Articles |
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
| Introduction |
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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.
| Fibroblasts, Myofibroblasts, and Coronary Restenosis |
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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
-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
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.
| Are Myofibroblasts a Model-Dependent Phenomenon? |
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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.
| Myofibroblasts in Other Cardiovascular Abnormalities |
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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
| Future Directions |
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-SM actinexpressing 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 factorbinding
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.
| Summary |
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-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.
| Acknowledgments |
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Received December 13, 1996; accepted January 13, 1997.
| References |
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