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© 1997 American Heart Association, Inc.
Articles |
Expression of Nonmuscle Myosin Heavy Chain-B Isoform in the Vessel Wall of Porcine Coronary Arteries After Balloon Angioplasty
From the Departments of Pathology (H. De L., K.E.B.) and Medicine (N.A.S., J.N.W.), Emory University School of Medicine, Atlanta, Ga, and Amgen Pharmaceuticals Inc (F.M., L.S.), Thousand Oaks, Calif.
Correspondence to Josiah N. Wilcox, PhD, Emory University, Division of Hematology/Oncology, 1639 Pierce Dr, Room 1115 WMRB, Atlanta, GA 30322. E-mail medjnw{at}emory.edu
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Abstract |
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Abstract Nonmuscle myosin heavy chain-B isoform (NMMHC-B) is expressed by proliferating vascular smooth muscle cells (SMCs), and its expression in primary lesions has been proposed to be predictive of restenosis after atherectomy. The present study was designed to study the time-course expression of NMMHC-B after angioplasty of porcine coronary arteries by in situ hybridization and immunohistochemistry. Domestic juvenile swine underwent percutaneous transluminal coronary angioplasty (PTCA) of the left anterior descending and circumflex coronary arteries with standard clinical angioplasty catheters. To identify proliferating cells, 5'-bromo-2'-deoxyuridine (BrdU) was administered and detected by immunohistochemistry on serial sections. Vessels were examined at 3, 7, and 14 days after balloon angioplasty, and uninjured coronary vessels were used as controls. Normal arteries showed hybridization to 35S-labeled NMMHC-B riboprobes localized mainly in the medial layer. NMMHC-B expression in the adventitia was markedly increased 3 days after balloon angioplasty. Seven and 14 days after injury, NMMHC-B mRNA–containing cells were localized in the adventitia and neointima at the arterial injury site. Cell proliferation, as indicated by BrdU staining, colocalized with NMMHC-B mRNA expression 3 and 7 days after angioplasty. These data indicate that cells proliferating in the adventitia and neointima express NMMHC-B; however, its expression is not limited to the proliferative state, since NMMHC-B mRNA was also found in quiescent SMCs of normal coronary arteries and in nonproliferating adventitial and neointimal cells 14 days after angioplasty.
Key Words: nonmuscle myosin • adventitia • smooth muscle • angioplasty • restenosis
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Introduction |
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Percutaneous transluminal coronary angioplasty has become increasingly accepted in the management of coronary artery disease. The procedure, however, is limited by the development of restenosis at the site of angioplasty in 30% to 40% of patients.1 Despite a considerable number of investigations, the pathophysiological mechanisms leading to restenosis remain unclear. The coronary lesion develops within 3 to 6 months and is composed largely of SMCs. Hyperplasia of SMCs has been cited as the predominant event in the restenotic process. However, whereas some studies suggest a high rate of SMC proliferation,2 others report a very low rate of proliferation.3 Two distinct phenotypes designated "contractile" and "synthetic" have been described for vascular SMCs in culture.4 Cells in the contractile or quiescent phenotype are morphologically and functionally similar to those of the intact vessel.5 6 Synthetic SMCs lose the capacity to contract and gain the ability to divide, resembling immature SMCs.6
Myosin, a cytoskeletal protein mainly studied in contractile tissues such as cardiac and skeletal muscle, is present in all eukaryotic cells and consists of a pair of heavy chains (200 kD) and two pairs of light chains (15 to 28 kD).7 Two isoforms of myosin heavy chain (SM1 and SM2) are derived from the same gene by alternative splicing and are expressed only in smooth muscle.8 9 10 Two separate genes encoding two isoforms of human NMMHC, NMMHC-A and NMMHC-B, have been identified.10 11 12 Myosin in nonmuscle cells has been implicated in different biological events, such as cytokinesis, capping of surface receptors, cell motility, and secretion.7 13 14 Inhibition of NMMHC expression using antisense NMMHC oligonucleotides has been shown to suppress cell proliferation of SMCs in vitro.15 Differential expression of myosin isoforms under various settings seems to support these molecules as potential molecular markers for the study of undifferentiated SMCs.16 17 NMMHC is expressed during vascular myogenesis of the rabbit aorta18 and in the neointima and underlying media of atherosclerotic aortas of cholesterol-fed rabbits.19 It has been shown that the appearance of NMMHC expression in synthetic-state SMCs correlates with the proliferative activity of these cells.20
Identification of genes specifically activated by synthetic SMCs is crucial in the investigation of their potential as therapeutic targets to inhibit cell proliferation in postangioplasty restenosis. Examination of biopsies of primary and restenotic lesions obtained percutaneously by directional atherectomy revealed that NMMHC-B mRNA was present in greater abundance in restenotic lesions than in primary atherosclerotic plaques.21 In addition, the increased expression of NMMHC-B isoform in atherosclerotic plaques has been suggested to identify a group of lesions at high risk for restenosis after atherectomy.17 Although the expression of NMMHC-B by SMCs in the vessel wall of human atherosclerotic and restenotic arteries was not investigated in those studies, an extensive previous characterization of the expression of NMMHC-B in normal human arteries revealed that NMMHC-B was expressed in the media of the aorta and the left anterior descending coronary artery at all ages examined.22
Morphological studies have characterized the kinetics of several models of vascular injury, including porcine coronary arteries.23 24 In this model, balloon-overstretch injury using clinical angioplasty catheters stimulates the formation of smooth muscle–rich vascular lesions that are morphologically similar to human postangioplasty lesions.25 The purpose of the present work was to examine the localization and time course of expression of NMMHC-B in the vessel wall of balloon catheter–injured pig coronary arteries by in situ hybridization.
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Materials and Methods |
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Angioplasty of Pig Coronary Arteries
Normal juvenile female domestic Yorkshire swine (n=9; weight range, 25 to 35 kg) were immobilized by an intramuscular injection of ketamine (25 mg/kg)/acepromazine (0.1 mL/kg) and atropine (0.06 mg/kg); brevital was then administered intravenously (10 mg/kg); and general anesthesia was maintained with 1% to 2% isoflurane. An 8F sheath (USCI) was inserted into the right femoral artery, and an 8F guide catheter (SciMed) with a hockey stick curve was advanced to the ostium of the left coronary artery under fluoroscopic guidance. After administration of intracoronary nitroglycerin (0.6 µg/kg) and angiography to estimate the size of the vessel, balloon injury was then performed on the left anterior descending and circumflex arteries with clinical PTCA catheters (Advanced Catheter Systems and Cordis Corp) sized so that the inflated balloon-to-artery ratio was
1.3. The
balloon was inflated to 10 atm for 30 seconds with a 1-minute rest
period, followed by inflation at the same site for a total of three
30-second inflations. The catheters were withdrawn, the cut-down site
was sutured, and the animals were allowed to recover from the
procedure. Animal studies were approved by the Emory University
Institutional Committee for the Care and Use of Animals and were in
accordance with federal guidelines.
BrdU Injection
BrdU (Sigma Chemical Co) was dissolved in sterile lactated
Ringer's solution (33 mg/mL) and administered via the ear vein in
three doses of 50 mg/kg at 24, 16, and 8 hours before necropsy. Animals
were killed with an overdose of barbiturate 3 days (n=3), 7 days (n=3),
or 14 days (n=3) after angioplasty; the heart was rapidly removed; and
the left coronary artery was perfused with saline to clear the blood.
The injured coronary segment was removed in block fashion and fixed by
immersion in 4% paraformaldehyde in 0.1 mol/L NaPO4 buffer
(pH 7.4). Proximal uninjured segments were used as controls.
Immunohistochemistry
BrdU localization was detected in tissues using a specific BrdU
monoclonal antibody (1/20 dilution, Dako) after predigestion of the
tissue with proteinase K (1 µg/mL) and 4N HCl. 
SM actin
localization was performed using a monoclonal anti-SM actin antibody
(clone 1A4, 1/800 dilution, Sigma). Briefly, frozen
paraformaldehyde-fixed tissue sections were thawed and fixed in acetone
for 5 minutes, dried, and rehydrated in PBS. The primary antibodies
were applied at the indicated dilutions in 1.0% BSA in PBS and
incubated with a biotinylated secondary antibody (horse anti-mouse IgG
at a 1/400 dilution, Vector Laboratories) in PBS containing 1.0% BSA
and 2.0% normal horse serum for 30 minutes at room temperature. This
was followed by washing in PBS and incubation with the avidin-biotin
enzyme complex and chromogenic substrate as described by the
manufacturer. SM actin and BrdU were visualized using Vectastin
Elite ABC peroxidase (brown reaction product) and Vectastin ABC
alkaline phosphatase (blue reaction product) systems (Vector
Laboratories), respectively. Serial sections treated with secondary
antibodies only or nonimmune IgG did not show any staining. Two
coronary vessels from each animal and three sections per each coronary
vessel were evaluated.
In Situ Hybridization
In situ hybridization using porcine-specific
35S-labeled riboprobes was performed as previously
described.26 Porcine cDNA fragments encoding for NMMHC-B
were amplified by reverse-transcriptase polymerase chain reaction from
porcine SMCs and subcloned into pCRII vectors (Invitrogen). The
following primer sequences were used for polymerase chain reaction
amplification: 5'-GTGTAGGATATGGCAGAATTGAC and
3'-TGGAGTGGGAACCTTGCTCTTG. Sequencing of the cDNA probe used in the
present experiments indicates that it encodes a 5' region of the
NMMHC-B gene and that it is 93% homologous to human
NMMHC-B11 but only 75% homologous to human
NMMHC-A11 and rabbit SM1 and SM2.8 Briefly,
cryosections were pretreated with paraformaldehyde and proteinase K
(Sigma) and prehybridized in 100 µL hybridization buffer (50%
formamide, 0.3 mol/L NaCl, 20 mmol/L Tris, pH 8.0, 5 mmol/L
EDTA, 0.02% polyvinylpyrrolidone, 0.02% Ficoll, 0.02% bovine serum
albumin, 10% dextran sulfate, and 10 mmol/L dithiothreitol) at
42°C. Serial sections were hybridized with 6x105 cpm of
35S-labeled riboprobes at 55°C. After hybridization, the
sections were washed with 2x SSC (1x SSC contains 150 mmol/L
NaCl and 15 mmol/L sodium citrate, pH 7.0), 10 mmol/L
ß-mercaptoethanol, and 1 mmol/L EDTA, treated with RNase A
(Sigma), and washed in the same buffer, followed by a high-stringency
wash in 0.1x SSC with 10 mmol/L ß-mercaptoethanol and 1
mmol/L EDTA at 55°C. The slides were then washed in 0.5x SSC and
dehydrated in graded alcohols containing 0.3 mol/L NH4Ac.
The sections were dried, coated with NTB2 nuclear track emulsion
(International Biotechnologies), and exposed in the dark at 4°C for 4
to 12 weeks. After development, the sections were counterstained with
hematoxylin and eosin to aid in cell identification. Two coronary
vessels from each animal and three sections per each coronary vessel
were examined.
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Results |
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In situ hybridization for NMMHC-B in uninjured arteries showed expression of this gene predominantly in SMCs of the medial layer and in luminal endothelial cells (Fig 1A
). The low
background observed by hybridizing with sense control
35S-labeled riboprobes demonstrated the specificity of the
antisense probes (Fig 1B). Immunohistochemistry was performed to
identify proliferating cells (BrdU staining) and SMCs (SM actin
staining). Neither layer of the vessel wall of uninjured arteries
showed cell proliferation (Fig 1C). Medial SMCs showed positive SM
actin staining, whereas adventitial cells were SM actin negative
(Fig 1D).
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A markedly elevated NMMHC-B mRNA expression was detected 3 days after
injury, primarily in the adventitia adjacent to the vessel medial tear
and the medial layer subjacent to the tear site (Fig 2A). Control hybridizations with 35S-labeled
sense riboprobes depicted in Fig 2B were negative. BrdU staining on day
3 after injury revealed a large number of proliferating cells in the
adventitia (Fig 2C). BrdU-positive cells were also found in the media,
near the site of the tear, in regions rich in cells expressing NMMHC-B
mRNA (Fig 2C). Few SM actin–positive cells were found in the
adventitia 3 days after angioplasty (Fig 2D), suggesting that the
adventitial proliferating cells were not of smooth muscle origin. Cells
close to the luminal side of the external elastic lamina in the break
site did not express NMMHC-B mRNA, and they were clearly BrdU and SM
actin negative. NMMHC-B mRNA expression and cell proliferation
colocalized in all areas examined 3 days after angioplasty (Fig 2A and 2C).
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Seven days after balloon angioplasty, NMMHC-B mRNA expression was found
primarily in the developing neointima (Fig 3A). At this
time point, the number of cells expressing NMMHC-B in the adventitia
decreased (Fig 3A). BrdU-positive cells were still observed in the
adventitia and the luminal surface of the neointima (Fig 3C). SM
actin staining changed dramatically at 7 days: SM actin–positive
cells were found not only in the neointima but also in the adventitia
(Fig 3D). A similar pattern was observed 14 days after injury, and
NMMHC-B mRNA expression was primarily found in the well-developed
neointima and in the adventitia (Fig 4A). Adventitial
and neointimal proliferation decreased 14 days after
balloon-overstretch injury, but few BrdU-positive cells were still
present in both layers (Fig 4C). SM actin staining 2 weeks after
injury revealed SM actin–positive cells in all neointimal and most
adventitial regions (Fig 4D), similar to 7 days after angioplasty.
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Discussion |
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Mechanical injury of porcine coronary arteries produces arterial stenosis, which seems to be histopathologically similar to human coronary restenosis.25 As in clinical PTCA, the primary mechanism for experimental luminal enlargement of porcine coronary arteries is tearing of the intima, internal elastic lamina, and media, with exposure of the outer elastic lamina. Although the sequence of cellular events of the human restenotic healing process remains unknown, the porcine coronary injury model has been considered one approach toward understanding the time course of human vascular lesion formation.23 27 Although expression of NMM has been associated with a dedifferentiated SMC phenotype,16 the contractile and synthetic phenotypes described for vascular SMCs28 might be only two points on a continuous spectrum of smooth muscle phenotypic expression.6 Coexistence of two distinct phenotypes in the normal vascular wall is suggested by the simultaneous expression of both NMM and SMM in vascular SMCs.19 29 30 31 32 In the present series of experiments, we found NMMHC-B mRNA expression in the medial layer of normal uninjured porcine coronary arteries, in agreement with recent findings showing NMMHC-B expression in normal human aorta and coronary arteries22 and in fully differentiated vascular SMCs.29
Three days after angioplasty, NMMHC-B mRNA was predominantly expressed in proliferating medial and adventitial cells. A decreased medial and adventitial NMMHC-B mRNA expression was found 7 and 14 days after balloon injury. Fourteen days after angioplasty, NMMHC-B mRNA expression was observed in both proliferating and nonproliferating adventitial and neointimal cells, the vast majority of which were not proliferating. Data from experiments with aortic SMCs in culture indicate that subconfluent rapidly proliferating SMCs have reduced the expression of SMMHC and increased NMMHC expression, whereas postconfluent growth-arrested SMCs expressed SMMHC along with large amounts of NMMHC.33 Thus, our findings are consistent with experiments showing that NMMHC expression is not limited to the proliferative state of vascular SMCs.20 22 29 33 34 The highly conserved sequences of SMM and NMM across species raises the possibility of cross hybridization of our porcine NMMHC-B probe with other myosin molecules. However, sequence analysis of our NMMHC-B cDNA probe revealed that the longest homologous fragments spanned regions shorter than 11 bp for SM1 and SM2 and shorter than 14 bp for NMMHC-A. The RNase A treatment, which eliminates single-stranded RNA and the high-stringency washing step (0.1x SSC at 55°C for 2 hours) included in the in situ hybridization technique, should eliminate the spurious complementary base pairing of short sequences, thus ensuring that the probe is properly complexed to the mRNA.26 Nonetheless, cross hybridization of NMMHC-B with other myosin and/or nonmyosin molecules cannot be ruled out in the present experiments.
The positive staining for SM actin in the media of uninjured
arteries and the neointima of arterial lesions 7 and 14 days after
injury might support the concept that most of those cells were of
smooth muscle origin. However, proliferating adventitial cells 3 days
after injury were SM actin negative but showed an induced expression
of SM actin 14 days after angioplasty. The induced expression of
SM actin and the negative staining by SMC markers (desmin,
h-caldesmon, and SMM) previously reported by our laboratory at the same
time points24 suggests that proliferating adventitial
cells undergo a phenotypic alteration similar to that observed in
myofibroblasts associated with skin wound healing35 and
neoplasias.36 37 38 Myofibroblasts have also been identified
at sites of healing human myocardial infarctions.39
Myofibroblasts are specialized fibroblast-like cells that show induced
expression of SM actin and other SMC markers, including
SMMHC.38 Synthesis of SM actin in myofibroblasts is
stimulated in response to a variety of stimuli, including
heparin,40 interferon gamma,41 and
transforming growth factor-ß.42 Previous work indicated
that cultured human fibroblasts express high levels of NMMHC-B
mRNA.22 In addition, a recent study reported NMMHC-B
expression in myofibroblasts of the myocardial
interstitium.43 Taken together, these studies and our
experiments suggest that NMMHC-B might also be expressed by
myofibroblasts.
Studies performed on rabbits showed that the NMMHC-B isoform is expressed in embryonic and perinatal aortas but not in the adult artery.16 However, NMMHC-B was reexpressed in proliferating SMCs of rabbit aortic arteriosclerotic neointimas.16 In contrast, NMMHC-B is expressed in adult and fetal human aortas and coronary arteries.22 In the latter study, expression of NMMHC-B in the nonatheromatous coronary and aortic intima at all ages examined led the authors to suggest that "NMMHC-B expression is not necessarily a phenomenon specific to restenosis after angioplasty."22 Accordingly, in the present experiments, NMMHC-B mRNA expression was found in the medial layer of uninjured arteries and the three layers of injured porcine coronary arteries.
A striking finding of the present report was the marked increase of the
proliferating adventitial cell population expressing NMMHC-B 3 days
after balloon injury. The kinetics of the proliferative and NMMHC-B
mRNA expression patterns suggests that adventitial cells are the first
line of response to vascular injury in the porcine model. Stripping of
the adventitia of the rat aorta and rabbit carotid artery has been
shown to provoke intimal hyperplasia.44 45 The adventitia
also responds to experimental vascular injury by activating the
expression of tissue factor46 and
angiotensinogen.47 Balloon-overstretch injury of porcine
coronary arteries tears the medial wall and exposes the external
elastic lamina. Vascular lesion formation then occurs in the region
between the broken ends of the media on the luminal side of the
external elastic lamina. It has been assumed that the neointimal cells
arise from the broken ends of the medial wall. In fact, SM actin
staining of the neointima has been used to support this. However, a
recent report by our laboratory suggests that some of the neointimal
cells in this model may have migrated from the
adventitia.24 Although the mechanisms underlying the
activation of adventitial cell proliferation are unclear, we have
previously shown that adventitial myofibroblasts synthesize
platelet-derived growth factor-A and -ß receptors.24
Thus, proliferating cells in the adventitia may contribute to vascular
lesion formation by synthesizing growth factors, which in turn may
affect not only cell growth but also cell migration of medial and/or
adventitial cells. Further work will have to be done to establish the
role of migrating adventitial cells in neointimal lesion formation in
this model.
In summary, the present experiments showed that balloon injury of
porcine coronary arteries activated adventitial cells and that such
activation resulted in adventitial cell proliferation and expression of
NMMHC-B and SM actin. NMMHC-B expression was not confined to
proliferating SMCs, since medial quiescent SMCs from uninjured arteries
showed expression as well. A phenotypic modulation of adventitial
myofibroblasts might be responsible for the early proliferative
response after balloon angioplasty of the porcine model of arterial
injury.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a fellowship grant from the National Kidney Foundation (Dr De Leon), National Institutes of Health grant HL-47838-03 (Dr Wilcox), the Robert Wood Johnson Foundation for Minority Faculty Development (Dr Scott), and the Andreas Gruentzig Cardiovascular Center. We also thank Romesh Subramanian and Cheryl Ross for their technical assistance.
Received May 20, 1996; accepted January 6, 1997.
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