also
enhanced smooth muscle cell migration 4 days after
injury by 90% above
normal and high flows
(
P<0.01). Two days
after
injury, low flow significantly increased levels of mRNAs
encoding
promigratory peptides (integrin
vß
3, transforming
growth
factor-ß
1, CD44v6, MDC9, urokinase
plasminogen activator
receptor, and
ß-inducible gene h3); these changes persisted
10 days after injury
and were localized to the neointima. Low
blood flow may
promote restenosis after angioplasty because
of its adverse
effect on vessel remodeling, and it is associated
with the augmented
expression of multiple genes central to cell
migration and
restenosis.
Key Words: angioplasty restenosis remodeling blood flow
 |
Introduction
|
|---|
Inward remodeling,
or reduction in vessel size, is now considered
the predominant cause of
restenosis after
angioplasty
1 2 ;
however,
the mechanisms responsible are poorly understood. Mechanical
shear
stress on endothelial cells, which is due to an
alteration in
blood flow, is a major regulator of remodeling and vessel
size
in developing blood
vessels
3 and in blood vessels
affected
by atherosclerotic
lesions.
4 Coronary
blood flow is frequently
impaired in patients with
hypercholesterolemia and advanced
age,
5 and it can become
further impaired after
angioplasty,
6 raising
the
possibility that flow may also influence remodeling after
angioplasty.
In uninjured vessels, endothelial cells are central
to
structural adaptations to sustained changes in blood flow
because of
their ability to sense changes in blood flow and
to alter
production of the growth factors and metalloproteinases
required
by the vessels to
remodel.
7 Recent studies
indicate that when
cultured vascular smooth muscle cells (VSMCs) are in
the synthetic
phenotype, they respond to shear stress in an
analogous manner,
altering their production of growth
factors.
8 9 In the
balloon
catheterinjured and deendothelialized
rat carotid artery,
the VSMCs that migrate over the internal elastic
lamina to form
the neointima rapidly change to the
synthetic phenotype, and
they maintain phenotypic modulation
until at least 2 weeks after
injury.
10 11 Thus,
it is possible that juxtaluminal synthetic VSMCs could
respond to
abnormal shear forces in a manner similar to the
endothelium
in uninjured vessels and hence potentially
influence inward
remodeling. These observations prompted us to examine
how reductions
in blood flow affect luminal narrowing after
experimental angioplasty
in the rat carotid artery, through either
inward remodeling
or enlarging the neointima. Our findings
led us to further examine
how blood flow affects cellular migration and
the molecular
events that regulate it.
 |
Methods
|
|---|
Animals and Surgery
Male Sprague-Dawley rats, 400 to 500 g, were
anesthetized as
previously
described,
12 and a 2F Fogarty
arterial embolectomy
catheter (Baxter) was passed through
an arteriotomy in the left
common femoral into the left common carotid
artery to its bifurcation.
The balloon was inflated with 25 µL of
saline, withdrawn
with a rotating action to the aortic arch, and
reintroduced,
and withdrawal of the inflated balloon was repeated
twice. Flow
was then reduced by ligating the left internal carotid
artery
or increased by ligating the right common carotid artery. We
and
others have previously shown that these ligations reliably
decrease
blood flow by a mean of 35% and increase flow by 29%,
respectively.
13 14
Five animals per group were used, and reverse transcription
(RT)polymerase
chain reaction (PCR) analysis of whole-vessel
mRNA expression
was carried out on high- and low-flow vessels 2 days
after injury
and was compared with that in balloon-injured vessels in
which
the flow was unaltered after injury. Persistence of these changes
was
assessed by analysis of mRNA levels in high- and low-flow
vessels
10 days after injury. To localize the changes in mRNA
expression
10 days after injury within the vessel wall, the
arterial layers
(intima, media, and adventitia) were
separated under a dissecting
microscope in an additional 6 high-flow
and 6 low-flow injured
vessels, and layers from 3 vessels were combined
for mRNA analyses
(n=2 data points for each layer in each flow
group). Animals
were euthanized with an overdose of pentobarbital, and
vessels
were collected for mRNA analyses as previously
described.
12 Fifteen minutes
before perfusion fixation, Evans blue dye (Sigma
Chemical Co) was
injected intravenously (60 mg/kg) to demarcate
the degree
of endothelial regrowth in each vessel as previously
described.
15 Vessels for
morphometry were perfusion-fixed with 4% formalin
in PBS (pH 7.4) at
90 to 100 mm Hg pressure for 5 minutes, dissected
free of
surrounding tissue as previously
described,
15 and then
fixed
for a further 24 hours in 4% formalin before embedding.
Five vessels
with high flow and 5 with low flow were used for
morphometry at each
time point (4, 10, and 28 days).
Morphometry and Immunohistochemistry
Formalin-fixed carotid arteries were cut into 5
segments and embedded in paraffin, and 4-µm-thick cross sections were
cut with a microtome. After deparaffinization, the sections were
stained with hematoxylin, and then the area of the
neointima and media, the area encompassed by the external
elastic lamina, and the luminal area were measured from each segment of
vessel by use of computed planimetry as previously
described,15 and the results
were averaged from the 5 segments for each vessel. Immunohistochemistry
to confirm VSMC identity in the neointima 4 days after
injury was carried out as previously
described15 with the use of a
mouse monoclonal anti-human
-smooth muscle actin antibody (Sigma)
and a biotinylated secondary horse anti-mouse antibody (Vector
Laboratories). After staining for
-smooth muscle actin with the use
of the chromogen 3,3'-diaminobenzidine tetrachloride and
counterstaining with hematoxylin, nuclei present in the
neointima 4 days after injury were counted and averaged
over the cross sections from the 5 segments of each
vessel.
mRNA Analyses by Standardized
RT-PCR
For analysis of mRNA levels in segments of
the injured arteries, total RNA was extracted and treated with DNase
(Promega) to ensure a final DNA-free RNA preparation, exactly as
previously described.12 Two
hundred nanograms of RNA was reverse-transcribed by use of a GeneAmp
RNA-PCR kit (Perkin-Elmer), and then specific fragments were amplified
from mRNAs encoding the disintegrin-metalloprotease MDC9, ß-inducible
gene h3 (ß-igh3), urokinase plasminogen
activator (uPA) and its cell surface receptor (uPAR), the
hyaluronate receptor CD44v6, integrins
v and
ß3, transforming growth factor
(TGF)-ß1 and its receptors ALK-5 and TßR-II,
and the housekeeping gene L7 by use of thermal cycling conditions as
previously described.12 The
oligonucleotide primers used to amplify the integrins
v, ß3,
TGF-ß1, ALK-5, TßR-II, and L7 were as
previously described.12
The sense and antisense oligonucleotides for
MDC9 were targeted to base pairs 1008 to 1037 and 1510 to 1539,
respectively, of the rat
cDNA16 ; sense and antisense
CD44v6 oligonucleotides, to base pairs 691 to 720 and
1111 to 1140, respectively, of the rat
cDNA17 ; sense and antisense
ß-igh3 oligonucleotides, to base pairs 246 to 271 and
713 to 742, respectively, of its rat
cDNA18 ; sense and antisense
uPA oligonucleotides, to base pairs 680 to 709 and 993
to 1012, respectively, of its rat
cDNA19 ; and sense and
antisense uPAR, to base pairs 431 to 460 and 712 to 737, respectively,
of its rat cDNA.20
RT-PCRgenerated cDNA fragment identities were confirmed by use of
either diagnostic restriction endonucleases or
nucleotide sequencing
(TaqTrack, Promega) after
cloning into pGEM-T vectors (Promega). The number of cycles optimum for
each primer pair to accurately estimate mRNA levels was determined, and
the assays were validated as previously
described.12 The amount of
PCR product generated from the different
oligonucleotide primers was expressed relative to the
L7 RT-PCR product, a noninducible cell cycleindependent ribosomal
protein that is unaltered during VSMC
proliferation.21 PCR
products were quantified by laser densitometry from the
photographic negatives of agarose gels, in which the fragments were
electrophoresed, under UV light. We have previously shown this method
to be highly reliable in estimating mRNA levels with
R values >0.95 and an average
coefficient of variation of
<10%.12
Statistical Analysis
Results are expressed as mean±SEM.
Parameters of vessel structure and changes in mRNA levels
were analyzed by ANOVA or ANOVA on ranks as appropriate,
followed by multiple pairwise comparison with Student-Newman-Keuls
test. A value of P<0.05 was
considered statistically significant. Simple linear regression was used
to examine the relationship between time and luminal area or vessel
area.
 |
Results
|
|---|
Effects of Blood Flow on Vessel Structure
After Angioplasty
Initially, we compared how changes in blood flow
through the
left common carotid artery made at the time of balloon
injury
affected its overall structure during healing. Twenty-eight
days
after injury, the luminal area of the vessels with low
blood flow was
reduced by 43% compared with those with high
blood flow
(
P<0.01,
Figure 1

) and by 30% relative to vessels
with normal flow
(
P<0.05,
Table 1

). The difference in luminal
size between
arteries with high and low blood flow was progressive
with time
(Figure 1

). Luminal area (LA,
mm
2) in relation to
time (T, days) after
injury was best described by the following
equations: for low flow,
LA=0.569-0.291 log T
(
R2=0.78,
P<0.001);
for normal flow,
LA=0.575-0.231 log T
(
R2=0.39,
P<0.01);
and for high flow,
LA=0.581-0.195 log T
(
R2=0.26,
P=0.07).

View larger version (59K):
[in this window]
[in a new window]
|
Figure 1. Blood flow and vessel remodeling. Top, Representative hematoxylin-stained sections of vessels 28 days after balloon injury with low flow (left) and high flow (right). Bottom, Temporal changes in lumen cross-sectional area (left) and cross-sectional area encompassed by the external elastic lamina (right) after angioplasty of vessels with high and low flow. Bars represent mean±SEM from 5 vessels per time point.
|
|
This was accompanied by a 20% reduction in vessel area, or
cross-sectional area within the external elastic lamina (aEEL),
compared with vessels with high or normal blood flow
(P<0.05). Approximately 80%
of the flow-dependent reduction in luminal size was due to reduction in
vessel area. The time course of reduction in area encompassed by the
external elastic lamina was similar to the time course of luminal loss.
In the low-flow vessels, aEEL (mm2) was best
described by the following equation: aEEL=0.662-0.168 log T
(R2=0.41,
P=0.02). The relationships
between reductions in vessel area and time were not statistically
significant in normal- and high-flow vessels.
The neointimal area increased rapidly in the
vessels with low blood flow, and 10 days after injury, this area was
significantly greater than that in vessels with both high and normal
flow. By 28 days, however, this difference was reduced and accounted
for only
20% of the difference in luminal size between high- and
low-flow vessels
(Table 1
). Neither cross-sectional area nor thickness of the
media in the injured vessels was significantly affected by change in
blood flow
(Table 1
). As has been previously
described,22 there was no
apparent difference between high- and low-flow vessels in the degree of
endothelial regrowth, which was always <25% of the
length of the vessel (not shown).
Blood Flow and Smooth Muscle Cell
Migration
The cellular rearrangements necessary for a
vessel to remodel likely involve cellular migration. Others have
previously postulated that low flow may augment VSMC migration,
inasmuch as low flow does not affect VSMC proliferation rates despite
increasing neointimal
formation.13 Augmentation of
inward remodeling in vessels with low blood flow appeared to be
initiated early after balloon catheter injury, which is
consistent with a role for altered cell migration in
flow-dependent luminal loss. Although migration is difficult to
quantify in vivo, the accumulation of cells in the intima early (
4
days) after injury is considered to be mostly due to the migration of
VSMCs from the injured
media.23 Therefore, we
examined how flow affected intimal VSMC accumulation in injured
vessels. Four days after the injury, there were 90% more cells in the
neointima of vessels with low flow than in those with high
and normal flow (P<0.01,
Figure 2
). Immunohistochemical staining showed that all
intimal cells contained
-smooth muscle actin (not shown), confirming
their smooth muscle cell identity.

View larger version (14K):
[in this window]
[in a new window]
|
Figure 2. Intimal smooth muscle cell (SMC) accumulation 4 days after angioplasty in vessels with high and low blood flow. Bars represent the mean±SEM from 5 injured vessels of the number of intimal cells averaged over 5 segments per vessel. *P<0.01 vs high-flow group.
|
|
Blood Flow Regulates Genes Essential for
Cell Migration
We then examined how blood flow influences the activity
of genes that others have shown to regulate cell migration: the
integrin subunits
v and
ß3, whose dimer is known to be critical for
VSMC migration, and osteopontin (its chief matrix
ligand),24 uPA and its cell
surface receptor uPAR,25
transforming growth factor-ß1 and its type I
and type II signaling receptors (ALK-5 and TßRII), and ß-igh3,
which inhibits cell-matrix attachment and is thought to reflect TGF-ß
bioactivity.26 Two novel mRNA
species were also selected for analysis: the
disintegrin-metalloprotease MDC9, which plays a critical role in cell
migration through directed membrane-bound protease and
Arg-Gly-Aspblocking
activities,16 and the splice
variant of the hyaluronate receptor CD44v6, which is preferentially
upregulated after vessel injury and potentiates VSMC migration by
increasing interaction with hyaluronate in the extracellular
matrix.27
Although injury alone (normal flow group) is known to
significantly upregulate the expression of these mRNAs, 2 days after
balloon injury there was significant further mRNA expression in the
low-flow group of MDC9, ß-igh3, CD44v6, integrins
v and ß3, uPAR,
TGF-ß1, ALK-5, and TßR-II
(Table 2
). Flow did not affect the expression of osteopontin
or urokinase. In vessels with high flow, mRNA levels were similar to
those with normal flow. The heightened expression of these mRNA species
in low-flow conditions fell over time, although those encoding MDC9,
CD44v6, TGF-ß1, and integrins
v and ß3 continued
to be significantly higher 10 days after the initial injury in vessels
with low flow compared with those with high flow by 5.7±2.7-,
1.7±0.2-, 3.1±0.9-, 1.7±0.3-, and 1.5±0.3-fold, respectively (all
P<0.05). Additional
experiments in which RNA was extracted from the neointima,
media, and adventitia separately indicated that the higher MDC 9 and
CD44v6 mRNA levels in the low-flow vessels were localized to the
neointima but that integrin
v and
TGF-ß mRNA were greater in the neointima and media of the
low-flow vessels than the high-flow vessels (data not
shown).
View this table:
[in this window]
[in a new window]
|
Table 2. Effects of Changes in Blood Flow in Balloon
CatheterInjured Arteries on Expression of mRNAs Encoding Proteins
Implicated in Cell Migration
|
|
 |
Discussion
|
|---|
The present study demonstrates that low blood flow
in injured
deendothelialized arteries
accelerates inward remodeling and
significantly augments the reduction
in luminal size observed
late after injury. Reduced flow also
potentiates VSMC migration
in the injured artery and enhances the mRNA
expression of several
proteins involved in migration, providing 1
potential contributing
mechanism to flow-dependent inward remodeling.
These findings
have major implications for restenosis after
angioplasty, in
which the majority of late luminal loss occurs as a
result of
inward vessel
remodeling,
1 2
because impaired flow is common
in atherosclerotic
arteries,
5 particularly after
angioplasty,
6 and is
associated with increased rates of
restenosis.
28 29
Our findings indicate that injured vessels devoid of
endothelium can be remodeled in a flow-dependent
manner. Although others have previously used computer modeling of shear
stress to show that inward remodeling after angioplasty is correlated
with reduced shear,30 this is
the first direct evidence that poor flow in a newly injured vessel will
exacerbate inward remodeling. The present study may appear in
direct conflict with previous investigators who have found that gentle
removal of the endothelium prevents inward remodeling
in response to reduced
flow.31 However, in these
studies, the atraumatic techniques used for gentle
deendothelialization appeared not to induce the usual
injury-induced medial smooth muscle cell phenotypic modulation (from
"contractile" to "synthetic"), inasmuch as
neointimal formation due to cell migration and
proliferation was absent and vasoconstriction to neoepinephrine
was preserved. Phenotypic modulation may be critical in determining the
response to altered flow because flow-responsive production of
the growth factors and matrix metalloproteinases to which
flow-sensitive
remodeling8 9 32 33
has been attributed has been demonstrated only in VSMCs of the
synthetic phenotype (cultured VSMCs or flow-exposed VSMCs after
injury).10 11 34
Presumably, VSMCs of the contractile phenotype are either
unable to sense flow or have insufficient protein synthetic systems to
respond to flow. These observations have specific relevance to
restenosis after coronary angioplasty, in which
flow-exposed VSMCs are also dedifferentiated for some time after human
percutaneous transluminal coronary
angioplasty.35 36
Although the most likely causes of the effects of flow on
remodeling, migration, and mRNA expression are shear-responsive
transcriptional events, other factors, including the effects of flow on
platelet activation, paracrine cell activation, vessel wall
stretch, and compression due to wave-form changes, may play a role. The
minor endothelial regrowth observed in high- and
low-flow vessels suggests that other flow-exposed cells are responsible
for the flow-dependent remodeling. In the present study,
flow-dependent mRNA expression 10 days after injury was chiefly
localized to the neointima, which is consistent
with production by flow-exposed synthetic smooth muscle
cells.
Remodeling is a complex and poorly understood process that
involves alteration in the balance between cell proliferation and
apoptosis3 and matrix
protein production and
degradation.37 Augmented
smooth muscle cell migration (within the media, from the media to the
intima or adventitia, and vice versa) likely also contributes to the
structural rearrangement of vascular remodeling. In the present
study, increased VSMC migration into the intima was associated with
accentuated inward remodeling and may be a surrogate marker for total
vessel cellular motility. Such morphological measures of stimulated
migration were preceded by enhanced expression of mRNAs, which have
previously been reported to be important in cell migration. Several of
these mRNAs and their immunoreactive protein products are
significantly upregulated by injury
itself12 25 27
and have been implicated in negative
remodeling38 39 and
restenosis after
angioplasty.26 40
However, although the genes all affect cell migration, they also have
significant effects on cell proliferation/apoptosis
(TGF-ß1 and integrin
vß3) and matrix
turnover (TGF-ß1 and uPA/uPAR), and their
association with enhanced inward remodeling may reflect their influence
on multiple components of the remodeling process. Intervention to
specifically block either cell migration or these proteins or both
would enhance our appreciation of the relationship between these genes,
cell migration, and remodeling.
In the present study, low flow significantly enhanced
neointimal formation at 10 days, but this effect declined
and was not significant at 28 days, similar to the pattern of growth in
previous studies.13 The lack
of growth of the intima in low-flow vessels between 10 and 28 days
likely reflects the stimulatory effect of low flow on
apoptosis,3 which
becomes increasingly important in this time
period,41 or the
normalization of shear stress resulting from luminal loss and inward
remodeling.
Interestingly, there were no differences in migration,
migratory protein expression, and remodeling between high- and
normal-flow vessels. Previous studies of flow-mediated outward
remodeling in uninjured vessels have demonstrated no vessel enlargement
with up to 60% increases in flow, although much larger increases
stimulate vessel
enlargement.42 The authors
concluded that the events that regulate shear-responsive outward
remodeling may have a threshold for activation, and it appears that
similar thresholds may exist in injured vessels.
The findings of the present study have specific
relevance for restenosis after human angioplasty and stenting.
Impaired coronary flow may persist after dilatation of
flow-limiting stenoses because of microvascular dysfunction,
infarction of some of the tissue downstream, or the presence of
persistent collateral circulation. An excess incidence of
restenosis is observed when impaired coronary flow
reserve persists after angiographically successful
angioplasty,28 29
and it is observed specifically in patients with persistent collateral
flow after the opening of a chronic total
occlusion.43 Although inward
remodeling does not occur in stented vessels, low flow also appears to
increase stent
restenosis44 ; this
increase is presumably due to prolonged stimulation of intimal
hyperplasia by persistently low shear stress in the absence of inward
remodeling.
In conclusion, the present study indicates that blood
flow is an important regulator of vessel remodeling after angioplasty
and that reduced blood flow enhances many mechanisms involved in cell
migration, providing a link between the effects of flow on molecular,
cellular, and morphological processes. Although the basic molecular
mechanisms by which low flow ultimately affects gene activity remain to
be fully elucidated, these responses provide potential targets through
which it may be possible to influence remodeling after
angioplasty.
 |
Acknowledgments
|
|---|
This work was funded in part by an
NH&MRC of Australia block
grant and an NHF of Australia
project grant. Michael Ward was
supported by an NH&MRC (Australia)
postgraduate medical
scholarship.
Received April 10, 2000;
accepted June 5, 2000.
 |
References
|
|---|
-
Kimura T,
Kaburagi S, Tamura T, Yokoi H, Nakagawa Y, Yokoi H, Hamasaki N, Nosaka
H, Nobuyoshi M, Mintz GS, et al. Remodeling of human coronary
arteries undergoing coronary angioplasty or atherectomy.
Circulation. 1997;96:475483.[Abstract/Free Full Text]
-
Mintz GS, Popma JJ,
Pichard AD, Kent KM, Satler LF, Wong C, Hong MK, Kovach JA, Leon MD.
Arterial remodeling after coronary angioplasty: a
serial intravascular ultrasound study.
Circulation. 1996;94:3543.[Abstract/Free Full Text]
-
Cho A, Mitchell L,
Koopmans D, Langille BL. Effects of changes in blood flow rate on cell
death and cell proliferation in carotid arteries of immature rabbits.
Circ Res. 1997;81:328337.[Abstract/Free Full Text]
-
Kramsch DM, Aspen
AJ, Abramowitz BM, Kreimendahl T, Hood WB Jr. Reduction of
coronary atherosclerosis by moderate
conditioning exercise in monkeys on an atherogenic diet.
N Engl J Med. 1981;305:14831489.[Abstract]
-
Zeiher AM, Drexler
H, Saurbier B, Just H. Endothelium-mediated
coronary blood flow modulation in humans: effects of age,
atherosclerosis,
hypercholesterolemia, and hypertension.
J Clin Invest. 1993;92:652662.
-
Uren NG, Crake T,
Lefroy DC, de Silva R, Davies GJ, Maseri A. Delayed recovery of
coronary resistive vessel function after coronary
angioplasty. J Am Coll
Cardiol. 1993;21:612621.[Abstract]
-
Traub O, Berk BC.
Laminar shear stress: mechanisms by which endothelial
cells transduce an atheroprotective force.
Arterioscler Thromb Vasc Biol. 1998;18:677685.[Abstract/Free Full Text]
-
Sterpetti AV, Cucina
A, Fragale A, Lepidi S, Cavallaro A, Santoro DAL. Shear stress
influences the release of platelet derived growth factor and basic
fibroblast growth factor by arterial smooth muscle cells.
Eur J Vasc Surg. 1994;8:138142.[Medline]
[Order article via Infotrieve]
-
Ueba H, Kawakami M,
Yaginuma T. Shear stress as an inhibitor of vascular smooth
muscle cell proliferation: role of transforming growth factor-beta 1
and tissue-type plasminogen activator.
Arterioscler Thromb Vasc Biol. 1997;17:15121516.[Abstract/Free Full Text]
-
Bobik A,
Dilley RJ, Wong J, Krushinsky A. Cytokines,
atherosclerosis and neointimal hyperplasia.
In: Meyers KA, Nicolaides AN, Sumner DS, eds.
Lower Limb Ischaemia. London,
UK: Med-Orion; 1997:654672.
-
Thyberg J,
Blomgren K, Hedin U, Dryjski M. Phenotypic modulation of smooth muscle
cells during the formation of neointimal thickenings in the
rat carotid artery after balloon injury: an electron-microscopic and
stereological study. Cell Tissue
Res. 1995;281:421433.[Medline]
[Order article via Infotrieve]
-
Ward MR, Agrotis
A, Kanellakis P, Dilley R, Jennings G, Bobik A. Inhibition of protein
tyrosine kinases attenuates increases in expression of transforming
growth factor-beta isoforms and their receptors following
arterial injury. Arterioscler
Thromb Vasc Biol. 1997;17:24612470.[Abstract/Free Full Text]
-
Kohler TR, Jawien
A. Flow affects development of intimal hyperplasia after
arterial injury in rats.
Arterioscler Thromb. 1992;12:963971.[Abstract/Free Full Text]
-
Ueno H, Kanellakis
P, Agrotis A, Bobik A. Blood flow regulates the development of vascular
hypertrophy, smooth muscle cell proliferation and
endothelial cell nitric oxide synthase in hypertension.
Hypertension. 2000;36:8996.[Abstract/Free Full Text]
-
Wong J, Rauhoft C,
Dilley RJ, Agrotis A, Jennings GL, Bobik A.
Angiotensin-converting enzyme inhibition abolishes medial
smooth muscle PDGF-AB biosynthesis and attenuates cell proliferation in
injured carotid arteries: relationships to neointima
formation. Circulation. 1997;96:16311640.[Abstract/Free Full Text]
-
Weskamp G,
Kratzschmar J, Reid MS, Blobel CP. MDC9, a widely expressed cellular
disintegrin containing cytoplasmic SH3 ligand domains.
J Cell Biol. 1996;132:717726.[Abstract/Free Full Text]
-
Gunthert U,
Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A,
Ponta H, Herrlich P. A new variant of glycoprotein CD44
confers metastatic potential to rat carcinoma cells.
Cell. 1991;65:1324.[Medline]
[Order article via Infotrieve]
-
Skonier J,
Neubauer M, Madisen L, Bennett K, Plowman GD, Purchio AF. cDNA cloning
and sequence analysis of beta ig-h3, a novel gene induced in a
human adenocarcinoma cell line after treatment with transforming growth
factor-beta. DNA Cell Biol. 1992;11:511522.[Medline]
[Order article via Infotrieve]
-
Ragno P, Cassano
S, Degen J, Kessler C, Blasi F, Rossi G. The receptor for the
plasminogen activator of urokinase type is
up-regulated in transformed rat thyroid cells.
FEBS Lett. 1992;306:193198.[Medline]
[Order article via Infotrieve]
-
Kristensen P,
Eriksen J, Blasi F, Dano K. Two alternatively spliced mouse urokinase
receptor mRNAs with different histological localization
in the gastrointestinal tract. J Cell
Biol. 1991;115:17631771.[Abstract/Free Full Text]
-
Wick M, Burger C,
Brüsselbach S, Lucibello FC, Muller R. Identification of
serum-inducible genes: different patterns of gene regulation during
G0
S and G1
S progression. J Cell
Sci. 1994;107:227239.[Abstract]
-
Sugiyama T,
Kawamura K, Nanjo H, Sageshima M, Masuda H. Loss of
arterial dilation in the reendothelialized
area of the flow-loaded rat common carotid artery.
Arterioscler Thromb Vasc Biol. 1997;17:30833091.[Abstract/Free Full Text]
-
Jackson CL, Raines
EW, Ross R, Reidy MA. Role of endogenous
platelet-derived growth factor in arterial smooth
muscle cell migration after balloon catheter injury.
Arterioscler Thromb. 1993;13:12181226.[Abstract/Free Full Text]
-
Panda D, Kundu GC,
Lee BI, Peri A, Fohl D, Chackalaparampil J, Stark K, Mukherjee AB.
Potential roles of osteopontin and alphaVbeta3 integrin in the
development of coronary artery restenosis after
angioplasty. Proc Natl Acad Sci
U S A. 1997;94:93089313.[Abstract/Free Full Text]
-
Tkachuk V,
Stepanova V, Little PJ, Bobik A. Regulation and role of urokinase
plasminogen activator in vascular remodelling.
Clin Exp Pharmacol Physiol. 1996;23:759765.[Medline]
[Order article via Infotrieve]
-
OBrien ER,
Bennett KL, Garvin MR, Zderic TW, Hinohara T, Simpson JB, Kimura T,
Nobuyoshi M, Mizgala H, Purchio A, et al. Beta ig-h3, a transforming
growth factor-ßinducible gene, is overexpressed in atherosclerotic
and restenotic human vascular lesions.
Arterioscler Thromb Vasc Biol. 1996;16:576584.[Abstract/Free Full Text]
-
Jain M, He Q, Lee
WS, Kashiki S, Foster LC, Tsai JC, Lee ME, Haber E. Role of CD44 in the
reaction of vascular smooth muscle cells to arterial wall
injury. J Clin Invest. 1996;97:596603.[Medline]
[Order article via Infotrieve]
-
Stankovic G,
Manginas A, Voudris V, Pavlides G, Athanassopoulos G, Ostojic M,
Cokkinos DV. Prediction of restenosis after coronary
angioplasty by use of a new index: TIMI frame count/minimal luminal
diameter ratio. Circulation. 2000;101:962968.[Abstract/Free Full Text]
-
Serruys PW, di
Mario C, Piek J, Schroeder E, Vrints C, Probst P, de Bruyne B, Hanet C,
Fleck E, Haude M, et al. Prognostic value of intracoronary flow
velocity and diameter stenosis in assessing the short- and
long-term outcomes of coronary balloon angioplasty: the DEBATE
Study (Doppler Endpoints Balloon Angioplasty Trial Europe).
Circulation. 1997;96:33693377.[Abstract/Free Full Text]
-
Krams R, Wentzel
JJ, Oomen JA, Schuurbiers JC, Andhyiswara I, Kloet J, Post M, de Smet
B, Borst C, Slager CJ, et al. Shear stress in
atherosclerosis, and vascular remodelling.
Semin Intervent Cardiol. 1998;3:3944.[Medline]
[Order article via Infotrieve]
-
Langille BL,
ODonnell F. Reductions in arterial diameter produced by
chronic decreases in blood flow are
endothelium-dependent.
Science. 1986;231:405407.[Abstract/Free Full Text]
-
Bassiouny HS, Song
RH, Hong XF, Singh A, Kocharyan H, Glagov S. Flow regulation of 72-kD
collagenase IV (MMP-2) after experimental
arterial injury.
Circulation. 1998;98:157163.[Abstract/Free Full Text]
-
Kraiss LW, Geary
RL, Mattsson EJ, Vergel S, Au YP, Clowes AW. Acute reductions in blood
flow and shear stress induce platelet-derived growth factor-A
expression in baboon prosthetic grafts.
Circ Res. 1996;79:4553.[Abstract/Free Full Text]
-
Chamley-Campbell
J, Campbell GR, Ross R. The smooth muscle cell in culture.
Physiol Rev. 1979;59:161.[Free Full Text]
-
Ueda M, Becker AE,
Naruko T, Kojima A. Smooth muscle cell de-differentiation is a
fundamental change preceding wound healing after
percutaneous transluminal coronary angioplasty
in humans. Coron Artery Dis. 1995;6:7181.[Medline]
[Order article via Infotrieve]
-
Aikawa M, Sakomura
Y, Ueda M, Kimura K, Manabe I, Ishiwata S, Komiyama N, Yamaguchi H,
Yazaki Y, Nagai R. Redifferentiation of smooth muscle cells after
coronary angioplasty determined via myosin heavy chain
expression. Circulation. 1997;96:8290.[Abstract/Free Full Text]
-
Coats WD, Jr,
Whittaker P, Cheung DT, Currier JW, Han B, Faxon DP. Collagen content
is significantly lower in restenotic versus
nonrestenotic vessels after balloon angioplasty in the
atherosclerotic rabbit model.
Circulation. 1997;95:12931300.[Abstract/Free Full Text]
-
Smith JD, Bryant
SR, Couper LL, Vary P, Gotwals PJ, Koteliansky VE, Lindner V. Soluble
transforming growth factor-ß type II receptor inhibits negative
remodeling, fibroblast transdifferentiation, and intimal lesion
formation but not endothelial growth.
Circ Res. 1999;84:12121222.[Abstract/Free Full Text]
-
Shi Y, OBrien JE
Jr, Fard A, Zalewski A. Transforming growth factor-ß1 expression and
myofibroblast formation during arterial repair.
Arterioscler Thromb Vasc Biol. 1996;16:12981305.[Abstract/Free Full Text]
-
Strauss BH, Lau
HK, Bowman KA, Sparks J, Chisholm RJ, Garvey MB, Fenkell LL, Natarajan
MK, Singh I, Teitel JM, et al. Plasma urokinase antigen and
plasminogen activator inhibitor-1
antigen levels predict angiographic coronary
restenosis.
Circulation. 1999;100:16161622.[Abstract/Free Full Text]
-
Bochaton-Piallat
ML, Gabbiani F, Redard M, Desmouliere A, Gabbiani G. Apoptosis
participates in cellularity regulation during rat aortic intimal
thickening. Am J Pathol. 1995;146:10591064.[Abstract]
-
Brownlee RD,
Langille BL. Arterial adaptations to altered blood flow.
Can J Physiol Pharmacol. 1991;69:978983.[Medline]
[Order article via Infotrieve]
-
Billinger M,
Fleisch M, Meier B, Seiler C. Coronary collaterals and
restenosis following percutaneous
revascularisation. J Am Coll
Cardiol. 1998;31:242A. Abstract.
-
Wentzel JJ, Kloet
J, Krams R, Serruys PW, Slager CJ. The relationship between
neointimal thickness and shear stress after wall stent
implantation in human coronary arteries at 6 months follow-up.
Circulation. 1999;100(suppl
I):I-727. Abstract.
This article has been cited by other articles:

|
 |

|
 |
 
V. A. Korshunov, S. M. Schwartz, and B. C. Berk
Vascular Remodeling: Hemodynamic and Biochemical Mechanisms Underlying Glagov's Phenomenon
Arterioscler. Thromb. Vasc. Biol.,
August 1, 2007;
27(8):
1722 - 1728.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
W. T. Gerthoffer
Mechanisms of Vascular Smooth Muscle Cell Migration
Circ. Res.,
March 16, 2007;
100(5):
607 - 621.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. O. Platt, R. F. Ankeny, and H. Jo
Laminar Shear Stress Inhibits Cathepsin L Activity in Endothelial Cells
Arterioscler. Thromb. Vasc. Biol.,
August 1, 2006;
26(8):
1784 - 1790.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Dorffler-Melly, F. Mahler, D.-D. Do, J. Triller, and I. Baumgartner
Adjunctive Abciximab Improves Patency and Functional Outcome in Endovascular Treatment of Femoropopliteal Occlusions: Initial Experience
Radiology,
December 1, 2005;
237(3):
1103 - 1109.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Agrotis, P. Kanellakis, G. Kostolias, G. Di Vitto, C. Wei, R. Hannan, G. Jennings, and A. Bobik
Proliferation of Neointimal Smooth Muscle Cells after Arterial Injury: DEPENDENCE ON INTERACTIONS BETWEEN FIBROBLAST GROWTH FACTOR RECEPTOR-2 AND FIBROBLAST GROWTH FACTOR-9
J. Biol. Chem.,
October 1, 2004;
279(40):
42221 - 42229.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
X. Lu, X. Guo, C. Linares, and G. S. Kassab
A new method to denude the endothelium without damage to media: structural, functional, and biomechanical validation
Am J Physiol Heart Circ Physiol,
May 1, 2004;
286(5):
H1889 - H1894.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. Li, E. W. Lee, H. Ji, and Z. Zukowska
Neuropeptide Y-Induced Acceleration of Postangioplasty Occlusion of Rat Carotid Artery
Arterioscler. Thromb. Vasc. Biol.,
July 1, 2003;
23(7):
1204 - 1210.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Ward, C. Indolfi, and D. Torella
Physical Training and Restenosis * Response
Circ. Res.,
April 4, 2003;
92
(6):
e60 - e60.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. J. Sullivan and J. B. Hoying
Flow-Dependent Remodeling in the Carotid Artery of Fibroblast Growth Factor-2 Knockout Mice
Arterioscler. Thromb. Vasc. Biol.,
July 1, 2002;
22(7):
1100 - 1105.
[Abstract]
[Full Text]
[PDF]
|
 |
|