(Circulation. 1997;96:82-90.)
© 1997 American Heart Association, Inc.
Articles |
Redifferentiation of Smooth Muscle Cells After Coronary Angioplasty Determined via Myosin Heavy Chain Expression
From the Third (M.A., Y.S., I.M., Y.Y., R.N.) and Second (K.K.) Departments of Internal Medicine, University of Tokyo, Faculty of Medicine; Department of Cardiology, Juntendo University School of Medicine (M.A., H.Y.); Department of Cardiology, Tokyo Women's Medical College (Y.S.); Department of Cardiology, Toranomon Hospital (S.I., N.K.), Tokyo; Second Department of Internal Medicine, Gunma University School of Medicine (R.N.), Gunma; and Department of Pathology, Osaka City University Medical School (M.U.), Osaka, Japan.
Correspondence to Ryozo Nagai, MD, Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371, Japan. E-mail nagai{at}news.sb.gunma-u.ac.jp
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Abstract |
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Background The pathophysiology of phenotypic modulation of smooth muscle cells (SMCs) involved in restenosis after angioplasty is not well understood. Smooth muscle myosin heavy chain (SM MHC) isoforms (SM1 and SM2) are specific markers for SMC differentiation. In particular, SM2 is useful as a marker of mature SMCs. SMemb is a nonmuscle myosin heavy chain (NM MHC) whose expression is upregulated in immature or activated SMC.
Methods and Results To determine SMC phenotypes in
neointimal tissues after percutaneous
transluminal coronary angioplasty (PTCA), we performed
immunohistochemistry on human coronary arteries with antibodies
against 
-SM actin, SM1, SM2, and SMemb. Tissues were obtained from
six autopsied patients and from atherectomy specimens from 16 patients
who had undergone PTCA. Medial SMCs were positive for -actin, SM1,
and SM2. Expression of SM1 and SM2 in the neointima varied
with the time after intervention, whereas -actin was constitutively
expressed in all cases studied. Neointimal cells at 16 and
20 days after PTCA contained -actin but little or no SM1 or SM2,
indicating that these cells modulated their phenotype to the
immature state. Neointimal SMCs recovered SM MHC
expression, first SM1 and then SM2, by 6 months after PTCA. Increased
expression of SMemb was found in the neointima but without
apparent relationship to the time after PTCA.
Conclusions Neointimal SMCs show features of an undifferentiated state, indicated by altered expression of SM MHC, and undergo redifferentiation in a time-dependent manner. The expression of SM MHC isoforms provides insight into the biology of healing after angioplasty and furnishes useful tools for the understanding of the roles of differentiation and phenotypic modulation of SMCs in human vascular lesions.
Key Words: angioplasty • coronary disease • muscle, smooth • myosin • restenosis
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Introduction |
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Restenosis after a coronary angioplasty procedure such as PTCA or DCA is a major problem in clinical cardiology, occurring in 30% to 50% of patients who have undergone these procedures within 3 to 6 months.1 2 3 Major causes of restenosis are considered to be thrombus formation at the early phase and obstructive neointimal tissue formation due to fibrocellular proliferation and medial recoil of overstretched arterial walls at the relatively late phase.4 5 Proliferation and extracellular matrix production of vascular SMCs appear to play an important role in the development of the neointima according to a number of studies on animal models and humans.6 7 8 9 10 SMCs in experimental neointima and in culture are known to be phenotypically modulated.11 12 13 14 15 16 17 Phenotypic modulation of SMCs from the contractile state to the synthetic state was first described by Campbell et al.14 Electron microscopic studies revealed that synthetic-state SMCs in culture lose much myofilament and are abundant in subcellular organelles involved in protein synthesis. To understand the role of phenotypically modulated SMCs in the development of restenosis, it is important to investigate SM phenotypes not only in animal models but also in human arteries after angioplasty. In doing so, it is essential to use sensitive markers to detect phenotypically modulated SMCs.
We have demonstrated that SM MHC isoforms are useful markers for vascular SMC differentiation18 19 20 21 (for a review, see Reference 2222 ). Vascular SMCs contain two types of MHC isoforms: SM1 and SM2.19 21 23 The expression of SM MHC is completely restricted to SM tissue18 19 21 24 and is developmentally regulated. SM1 is found in vascular SMCs from the late fetal stage through adulthood.20 21 24 On the other hand, SM2 appears only in fully differentiated SMCs after birth.20 21 SM1 and SM2 are generated from a single gene through alternative RNA splicing.20 21 25 SM2 expression is downregulated in proliferating SMCs in culture.16 17 We have reported electron microscopic evidence that SMCs without SM2 expression resemble the synthetic state.26 27 We also showed that SM MHC isoforms are useful markers for SMC differentiation during progression of atherosclerosis in humans.21 SMemb is known as a non–muscle-type MHC (NM MHC) and was isolated from both fetal aorta and brain12 21 ; SMemb is identical to MHC-B.28 29 SMemb/MHC-B is predominantly expressed in undifferentiated vascular SMCs in the fetal stage and reduced during vascular development.12 21 The apparently normal media of young adults, however, exhibit a low level of SMemb/MHC-B expression.21
Neointimal cells in balloon-injured rabbit aortas express SM1 and SMemb/MHC-B, but not SM2, indicating that these cells express an immature phenotype like that in fetal aorta, relative to MHC expression.12 27 30 We thus suggested that phenotypic modulation of SMCs toward an immature state (dedifferentiation) may be involved in the pathogenesis of experimental neointima formation after vascular injury. Furthermore, we hypothesized that understanding of molecular mechanisms regulating MHC expression would shed light on the development of effective therapies of restenosis. Whether altered expression of MHC isoforms occurs in human neointima has not been demonstrated.
In the present study, we examined changes in SM phenotypes of human neointimal tissue after coronary angioplasty and specific features of human coronary restenosis in comparison to spontaneous coronary atherosclerosis and experimental neointima formation. We report here the immunohistochemical studies on human coronary specimens at various time points after PTCA with the use of monoclonal antibodies against three types of MHC isoforms. To our knowledge, this is the first report demonstrating diversity of SM phenotypes in human neointimal tissues at times after coronary angioplasty, as determined through SM MHC expression.
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Methods |
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Study Patients and Coronary Tissue Preparation
The coronary tissues were obtained from six autopsied patients who had previously undergone successful PTCA. Autopsy specimens were obtained in an accordance with guidelines of each institution. Clinical and angiographic characteristics and causes of death of patients are shown in Table 1
. All hearts were
fixed in methanol-Carnoy's fixative (60% methanol, 30% chloroform,
and 10% glacial acetic acid). The coronary arteries were
removed from the epicardial surface.
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Localization of the angioplasty site was determined through precise measurements of angiograms at PTCA, with coronary ostia and bifurcation sites used as an index. Angioplasty sites of the arteries were sectioned serially at 1-mm intervals. Each 1-mm coronary segment was routinely processed and embedded in paraffin. Thirty serial sections from each segment were cut at a 5-µm thickness. Every eighth and ninth sections were stained with hematoxylin and eosin and Weigert's elastic van Gieson's stain, respectively; the other sections were used for immunohistochemical staining.
Atherectomy specimens were obtained from 16 patients at various times
after PTCA. All these patients had symptoms or signs related to
restenosis of the dilated artery. Clinical and angiographic
characteristics of patients are shown in Table 2.
Specimens were fixed with ethanol fixative (95% ethanol and 1% acetic
acid), which provided similar results to Carnoy-fixed specimens. The
neointima was characterized by a large proportion of SMCs
arranged in a loose reticular pattern, while preexisting intima
appeared hypocellular with dense extracellular
matrices.31
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Immunohistochemistry
After deparaffinization and rehydration, immunoenzymatic
staining was performed according to the LSAB method with the DAKO LSAB
Kit (Dako Corp). Monoclonal antibodies against human SM1, SM2, and
SMemb were produced as previously described.21 The
specificity of these antibodies was determined by use of Western
blotting.21 32 Sections were preincubated with 0.3%
hydrogen peroxide and normal rabbit serum to reduce nonspecific
reactions. Antibody against human SM1, SM2, SMemb, and human -SM
actin (1A4; DAKO A/S)33 was applied and incubated for 20
minutes at room temperature. Sections were incubated with biotinylated
anti-mouse goat immunoglobulin for 10 minutes and then incubated with
horseradish peroxidase–labeled streptavidin solution for 10 minutes.
The slides were rinsed in Tris-buffered saline with 0.1% Tween 20
(Wako Pure Chemical Industries) after each incubation step. Peroxidase
activity was revealed with the use of 3,3'-diaminobenzidine
tetrahydrochloride (0.2 mg/mL, Sigma Chemical Co) with hydrogen
peroxide (0.014%). The sections were counterstained with hematoxylin
solution, dehydrated, and mounted.
All specimens were reviewed, and the intensity of staining was graded by two independent observers who were blinded to clinical data on a scale from - to ++, with - indicating little to no staining; +/–, some cells positive (<25%); +, approximately half of all cells positive (25% to 75%); and ++, most cells positive (75% to 100%).
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Results |
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MHC Expression in Autopsied Coronary Arteries After PTCA
All the dilated arterial segments from autopsied patients revealed lacerations extending into the media. Each of these segments contained distinct fibrocellular proliferative tissue at the site of injury. The results of the immunohistochemical studies are summarized in Table 3
.
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In early lesions at 16 and 20 days after PTCA, the expression of
SM MHC isoforms SM1 and SM2 was reduced. -SM actin–positive cells
accumulated at the site of medial laceration at 16 days after PTCA (Fig 1). A few of the cells stained positively with SM1, and
all cells were negative with SM2. The cells within the lesion at 20
days also stained positively for -actin. These were also weakly
positive for SM1 and negative for SM2 (data not shown). These results
indicate that in early lesions, the majority of neointimal
cells that express -actin also display reduced SM-specific MHC (SM1
and SM2) expression and suggest that these cells underwent phenotypic
modulation toward the synthetic, or immature, state. In support of this
supposition, neointimal cells expressed NM MHC
(SMemb/MHC-B) at 16 days (Fig 1) and 20 days (data not shown) after
PTCA.
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At 2 to 4 months after PTCA, more neointimal cells were
positive for SM1 than were at 16 and 20 days after PTCA, but SM2
expression remained low to absent. Fig 2 shows
immunoreactivity of neointimal cells at 4 months after PTCA
with antibodies against -actin and MHC isoforms. -Actin–positive
cells accumulating at the site of medial injury were stained positive
with SM1 but not with SM2. Similar results were also observed in other
sections at 2 and 4 months (Table 3
). These neointimal
cells at 2 to 4 months after PTCA are considered to be SMCs but
expressed an immature phenotype based on the presence of SM1
and lack of SM2. These results suggest that phenotypic modulation of
neointimal SMCs continues for 
4 months after the
procedure. SMemb/MHC-B was detected in the LAD lesion of patient 3 at 4
months after PTCA at levels similar to that of SM1 (Fig 2), However,
SMemb/MHC-B was expressed at lower levels in other sections (Table 3).
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At later phases, SMCs in the fibrocellular lesions stained positively
with -actin (data not shown), SM1, and SM2. Figs 3 and 4 show expression of MHC isoforms in
neointimal cells at 10 or 12 (this patient underwent PTCA
twice at 10 and 12 months before autopsy) and 17 months after PTCA,
respectively. The cells in these lesions displayed both SM MHC isoforms
(SM1 and SM2), like those in the underlying media (Fig 4). SMemb/MHC-B
expression was also detected in the neointimal cells but
was weaker than that in earlier lesions. Thus, neointimal
SMCs appear to regain a differentiated state (redifferentiation) and
resemble medial SMCs at later stages (10 to 17 months) after PTCA.
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MHC Expression in DCA Specimens After PTCA
We also examined the expression of SM and NM MHC isoforms in
atherectomy specimens from 16 patients who had undergone PTCA and had
symptoms or signs related to restenosis of the dilated artery
(Table 3).
-SM actin (data not shown) and SM1 were constitutively
present in all specimens studied. However, at <6 months after
PTCA, the majority of cells were negative for SM2 but were positive
after 7 months. On the other hand, SMemb was found in almost all
specimens studied, and its expression pattern varied regardless of time
interval between PTCA and atherectomy. Fig 5A and 5B
show SM and NM MHC expression in DCA specimens obtained from four
patients at 4, 5, 7, and 8 months after PTCA.
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Discussion |
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This study demonstrates phenotypic modulation of SMCs toward an immature state (dedifferentiation) and redifferentiation in a time-dependent manner after PTCA, as determined through SM MHC isoform expression. We further discuss the specific nature of human coronary neointima formation after angioplasty compared with spontaneous coronary atherosclerosis in humans and experimental neointima formation in animal models.
Reversible Alterations of SM MHC Expression (SM1 and SM2):
Redifferentiation of Neointimal SMCs
We previously demonstrated changes in SM MHC (SM1 and SM2)
expression during vascular development.20 21 Miano et
al24 showed that medial SMCs at the late fetal stage begin
to express SM MHC (SM1) mRNA. Late fetal SMCs stain with specific
antibodies against SM1 but not against SM2.20 21 Fully
differentiated SMCs in the apparently normal media of adults stained
positively for SM1 and SM2. This upregulation of SM2 was also reported
by Frid et al.34 During progression of
atherosclerosis, the intimal SMCs of human aorta and
coronary artery show reduced expression of SM MHC isoforms,
first of SM2 and then of SM1, whereas -SM actin is well
preserved.21 We recently reported that reduced expression
of SM2 is also found at the early stage of heart transplant–associated
arteriosclerosis.35 We thus suggest
that SM MHC isoforms are useful markers for differentiation and
phenotypic modulation of vascular SMCs.
SM MHC is a highly specific marker for SMC
lineage.18 19 22 24 On the other hand, it is known that
other SMC markers, such as -SM actin, are expressed not only by SMCs
but also by other cell types.22 36 37 For example,
-actin is expressed by activated fibroblasts in transplanted
hearts and proliferating mesangial cells in
glomerular disease.35 38 Thus, SM -actin
cannot be used as a definitive marker of SMC lineage. It is, however,
a useful differentiation marker for SMCs because it is the
first cell type–selective protein expressed by SMCs during
differentiation and is one of the last proteins downregulated during
the process of phenotypic modulation.22
In the present study, neointimal SMCs appeared to
express an immature phenotype at an early stage after PTCA,
based on MHC isoform expression. At 16 and 20 days after PTCA, a
majority of neointimal cells were negative for SM MHC
isoforms (SM1 and SM2), whereas they were reactive for -SM actin
expression. These neointimal cells are considered to be of
SMC origin because of morphological continuity between
neointimal cells and the media. Despite the lack of
SM-specific MHC expression, we suggest that these SM1- and SM2-negative
cells are phenotypically modulated SMCs for the following reasons.
First, we recently observed that cultured SMCs obtained through
explantation do not express SM1 or SM2.27 Others reported
similar findings in terms of reduced expression of
MHC.16 17 Second, on the basis of electron microscopic
observations, the SM1- and SM2-negative cells in balloon-injured rabbit
aorta show features of the synthetic-type SMCs with basal laminae
unlike fibroblasts and with very few myofilaments but highly abundant
synthetic cellular organelles such as rough endoplasmic reticulum and
Golgi apparatus.27 Third, we previously
observed reduced expression of both SM1 and SM2 in SMCs in
atherosclerotic coronary intima, whereas -actin expression
was well preserved.21 Scott et al39 recently
demonstrated a possible role of activated adventitial
myofibroblasts characterized by -SM actin expression in the
pathogenesis of neointimal formation in pigs. However,
-actin expression in the adventitial fibroblasts was not detected in
any of the patients that we studied here.
At 2 to 5 months after PTCA, neointimal cells reexpressed SM1 but not SM2. In the neointima at >6 months, almost all SMCs were positive for both SM1 and SM2, like those in the normal media. These results indicate that SMCs after PTCA initially lose their differentiated phenotype but redifferentiate in a time-dependent manner.
Ueda et al40 41 studied phenotypic modulation of
neointimal SMCs after PTCA using two antibodies against
actin: HHF-35 and CGA7. HHF-35 recognizes - and 
-isoforms of
skeletal, cardiac, and SM actin, whereas CGA7 recognizes - and
-SM actin. In other words, CGA7 is more specific to SMCs than is
HHF35. They reported that the earliest neointimal lesion at
5 days after PTCA was negative for both HHF35 and CGA7 and the lesions
at 16-20 days were positive for HHF35 but negative for CGA7. At 4
months, neointimal cells stained with CGA7 as well. These
findings are consistent with the present study relative to
reversible changes of SM phenotype after angioplasty.
Reversible changes of SM phenotype after PTCA may
contribute to a transient healing process of the injured vascular wall;
however, this process frequently results in obstruction of the vascular
lumen. In the present study, the time span between the PTCA and
redifferentiation of neointimal SMCs was 
6 months, which
is consistent with clinical observations that evidence of
restenosis is usually apparent within 6 months after the PTCA
procedure.1 2 3 The mechanisms of redifferentiation are not
known. Ueda et al41 reported that regeneration of
endothelial cells was observed by 4 months after PTCA.
Potential antiatherogenic effects42 of regenerated
endothelial cells may provide one explanation for the
mechanisms of redifferentiation of underlying neointimal
cells.
Expression of Nonmuscle MHC in Neointimal SMCs
After Angioplasty
SMCs express at least two types of NM MHC isoforms: MHC-A and
SMemb/MHC-B. SMemb/MHC-B is abundantly expressed in the fetal aorta and
coronary artery and is downregulated during vascular
development.12 21 23 Unlike SMemb/MHC-B, MHC-A expression
is not dramatically changed during development (Dr Aikawa, Dr Nagai,
unpublished observations, 1993).28 34 SMemb/MHC-B is
upregulated in experimental atherosclerosis after
balloon injury or by high cholesterol
feeding.12 27 30 43 In our study of human spontaneous
atherosclerosis, SMemb/MHC-B is expressed in diffuse
intimal thickening in the young but not necessarily upregulated in the
atherosclerotic lesions.21 Thus, the functional
significance of SMemb/MHC-B expression in atherosclerotic lesion
formation remains unclear. In the present study, SMemb/MHC-B was
abundantly expressed in the neointima after PTCA. These
differences in SM phenotype relative to MHC expression may
suggest that the pathophysiology of restenosis differs from
that of spontaneous atherosclerosis.44
MHC in nonmuscle cells likely plays an important role in cell division.45 46 Grainger et al47 showed increased accumulation of NM MHC at the first M phase in cultured SMCs and suggested that NM MHC may be necessary for cell division. We recently demonstrated that SMemb/MHC-B is expressed in arterial SMCs and interstitial fibroblasts in rejected hearts after transplantation35 and proliferating mesangial cells in various types of glomerular disease.38 Thus, SMemb/MHC-B may play important roles in cell activation and/or cell division. Leclerc et al48 showed using in situ hybridization that SMemb/MHC-B mRNA is expressed in restenotic lesions obtained through DCA. Simons et al49 demonstrated that there is a linear relation between the presence of cells expressing SMemb/MHC-B mRNA in primary lesions and the severity of angiographic restenosis. At present, however, the functional aspects of SMemb/MHC-B–positive cells remain unclear.
Different Features of Neointimal Formation in Humans
and Experimental Animals
It is known that neointimal lesions develop within 2
to 4 weeks in vascular injury models of small animals such as the rat
and rabbit.50 51 In our experimental study on rabbits,
proliferating SMCs in the neointima at 2 weeks after
balloon injury were dedifferentiated as revealed by the reduced
expression of SM2.12 We recently demonstrated that rabbit
neointimal cells at 4 and 8 weeks after balloon injury
reexpressed SM2 like underlying medial SMCs, indicating that
redifferentiation occurs by 4 to 8 weeks.27 The
present study on humans, however, documented reduced expression of
SM2 even in 4- to 6-month-old neointimal lesions after
PTCA, indicating that phenotypic modulation of human
neointimal SMCs toward an immature state lasts longer than
that of animal models.
One possible explanation for this discrepancy is that a more complex milieu (eg, activated SMCs, macrophages and lymphocytes producing various growth factors or cytokines) may be involved in the pathogenesis of human restenosis than in experimental neointima formation. The failure of antirestenosis therapies in a number of clinical trials, despite significant effects in animal models, may reflect a pathological or biological distinction between atherosclerotic and normal arteries as well as differences in effective dosage.52 53 54 To evaluate the pathogenesis of restenosis and discover effective anti-restenosis therapies, further examinations should be performed to characterize the pathological or biological features after vascular injury with not only animal models but also human specimens.
Understanding of Molecular Mechanisms of SM
Differentiation
MHC isoforms can be important tools not only as pathological
markers but also for elucidating the molecular mechanisms underlying
the formation of vascular lesions. We have demonstrated that switching
of MHC gene expression occurs during normal vascular development and
arterial lesion formation in both animal models and humans.
Several studies by us and others12 16 17 27 have shown
that this phenomenon is also found in cultured SMCs. Holycross et
al55 reported that platelet-derived growth factor–BB
suppresses SM MHC expression in cultured SMCs. However, the molecular
mechanisms underlying altered expression of MHC genes (downregulation
of SM1/2 gene and upregulation of SMemb/MHC-B gene) are still
uncertain.
5'-Flanking regions of mouse and rabbit SM1/2 genes were recently isolated and characterized by us and another group.56 57 We also analyzed the promoter region of the rabbit SMemb/MHC-B gene.58 Understanding the molecular mechanisms regulating SM and NM MHC gene expression may not only contribute to clarification of the mechanisms of SMC differentiation and modulation but also lead to new effective therapies for restenosis and other vascular diseases.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by Japanese Ministry of Education Grant-in-Aid for Scientific Research 06454287 (Dr Nagai) and Grant-in-Aid for Developmental Scientific Research 12301 (Dr Nagai). We thank Masako Nakamura and Sanae Ogawa for their excellent technical assistance.
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Footnotes |
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Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 16, 1994, and published in abstract form in Circulation (1994;90[suppl II]:I-511).
Dr Aikawa's current address is Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Received August 26, 1996; revision received January 22, 1997; accepted February 2, 1997.
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