© 1997 American Heart Association, Inc.
Articles |
Vascular Myofibroblasts
Lessons From Coronary Repair and Remodeling
From the Department of Medicine (Cardiology), Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Andrew Zalewski, MD, Cardiovascular Research Center, Division of Cardiology, Thomas Jefferson University, 1025 Walnut St, Suite 410N, Philadelphia, PA 19107.
Key Words: coronary artery • myofibroblast • smooth muscle • adventitia
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Introduction |
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 Top Introduction Fibroblasts, Myofibroblasts, and...Are Myofibroblasts a...Myofibroblasts in Other...Future DirectionsSummaryReferences |
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Vascular repair and remodeling represents a common theme of many cardiovascular abnormalities. This is not surprising, since frequent exposure of blood vessels to excessive hemodynamic stress (eg, hypertension), the noxious effects of blood contents (eg, atherogenic lipids), and locally released cytokines (eg, postangioplasty) require readily available mechanism(s) to counteract their adverse effects and to preserve the intactness of the vessel wall. These responses, which were evolutionarily developed to repair an injured tissue, often escape self-limiting control and result in lumen narrowing. Various vascular lesions contain mesenchymal cells, different from normal medial cells, which has been viewed as evidence that smooth muscle (SM) cells modulate their phenotype in response to changes in the environment in situ.1 2 3 This concept has been further reinforced by the dedifferentiation of SM cells to a "synthetic" phenotype in culture.4 The presence of "nonmuscle" cells in the normal vessel wall, however, raises an intriguing question regarding whether they contribute to vascular repair while acquiring markers of muscle differentiation. This review will examine the potential role of these cells in coronary repair and remodeling.
Seminal studies by Gabbiani and coworkers5 6 have
established that wound healing is associated with rapid activation of
fibroblasts, which proliferate, migrate, and undergo differentiation to
myofibroblasts. These cells acquire bundles of microfilaments (stress
fibers) and develop extensive connections with the surrounding
extracellular matrix, a change which is consistent with the primary
role of newly formed myofibroblasts to close an open wound by means of
extracellular matrix protein synthesis and contraction.7
Subsequent studies have confirmed the pivotal role of myofibroblasts in
a wide range of other pathological conditions associated with
fibrogenesis and organ remodeling.8 9 10 11 Although
myofibroblasts from such diverse sources are heterogeneous, their
common feature is the expression of 
-SM actin.12 When
wound healing is completed, myofibroblasts are usually eliminated by
apoptosis,6 except in cases of so-called fibrocontractive
disorders, in which their presence is sustained, leading to organ
fibrosis and/or constrictive remodeling.8 13 The
ubiquitous formation of myofibroblasts reflects a common mechanism of
tissue repair, which raises the fundamental question of whether a
similar phenomenon occurs in the vessel wall in response to injury. In
the normal artery, nonmuscle cells are primarily found in the
adventitia, which also contains vasa vasorum and rich sympathetic
innervation. Since activated fibroblasts are notorious for their
ability to acquire not only -SM actin but also several other markers
of muscle differentiation,12 the presence of
myofibroblasts in the vessel wall can be easily overlooked and their
impact on vascular repair attributed to abundant SM cells.
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Fibroblasts, Myofibroblasts, and Coronary Restenosis |
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TopIntroductionFibroblasts, Myofibroblasts, and...Are Myofibroblasts a...Myofibroblasts in Other...Future DirectionsSummaryReferences |
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Adventitial Response to Injury
In porcine coronary vasculature, balloon-induced injury often results in medial dissection and exposure of the adventitia to the lumen. This condition initiates a chain of events reminiscent of the wound-healing process. Cell proliferation is the early phenomenon, which involves the entire adventitia, with the majority of cells representing activated fibroblasts (see the Figure
, A).
This burst of proliferation is short-lived, lasting 
1
week.14 Coronary media shows a significantly lower level
of cell proliferation at any time point, consistent with a higher
degree of differentiation of resident SM cells. The activation of
fibroblasts is accompanied by their differentiation to myofibroblasts,
with the appearance of -SM actin in the adventitia beginning at 3
days and reaching a maximum at 7 to 14 days (Figure,
B).14 15 Thus, fibroblasts acquire some markers of muscle
differentiation, whereas medial SM cells are known to exhibit a loss of
-SM actin expression after arterial injury.1 16
Phenotypic changes affecting adventitial cells are accompanied by the
induction of procollagen 1(I) mRNA and intracellular protein in
fibroblasts and later in myofibroblasts (Figure, C). This is followed
by the deposition of mature extracellular collagen, which is abundant
in the adventitia at later times (
1 month). The activation of
adventitial fibroblasts results in focal enlargement of the adventitia,
initially due to its hypercellularity and tissue edema, followed by the
development of a collagen-rich scar.14 17 In contrast to
these dynamic changes, the media exhibits much less pronounced
alterations in collagen synthesis.17
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Remodeling of the adventitia raises questions as to the factors that
initiate and then sustain this response. Several cytokines released
from platelets or cell debris, and thrombin itself, which is deposited
at the site of balloon injury, undoubtedly contribute to the initial
wave of cell proliferation. Cell proliferation alone, however, cannot
entirely explain adventitial changes after coronary injury. The
expression of transforming growth factor (TGF) ß1, which is rapidly
induced in injured coronary adventitia (Figure
, D), may provide a
differentiation signal for fibroblasts to acquire -SM
actin,18 analogous to the induction of myodifferentiation
in nonvascular tissues, or even in medial SM cells.19 20
In injured coronary arteries, the autocrine TGFß1 expression is
highly localized to adventitial myofibroblasts, which reflects the
ability of TGFß1 to exert profibrotic and remodeling effects mediated
by myofibroblasts. The ultrastructural characteristics of these cells
demonstrate the abundance of stress fibers and dilated rough
endoplasmic reticulum, reminiscent of myofibroblasts originally
described in wound healing.18
Neointima and Its Origin
The mere presence of -SM actin does not necessarily reflect the
SM origin of neointimal cells, since markers of muscle differentiation
(even desmin) can be acquired by the adjacent adventitial fibroblasts
(Table).14 15 Furthermore, various
perivascular manipulations have been reported to induce the neointima
or conversely, adventitial applications of antiproliferative agents
decreased tissue growth at the luminal surface in some animal
models.21 22 23 These observations raise a provocative
question regarding whether myofibroblasts derived from adventitial
cells contribute to neointimal formation after severe medial injury,
analogous to activated wound fibroblasts invading the site of tissue
loss. Alternatively, the role of myofibroblasts could be limited to
adventitial remodeling, and the neointima may be solely derived from
the edges of disrupted media. The relationship between the adventitial
exposure to the lumen and neointimal formation suggests the
contribution of myofibroblasts to luminal repair.14 24 25
When activated adventitial fibroblasts are labeled with
bromodeoxyuridine (BrdU), which exploits their early proliferation,
labeled cells acquire -SM actin, traverse the external elastic
lamina, and then appear in the neointima (Figure, E).15 25
Although the precise number of translocating adventitial cells and
their ultimate fate are difficult to assess, it is striking that the
portions of the intact media appear to serve as a barrier, preventing
the activated cells from migrating.25 Consistent with the
above observations, when the coronary media and adventitia are
separated and then examined in organ culture, the latter demonstrates
preferential outward cell migration. This is paralleled by higher
activity of matrix-degrading metalloproteinases released from the
adventitia. Conversely, the media synthesizes more of the inhibitor of
matrix metalloproteinases, which may contribute to less accentuated
migration of medial SM cells (Y.S., unpublished data, 1997). It is
important to underscore that the above observations do not preclude the
participation of medial SM cells released from the protective sheath of
basal membrane at the edges of disrupted media.
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Constrictive Remodeling
Recent experimental and clinical findings have challenged the
previously accepted view that luminal narrowing (ie, restenosis) is
solely due to the growth of neointima after transcatheter
interventions.26 27 In fact, early formation of neointima
is often associated with compensatory vessel enlargement followed by
shrinkage of the arterial cross-sectional area. This observation raises
the possibility that adventitial myofibroblasts contribute to this
process, analogous to their nonvascular counterparts, which reduce
dimensions of collagen gels ex vivo and produce wound contraction in
vivo. The remodeling properties of myofibroblasts are related to the
presence of -SM actin, inasmuch as its depolymerization abrogates
this phenomenon in vitro.28 In addition, the expression of
integrins is likely involved, allowing for specific cell-matrix
interactions. Although adventitial myofibroblasts are the major source
of collagen and may initiate its reorganization after coronary injury,
other factors should also be considered. In contrast to wound
contraction, adventitial myofibroblasts are largely absent at the time
of the most notable constrictive arterial remodeling (3 months)
(Figure, F). This factor suggests that further realignment of
collagenous scar and intermolecular cross-linking continue within the
adventitia at the time of cellular quiescence.
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Are Myofibroblasts a Model-Dependent Phenomenon? |
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TopIntroductionFibroblasts, Myofibroblasts, and...Are Myofibroblasts a...Myofibroblasts in Other...Future DirectionsSummaryReferences |
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The complexity of human vascular lesions opens to criticism the findings regarding any mechanisms of vascular repair derived from animal models. This skepticism is further amplified by the failure of presumed therapies, which are effective in small animals (eg, rat), to translate to a clinical benefit in the prevention of coronary restenosis in patients. Thus, it is important to critically consider whether vascular myofibroblasts represent a model-dependent phenomenon or whether the conditions for their presence actually exist in patients with cardiovascular disorders.
Species Differences
Invaluable lessons concerning vascular repair have been learned
from many pioneering studies using small animal models (eg, rat,
rabbit).16 29 30 Without denying their importance,
however, the concern can be raised whether they are fully
representative of coronary arterial repair. Different degrees of SM
cell differentiation in lower species may explain higher proliferation
rates of medial cells and the ensuing neointimal formation without
adventitial exposure to the lumen. In larger animals (and presumably in
humans), arterial injury devoid of medial dissection induces only a
small neointima.25 Its origin has been recently linked to
cellular heterogeneity of the media, which appears to contain sparse
nonmuscle cells.31 These cells are virtually identical to
adventitial fibroblasts but differ from enzymatically isolated medial
SM cells, which are less likely to proliferate or adhere. In addition
to species-dependent considerations, well-recognized changes in the
phenotype of cultured SM cells could be accentuated by their release
from the stabilizing effects of the basal membrane in vitro or they may
represent the selection of myofibroblasts that are more responsive to
proliferative stimuli.31
Severity of Injury
The interruption of the media and the exposure of the adventitia
to the lumen are important for the rapid induction of myofibroblast
phenotype in balloon-injured porcine coronary arteries. Likewise,
coronary angioplasty in patients appears to result in vascular injury
extending to the adventitia, most often unrecognized
angiographically.3 Furthermore, intracoronary stent
deployment, which requires high pressure expansion, conceivably results
in even more extensive exposure of the adventitia. Although stents
reduce the rate of restenosis in patients owing to a larger acute gain
and the elimination of constrictive remodeling, the permanent
implantation of a foreign body increases the local thrombotic and
inflammatory responses, which may augment myofibroblast migration.
Coronary Versus Noncoronary Vasculature
Since coronary restenosis remains the "Achilles' heel" of
transcatheter coronary interventions, regional differences in response
to vascular injury should also be taken into consideration. Coronary
arteries differ from the aorta or peripheral arteries with regard to
fetal development, postnatal histological architecture, and
cytoskeletal characteristics of the resident cells.32 33
These factors suggest that the arterial "substrate" may influence
the contribution of myofibroblasts in coronary arterial repair as well
as provide the explanation for regional differences in the propensity
to develop atherosclerotic lesions.
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Myofibroblasts in Other Cardiovascular Abnormalities |
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TopIntroductionFibroblasts, Myofibroblasts, and...Are Myofibroblasts a...Myofibroblasts in Other...Future DirectionsSummaryReferences |
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Vein Graft Remodeling
Venous grafts undergo remodeling changes after their placement in the arterial system. In a porcine model of saphenous vein graft interposition in the carotid artery, the perigraft "wound" is transiently populated by myofibroblasts, which surround the vein and are subsequently replaced by the collagenous scar commonly encountered during reoperations.34 These changes may contribute to the failure of aortocoronary saphenous vein grafts to undergo compensatory dilation when atherosclerotic lesions begin to compromise the lumen.35 The activation of the perigraft fibroblasts brings to question the origin of the intima that almost invariably develops after these procedures. When perigraft fibroblasts are selectively labeled at the time of their proliferation, they appear to migrate through the media to the luminal surface, changing their phenotype to myofibroblasts. This process is facilitated by unavoidable medial injury induced by harvesting and the intraoperative storage of venous conduits as well as by a high number of reactive nonmuscle cells normally present in venous media (
25%).36
Atherosclerosis
The development of atherosclerosis is tightly linked to the
existence of intima, which has provided the basis for its recent
description as the "soil" for atherosclerosis.37 If
adventitial or medial fibroblasts can acquire several characteristics
of synthetic SM-like cells, their subsequent migration and synthetic
capabilities could favor lipid retention, leading to lesion development
over the course of several decades. Interestingly, the application of
the inflammatory cytokine interleukin-1ß to the adventitia induces
coronary vasospasm and neointimal formation even without endoluminal
manipulations in pigs.38 These findings bear relevance to
clinical settings, since the accumulation of mast cells and the
inflammatory reaction in the adventitia are notable in patients with
coronary vasospasm and fatal unstable coronary syndromes,
respectively.39 40 Several adhesion molecules are highly
expressed in intimal neovasculature and adventitial vasa vasorum of
human coronary lesions, suggesting the presence of additional routes
for inflammatory cell recruitment into developing atherosclerotic
plaque.41 Although the exact cause of these changes
remains to be determined, the adventitia may serve as a reservoir for
several cytokines that may initiate the activation of the surrounding
fibroblasts.
Myocardial Remodeling
Left ventricular remodeling is a common response to hypertension
and myocardial infarction. The accompanying increase in collagen
content contributes to abnormal left ventricular function. In
experimental renovascular hypertension, progressive scarring of the
adventitia of intramyocardial coronary arteries is associated with the
outward extension of collagen deposition into the interstitial
space.42 A different mechanism is involved after
myocardial infarction in which interstitial myofibroblasts with
abundant collagen expression appear to have a sustained
presence.13
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Future Directions |
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TopIntroductionFibroblasts, Myofibroblasts, and...Are Myofibroblasts a...Myofibroblasts in Other...Future DirectionsSummaryReferences |
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Myofibroblast Identification
Earlier studies have shown that
-SM actin–expressing cells,
derived from several nonvascular tissues, are of fibroblast origin and
do not represent the admixture by SM cells or pericytes.43
In the cardiovascular system, the identification of myofibroblasts has
been even more challenging because of the abundance of medial SM cells.
The recognition of myofibroblasts has been based on spatial (eg,
adventitia) and temporal (eg, after arterial injury) changes in the
expression of cytoskeletal markers (mainly -SM
actin).14 15 25 31 In addition, ultrastructural
characteristics and the synthesis of extracellular matrix proteins aid
in the recognition of these cells.17 18 There is clearly
the need for better cytoskeletal or molecular markers that can
distinguish the spectrum of myofibroblast phenotypes from medial SM
cells to discern their respective contributions in several
cardiovascular abnormalities.
Therapeutic Implications
The activation of adventitial fibroblasts after experimental
balloon-induced coronary injury raises the possibility of therapeutic
targeting of this response for the prevention of coronary restenosis.
Critical issues that need to be resolved include the selection of
inhibitor(s) and the mode of delivery. Several synthetic DNA-based
compounds ("antisense") directed against cell-cycle-regulating
genes have been proposed to abolish a short-lived cell proliferation.
These pleiotropic agents have also demonstrated growth factor–binding
properties, which enhance their antiproliferative
effects.44 The alternative may involve the inhibition of
TGFß1 and fibroblast differentiation, which has shown promising
results in nonvascular applications.45 The need for a
single endoluminal delivery of therapeutic compounds into relatively
inaccessible adventitia, however, remains the major challenge for these
strategies. Intracoronary stenting may provide an advantage by allowing
for more aggressive drug delivery without the risk of abrupt vessel
closure. The future development of technologies for stent coating and
the elution of desired agents promises to prolong the bioavailability
of locally administered compounds. Some of the above difficulties can
be alleviated by the application of a unique form of "local"
therapy, ie, intracoronary radiation (brachytherapy). A recent report
has suggested the attenuation of adventitial activation as a potential
explanation for the encouraging preclinical effects of this approach
postangioplasty.46
Pharmacological targeting of activated fibroblasts during bypass surgery with saphenous vein grafts (ie, vein graft "engineering") may offer some advantages compared with the strategies directed toward the prevention of coronary restenosis. The delivery of inhibitor(s) is less problematic, since the harvested vein and the perigraft region are obviously more accessible to therapies during a surgical procedure. The fundamental issue whether a single application of a therapeutic agent is sufficient to control a chronic process will require careful studies.
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Summary |
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TopIntroductionFibroblasts, Myofibroblasts, and...Are Myofibroblasts a...Myofibroblasts in Other...Future DirectionsSummaryReferences |
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Recent findings demonstrate that adventitial fibroblasts (ie, nonmuscle cells) are endowed with several characteristics previously attributed to medial SM cells. The response of the coronary artery to balloon angioplasty is associated with the activation of adventitial cells in a porcine model. They appear to be the most reactive in the arterial wall, as reflected by the extent of proliferation and the synthesis of collagen. Differentiation of adventitial cells, which acquire
-SM actin, illustrates the formation of vascular
myofibroblasts, a ubiquitous cellular mechanism of tissue repair.
Myofibroblasts are involved in remodeling of the adventitia and may
contribute to the formation of the neointima after balloon-induced
coronary injury. These findings suggest that at least some synthetic
SM-like cells present in intimal lesions may originate from medial or
adventitial nonmuscle cells. Myofibroblasts also appear to play a role
in other cardiovascular abnormalities (eg, vein graft remodeling),
which raises the possibility of targeted therapies.
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Acknowledgments |
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This study was supported in part by grants from the National Institutes of Health (HL-44150) and the American Heart Association, Delaware and Florida Affiliates, Inc. The authors acknowledge the contributions of John D. Mannion, MD; James E. O'Brien, Jr, MD; and Wooksung Chung, MD, in the studies regarding vein graft remodeling.
Received December 13, 1996; accepted January 13, 1997.
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TopIntroductionFibroblasts, Myofibroblasts, and...Are Myofibroblasts a...Myofibroblasts in Other...Future DirectionsSummaryReferences |
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  M. G. Frid, M. Li, M. Gnanasekharan, D. L. Burke, M. Fragoso, D. Strassheim, J. L. Sylman, and K. R. Stenmark Sustained hypoxia leads to the emergence of cells with enhanced growth, migratory, and promitogenic potentials within the distal pulmonary artery wall Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1059 - L1072. [Abstract] [Full Text] [PDF]
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 P. Roy-Chaudhury, Y. Wang, M. Krishnamoorthy, J. Zhang, R. Banerjee, R. Munda, S. Heffelfinger, and L. Arend Cellular phenotypes in human stenotic lesions from haemodialysis vascular access Nephrol. Dial. Transplant., September 1, 2009; 24(9): 2786 - 2791. [Abstract] [Full Text] [PDF]
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 X. Liu, R. J. Kelm Jr., and A. R. Strauch Transforming Growth Factor {beta}1-mediated Activation of the Smooth Muscle {alpha}-Actin Gene in Human Pulmonary Myofibroblasts Is Inhibited by Tumor Necrosis Factor-{alpha} via Mitogen-activated Protein Kinase Kinase 1-dependent Induction of the Egr-1 Transcriptional Repressor Mol. Biol. Cell, April 15, 2009; 20(8): 2174 - 2185. [Abstract] [Full Text] [PDF]
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 M. Puato, C. Piergentili, M. Zanardo, R. Rocchi, M. Giordan, P. Cardaioli, and P. Pauletto Vascular Remodeling After Carotid Artery Stenting Angiology, November 1, 2007; 58(5): 565 - 571. [Abstract] [PDF]
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L. Li, C. M. Terry, D. K. Blumenthal, T. Kuji, T. Masaki, B. C. H. Kwan, I. Zhuplatov, J. K. Leypoldt, and A. K. Cheung Cellular and morphological changes during neointimal hyperplasia development in a porcine arteriovenous graft model Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3139 - 3146. [Abstract] [Full Text] [PDF]
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 Q. Gan, T. Yoshida, J. Li, and G. K. Owens Smooth Muscle Cells and Myofibroblasts Use Distinct Transcriptional Mechanisms for Smooth Muscle {alpha}-Actin Expression Circ. Res., October 26, 2007; 101(9): 883 - 892. [Abstract] [Full Text] [PDF]
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 K. Maiellaro and W. R. Taylor The role of the adventitia in vascular inflammation Cardiovasc Res, September 1, 2007; 75(4): 640 - 648. [Abstract] [Full Text] [PDF]
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R. C.M. Siow and A. T. Churchman Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in Cardiovasc Res, September 1, 2007; 75(4): 659 - 668. [Abstract] [Full Text] [PDF]
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S. J. An, R. Boyd, M. Zhu, A. Chapman, D. R. Pimentel, and H. D. Wang NADPH oxidase mediates angiotensin II-induced endothelin-1 expression in vascular adventitial fibroblasts Cardiovasc Res, September 1, 2007; 75(4): 702 - 709. [Abstract] [Full Text] [PDF]
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 J. S. Garanich, R. A. Mathura, Z.-D. Shi, and J. M. Tarbell Effects of fluid shear stress on adventitial fibroblast migration: implications for flow-mediated mechanisms of arterialization and intimal hyperplasia Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3128 - H3135. [Abstract] [Full Text] [PDF]
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M. Weaver, J. Liu, D. Pimentel, D. J. Reddy, P. Harding, E. L. Peterson, and P. J. Pagano Adventitial delivery of dominant-negative p67phox attenuates neointimal hyperplasia of the rat carotid artery Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1933 - H1941. [Abstract] [Full Text] [PDF]
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 A K Mitra and D K Agrawal In stent restenosis: bane of the stent era. J. Clin. Pathol., March 1, 2006; 59(3): 232 - 239. [Abstract] [Full Text] [PDF]
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 A. S. Blom, R. Mukherjee, J. J. Pilla, A. S. Lowry, W. M. Yarbrough, J. T. Mingoia, J. W. Hendrick, R. E. Stroud, J. E. McLean, J. Affuso, et al. Cardiac Support Device Modifies Left Ventricular Geometry and Myocardial Structure After Myocardial Infarction Circulation, August 30, 2005; 112(9): 1274 - 1283. [Abstract] [Full Text] [PDF]
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 T. Schachner, A. Oberhuber, Y. Zou, A. Tzankov, H. Ott, G. Laufer, and J. Bonatti Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts Eur. J. Cardiothorac. Surg., February 1, 2005; 27(2): 302 - 306. [Abstract] [Full Text] [PDF]
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 J. Herrmann, S. Samee, A. Chade, M. R. Porcel, L. O. Lerman, and A. Lerman Differential Effect of Experimental Hypertension and Hypercholesterolemia on Adventitial Remodeling Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 447 - 453. [Abstract] [Full Text] [PDF]
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B. Somoza, M. C. Gonzalez, J. M. Gonzalez, F. Abderrahim, S. M. Arribas, and M. S. Fernandez-Alfonso Modulatory role of the adventitia on noradrenaline and angiotensin II responses: Role of endothelium and AT2 receptors Cardiovasc Res, February 1, 2005; 65(2): 478 - 486. [Abstract] [Full Text] [PDF]
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H. M. Dourron, G. M. Jacobson, J. L. Park, J. Liu, D. J. Reddy, M. L. Scheel, and P. J. Pagano Perivascular gene transfer of NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H946 - H953. [Abstract] [Full Text] [PDF]
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S. V. Subramanian, J. A. Polikandriotis, R. J. Kelm Jr., J. J. David, C. G. Orosz, and A. R. Strauch Induction of Vascular Smooth Muscle {alpha}-Actin Gene Transcription in Transforming Growth Factor {beta}1-Activated Myofibroblasts Mediated by Dynamic Interplay between the Pur Repressor Proteins and Sp1/Smad Coactivators Mol. Biol. Cell, October 1, 2004; 15(10): 4532 - 4543. [Abstract] [Full Text] [PDF]
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Y. Xu, H. Arai, X. Zhuge, H. Sano, T. Murayama, M. Yoshimoto, T. Heike, T. Nakahata, S.-i. Nishikawa, T. Kita, et al. Role of Bone Marrow-Derived Progenitor Cells in Cuff-Induced Vascular Injury in Mice Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 477 - 482. [Abstract] [Full Text]
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R. C.M Siow, C. M Mallawaarachchi, and P. L Weissberg Migration of adventitial myofibroblasts following vascular balloon injury: insights from in vivo gene transfer to rat carotid arteries Cardiovasc Res, July 1, 2003; 59(1): 212 - 221. [Abstract] [Full Text] [PDF]
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F. E. Rey and P. J. Pagano The Reactive Adventitia: Fibroblast Oxidase in Vascular Function Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1962 - 1971. [Abstract] [Full Text] [PDF]
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Y. Nakazato, Y. Yamaji, N. Oshima, M. Hayashi, and T. Saruta Calcification and osteopontin localization in the peritoneum of patients on long-term continuous ambulatory peritoneal dialysis therapy Nephrol. Dial. Transplant., July 1, 2002; 17(7): 1293 - 1303. [Abstract] [Full Text] [PDF]
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E. Mori, K. Komori, T. Yamaoka, M. Tanii, C. Kataoka, A. Takeshita, M. Usui, K. Egashira, and K. Sugimachi Essential Role of Monocyte Chemoattractant Protein-1 in Development of Restenotic Changes (Neointimal Hyperplasia and Constrictive Remodeling) After Balloon Angioplasty in Hypercholesterolemic Rabbits Circulation, June 18, 2002; 105(24): 2905 - 2910. [Abstract] [Full Text] [PDF]
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S. V. Subramanian, R. J. Kelm Jr., J. A. Polikandriotis, C. G. Orosz, and A. R. Strauch Reprogramming of vascular smooth muscle {alpha}-actin gene expression as an early indicator of dysfunctional remodeling following heart transplant Cardiovasc Res, June 1, 2002; 54(3): 539 - 548. [Abstract] [Full Text] [PDF]
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S. Sartore, A. Chiavegato, E. Faggin, R. Franch, M. Puato, S. Ausoni, and P. Pauletto Contribution of Adventitial Fibroblasts to Neointima Formation and Vascular Remodeling: From Innocent Bystander to Active Participant Circ. Res., December 7, 2001; 89(12): 1111 - 1121. [Abstract] [Full Text] [PDF]
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F. J. Miller Jr Adventitial Fibroblasts : Backstage Journeymen Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 722 - 723. [Full Text] [PDF]
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 M. A. Albassam, A. L. Metz, R. E. Potoczak, K. P. Gallagher, S. Haleen, H. Hallak, and E. J. Mcguire Studies on Coronary Arteriopathy in Dogs Following Administration of CI-1020, an Endothelin A Receptor Antagonist Toxicol Pathol, April 1, 2001; 29(3): 277 - 284. [Abstract] [PDF]
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K. L. Davenpeck, C. Marcinkiewicz, D. Wang, R. Niculescu, Y. Shi, J. L. Martin, and A. Zalewski Regional Differences in Integrin Expression : Role of {{alpha}}5{beta}1 in Regulating Smooth Muscle Cell Functions Circ. Res., February 16, 2001; 88(3): 352 - 358. [Abstract] [Full Text] [PDF]
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D. Godin, E. Ivan, C. Johnson, R. Magid, and Z. S. Galis Remodeling of Carotid Artery Is Associated With Increased Expression of Matrix Metalloproteinases in Mouse Blood Flow Cessation Model Circulation, December 5, 2000; 102(23): 2861 - 2866. [Abstract] [Full Text] [PDF]
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M. R. Ward, G. Pasterkamp, A. C. Yeung, and C. Borst Arterial Remodeling : Mechanisms and Clinical Implications Circulation, September 5, 2000; 102(10): 1186 - 1191. [Full Text] [PDF]
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P. Neuville, M.-L. Bochaton-Piallat, and G. Gabbiani Retinoids and Arterial Smooth Muscle Cells Arterioscler Thromb Vasc Biol, August 1, 2000; 20(8): 1882 - 1888. [Full Text] [PDF]
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G. Li, Y.-F. Chen, S. S. Kelpke, S. Oparil, and J. A. Thompson Estrogen Attenuates Integrin-{beta}3-Dependent Adventitial Fibroblast Migration After Inhibition of Osteopontin Production in Vascular Smooth Muscle Cells Circulation, June 27, 2000; 101(25): 2949 - 2955. [Abstract] [Full Text] [PDF]
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V. Ollivier, J. Chabbat, J. M. Herbert, J. Hakim, and D. de Prost Vascular Endothelial Growth Factor Production by Fibroblasts in Response to Factor VIIa Binding to Tissue Factor Involves Thrombin and Factor Xa Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1374 - 1381. [Abstract] [Full Text] [PDF]
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G. Li, S.-J. Chen, S. Oparil, Y.-F. Chen, and J. A. Thompson Direct In Vivo Evidence Demonstrating Neointimal Migration of Adventitial Fibroblasts After Balloon Injury of Rat Carotid Arteries Circulation, March 28, 2000; 101(12): 1362 - 1365. [Abstract] [Full Text] [PDF]
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S. Patel, Y. Shi, R. Niculescu, E. H. Chung, J. L. Martin, and A. Zalewski Characteristics of Coronary Smooth Muscle Cells and Adventitial Fibroblasts Circulation, February 8, 2000; 101(5): 524 - 532. [Abstract] [Full Text] [PDF]
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 A.-C. Desfaits, J. Raymond, and J. P. Muizelaar Growth Factors Stimulate Neointimal Cells In Vitro and Increase the Thickness of the Neointima Formed at the Neck of Porcine Aneurysms Treated by Embolization • Editorial Comment Stroke, February 1, 2000; 31(2): 498 - 507. [Abstract] [Full Text] [PDF]
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 B. H. Strauss and M. Rabinovitch Adventitial Fibroblasts . Defining a Role in Vessel Wall Remodeling Am. J. Respir. Cell Mol. Biol., January 1, 2000; 22(1): 1 - 3. [Full Text]
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E. Faggin, M. Puato, A. Chiavegato, R. Franch, P. Pauletto, and S. Sartore Fish Oil Supplementation Prevents Neointima Formation in Nonhypercholesterolemic Balloon-Injured Rabbit Carotid Artery by Reducing Medial and Adventitial Cell Activation Arterioscler Thromb Vasc Biol, January 1, 2000; 20(1): 152 - 163. [Abstract] [Full Text] [PDF]
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 M. Koyanagi, K. Egashira, M. Kubo-Inoue, M. Usui, S. Kitamoto, H. Tomita, H. Shimokawa, and A. Takeshita Role of Transforming Growth Factor-{beta}1 in Cardiovascular Inflammatory Changes Induced by Chronic Inhibition of Nitric Oxide Synthesis Hypertension, January 1, 2000; 35(1): 86 - 90. [Abstract] [Full Text] [PDF]
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S. Oparil, S.-J. Chen, Y.-F. Chen, J. N Durand, L. Allen, and J. A Thompson Estrogen attenuates the adventitial contribution to neointima formation in injured rat carotid arteries Cardiovasc Res, December 1, 1999; 44(3): 608 - 614. [Abstract] [Full Text] [PDF]
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G. Li, Y.-F. Chen, G. L. Greene, S. Oparil, and J. A. Thompson Estrogen Inhibits Vascular Smooth Muscle Cell-Dependent Adventitial Fibroblast Migration In Vitro Circulation, October 12, 1999; 100(15): 1639 - 1645. [Abstract] [Full Text] [PDF]
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T. Christen, M.-L. Bochaton-Piallat, P. Neuville, S. Rensen, M. Redard, G. van Eys, and G. Gabbiani Cultured Porcine Coronary Artery Smooth Muscle Cells : A New Model With Advanced Differentiation Circ. Res., July 9, 1999; 85(1): 99 - 107. [Abstract] [Full Text] [PDF]
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E. Faggin, M. Puato, L. Zardo, R. Franch, C. Millino, F. Sarinella, P. Pauletto, S. Sartore, and A. Chiavegato Smooth Muscle-Specific SM22 Protein Is Expressed in the Adventitial Cells of Balloon-Injured Rabbit Carotid Artery Arterioscler Thromb Vasc Biol, June 1, 1999; 19(6): 1393 - 1404. [Abstract] [Full Text] [PDF]
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Y. Shi, S. Patel, R. Niculescu, W. Chung, P. Desrochers, and A. Zalewski Role of Matrix Metalloproteinases and Their Tissue Inhibitors in the Regulation of Coronary Cell Migration Arterioscler Thromb Vasc Biol, May 1, 1999; 19(5): 1150 - 1155. [Abstract] [Full Text] [PDF]
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J. M. Miano, L. A. Kelly, C. A. Artacho, T. A. Nuckolls, R. Piantedosi, and W. S. Blaner all-Trans-Retinoic Acid Reduces Neointimal Formation and Promotes Favorable Geometric Remodeling of the Rat Carotid Artery After Balloon Withdrawal Injury Circulation, September 22, 1998; 98(12): 1219 - 1227. [Abstract] [Full Text] [PDF]
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 J. D. Mannion, M. L. Ormont, Y. Shi, J. E. O'Brien Jr.,, W. Chung, F. Roque, and A. Zalewski Saphenous vein graft protection: Effects of c-myc antisense J. Thorac. Cardiovasc. Surg., January 1, 1998; 115(1): 152 - 161. [Abstract] [Full Text] [PDF]
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C. L. Seidel Cellular Heterogeneity of the Vascular Tunica Media : Implications for Vessel Wall Repair Arterioscler Thromb Vasc Biol, October 1, 1997; 17(10): 1868 - 1871. [Full Text]
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C. A. J. Schulze-Bauer, P. Regitnig, and G. A. Holzapfel Mechanics of the human femoral adventitia including the high-pressure response Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2427 - H2440. [Abstract] [Full Text] [PDF]
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