(Stroke. 1997;28:1733-1738.)
© 1997 American Heart Association, Inc.
Articles |
Increase in Elastin Gene Expression and Protein Synthesis in Arterial Smooth Muscle Cells Derived From Patients with Moyamoya Disease
From the Department of Cell Biology, Tokyo Metropolitan Institute of Gerontology (M.Y., M.A., N.F., K.Y.); the Department of Neurosurgery, Tokyo Medical and Dental University (M.A., Y.M.); and the Department of Dermatology, National Defense Medical School, Saitama (S.T., H.W.), Japan.
Correspondence to Kiyotaka Yamamoto, PhD, Department of Cell Biology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173, Japan. E-mail kyama{at}tmig.or.jp
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Abstract |
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Background and Purpose Moyamoya disease is a progressive cerebrovascular occlusive disease that is rare in all ages but frequently presents in children. The etiology of the disease is unknown. We examined elastin gene transcripts and elastin synthesis in cultured arterial smooth muscle cells (SMCs) derived from moyamoya patients and compared them with those in SMCs from age-matched control subjects.
Methods We used six cell strains from moyamoya patients and four from controls. The expression of elastin protein was observed by Western blot analysis and metabolic labeling with 3H-valine. Elastin gene transcripts were identified by Northern blot analysis.
Results Elastin mRNA and protein levels were elevated in all SMCs from moyamoya patients compared with control SMCs. Although transforming growth factor-ß1 (TGF-ß1), a potent enhancer of the expression of elastin in arterial SMCs, upregulated elastin mRNA and protein levels in SMCs from both moyamoya patients and control subjects, the maximum levels of elastin synthesis and elastin gene transcripts in response to exogenous TGF-ß1 were significantly greater in moyamoya SMCs than control SMCs. In addition, quiescent moyamoya SMCs secreted significantly more TGF-ß1 into the culture medium than quiescent control SMCs (P<.01).
Conclusions Our findings suggest that moyamoya disease may result, at least in part, from an abnormal regulation of extracellular matrix metabolism that leads to increased steady state levels of elastin mRNA and elastin accumulation in the intimal thickening and that increased elastin accumulation is a stable marker of SMCs from patients with moyamoya disease.
Key Words: extracellular matrix • moyamoya disease • muscle, smooth • transforming growth factor
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Moyamoya disease is an unusual form of chronic cerebrovascular occlusive disease characterized by progressive stenosis or occlusion at the distal ends of the bilateral internal carotid arteries.1 2 The onset of the disease is frequently seen during the first decade of life, and the clinical symptoms are a variety of neurological deficits that depend on the specific artery occluded.3 Histopathological investigations on autopsy subjects have demonstrated that the main vascular lesions are stenosis or occlusion by fibrocellular intimal thickening with multilayered elastic laminae and few lipid deposits.4 5 6 7 Arteries outside the brain occasionally show similar stenosis with thickened intima.4 8 9 10
The etiology of the disease remains unknown. The findings that the incidence of the disease is highest in, but not confined to, Japanese11 12 and that the condition is frequently familial13 14 suggest the involvement of a genetic factor in its pathogenesis. We have postulated that functional alterations in vascular cells are involved in the development of intimal thickening in moyamoya disease.15 16 Recent studies indicate alterations in various angiogenic growth factors in patients with moyamoya disease.17 18 The elevation of basic fibroblast growth factor in the cerebrospinal fluid of patients with moyamoya disease may be a major factor in the development of stenosis of intracranial major arteries and angiogenesis of collateral circulation.18 We recently reported that the intimal thickening of the superficial temporal arteries from patients with moyamoya disease develops at an early age and that it shows strongly stained multilayered elastic fibers, whereas control subjects show only weakly stained elastic fibers.19 The increase in elastin accumulation in the thickened intima may represent a unique characteristic of the systemic and intracranial arteries in moyamoya disease. These findings suggest that elastin synthesis and/or accumulation are significantly increased in the vascular cells of moyamoya patients compared with those of control subjects.
In the present study, we examined elastin mRNA expression and elastin synthesis in cultured SMCs derived from the superficial temporal arteries of patients with moyamoya disease and compared them with those in SMCs from age-matched control subjects. We found increased elastin gene transcripts and elastin synthesis in quiescent moyamoya SMCs cultured from systemic arteries.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials
[3, 4-3H]-Valine (1.5 TBq/mmol) was supplied by Amersham. Eagle's minimum essential medium (MEM), Dulbecco's modified Eagle's medium (DMEM), and valine-free DMEM were purchased from GIBCO. Recombinant transforming growth factor-ß1 (TGF-ß1) was obtained from King Brewing Co.
Cell Culture
HMSMC and HCSMC were established as described
previously.15 No associated disease was found in any of
the six patients with moyamoya disease. Arterial
specimens were obtained from branches of scrap arteries (superficial
temporal arteries) that required division during indirect
bypass20 or other cranial operations. The age of the
moyamoya patients was 9.5±2.1 (mean±SD) and that of controls was
10.8±8.0 years, not statistically different (see
Table
). Informed consent was obtained
from the patients or their relatives and the study was approved by the
Ethical Committee of the Tokyo Metropolitan Institute of
Gerontology.
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We used six cell strains from moyamoya patients and four from control subjects. The cells were cultured in 60-mm Falcon dishes (3002) in 5 mL of MEM supplemented with 15% FBS (Biocell, 6201B304) at 37°C under humidified 5% CO2–95% air. The medium was renewed every 3 or 4 days. Confluent cultures were treated with 0.25% trypsin–0.02% EDTA in Ca2+- and Mg2+-free phosphate-buffered saline for 10 minutes at 37°C and subcultured at a 1:2 split ratio. The number of cells was measured with a hemocytometer after trypsin treatment. For the present study, we used cells within 10 passages. The cells were carefully examined for mycoplasma contamination by the method described previously.15
Metabolic Labeling and Sodium Dodecyl
Sulfate–Polyacrylamide Gel Electrophoresis
Metabolic labeling was performed according to the
method described previously.21 22 Briefly, cells grown to
confluence were incubated for 48 hours with TGF-ß1 (0 to 10
ng/mL) in DMEM containing 0.5% dialyzed FBS (quiescent cells).
During the last 6 hours of treatment, the cells were labeled with
3H-valine (25 µCi/mL) in valine-free DMEM. The culture
medium was collected and precipitated with ammonium sulfate (176
mg/mL) in the presence of protease inhibitors,
1 mmol/L EDTA, 1 mmol/L N-ethylmaleimide, and
1 mmol/L phenyl-methylsulfonyl fluoride. The
cell layer was homogenized with 0.5 mol/L acetic
acid containing protease inhibitors and centrifuged
at 10 000g for 30 minutes at 4°C. The resulting
supernatant was dialyzed overnight at 4°C against 0.1% acetic acid
containing protease inhibitors and then lyophilized.
SDS–polyacrylamide gel electrophoresis was carried out
according to the method described previously.23 The
proteins from the medium and cell layer were solubilized in lysis
buffer (0.2 mol/L Tris-HCl, pH 6.8, 50 mmol/L EDTA,
10% glycerol, 2% SDS, and 2 mmol/L phenylmethylsulfonyl
fluoride) and reduced with 1 mmol/L dithiothreitol.
Equal amounts of proteins were resolved on 4% to 15%
SDS-polyacrylamide slab gels and fluorographed. Elastin
synthesis was measured by densitometric scanning of the fluorograms to
compare relative levels using NIH Images for the Macintosh.
Western Blot Analysis
Quiescent cells were solubilized in lysis buffer. Equal amounts
of protein were loaded on 4% to 15% acrylamide slab gels
and developed at 25 mA for 2 hours. Samples were transferred from the
slab gel to Clearblot-P membranes (ATTO Co) at 1.5 mA/cm2
for 2 hours. After blocking with 0.1% casein and 0.1% gelatin for 1
hour, the membranes were incubated with a 1:100 dilution of monoclonal
anti-tropoelastin antibody (Elastin Products Co) at 24°C for 1
hour and then with a 1:500 dilution of peroxidase-conjugated anti-mouse
IgG (ICN Biomedicals Inc, Cappel Products) for 45 minutes. Color
was developed using 3-amino-9-ethylcarbazole as previously
described.23 Densitometric scanning was performed to
compare relative protein levels using NIH Images for the Macintosh.
Northern Blot Analysis
SMCs grown to confluence were incubated for 48 hours with or
without TGF-ß1 (10 ng/mL) in DMEM containing 0.5% FBS. Total
RNA was isolated from the quiescent cells according to a previously
described procedure24 and stored at -80°C after
adjusting the concentration to 1 µg/µL. The RNA (15 µg)
was denatured for 1 hour at 50°C in deionized 1 mol/L
glyoxal/10 mmol/L phosphate buffer (pH 6.5),
size-fractionated by electrophoresis on 1% agarose gels, and blotted
to nylon membranes (Pall BioSupport). Ethidium bromide staining of the
gels assured equal loading of RNA in each lane. The membranes were
hybridized for 18 hours at 42°C to 32P-labeled elastin
probes in 50% formamide, 5x SSC, 5x Denhardt's solution, 0.1% SDS,
and 250 µg/mL tRNA. The cDNA probes were radioactively labeled
by random priming (Amersham) to a specific activity of
108 dpm/µg DNA. The membranes were washed for 30
minutes in 1x SSC/0.1% SDS, then in 0.1x SSC/0.1% SDS for 30
minutes, and placed on x-ray film (Fuji RX) with an intensifying screen
(Kodak Lanex Regular) at -80°C for autoradiography.
The autoradiograms were scanned with a
densitometer.
Determination of TGF-ß Production
The production of TGF-ß1 from human
arterial SMCs was examined according to a previously
described procedure.25 SMCs grown to confluence were
incubated in MEM containing 0.5% FBS at 37°C for 48 hours. The
medium was collected, filtered through 0.22 µm filters, and
stored for up to 7 days at -70°C before use. TGF-ß1 secreted into
the medium was measured with a TGF-ß1 ELISA kit (Genzyme Co).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We examined the expression of elastin protein in arterial SMCs derived from moyamoya patients (HMSMC) and control subjects (HCSMC) by Western blot analysis. As shown in Fig 1a
, the anti-tropoelastin antibody
reacted with a 70-kD protein in homogenates of SMCs from
moyamoya patients and control subjects. The immunoreactive band was
clearly increased in intensity in HMSMC strains (Fig 1b).
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Elastin synthesis by quiescent HMSMC strains was significantly greater
than in the case of HCSMC strains. Elastin production in
culture medium by HMSMC strains was increased 3.1-fold compared with
HCSMC strains (Figs 2a and 3a). The amounts of intracellular elastin
synthesized by HMSMCs were also increased to the same degree (3.0-fold,
Fig 3b). TGF-ß is a peptide-signaling molecule that has been
implicated in neointimal formation after
arterial injury26 and that stimulates elastin
production and elastin mRNA expression in vascular
SMCs.27 28 29 TGF-ß1 (1 to 10 ng/mL) promoted
elastin production in culture medium by both cell strains in a
dose-dependent manner (Fig 3a). TGF-ß1 (10 ng/mL) markedly
elevated elastin synthesis in HCSMC (3.1-fold in culture medium,
3.0-fold in cells) and in HMSMC (2.2-fold in culture medium, 2.1-fold
in cells) (Figs 2b and 3). However, the maximum stimulation of elastin
synthesis by TGF-ß1 (10 ng/mL) was significantly greater in
HMSMC than in HCSMC.
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The level of elastin mRNA was measured by Northern blot
analysis (Fig 4). Elastin mRNA
was significantly (P<.002) upregulated in quiescent HMSMCs
compared with HCSMCs in the absence of TGF-ß1. In the presence of
TGF-ß1 (10 ng/mL), elastin mRNA expression was significantly
stimulated in HCSMC (3.6-fold) and HMSMC (2.2-fold). The levels of
elastin mRNA in TGF-ß1–stimulated cells differed significantly
between the two cell strains. These results are in good agreement with
those of elastin synthesis (Fig 3
) and correlate with
histological observations in the superficial temporal
arteries in patients with moyamoya disease.19
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Aortic SMCs and lung fibroblasts from neonatal rats contain more
elastin in their culture medium and tend to secrete more TGF-ß than
cells from adult animals, suggesting that endogenous
TGF-ß influences elastin production by neonatal
cells.28 We then examined the production of
TGF-ß1 by arterial SMCs from moyamoya patients and
control subjects. As shown in Fig 5, TGF-ß1 production by quiescent HMSMC strains (1.20±0.31
ng/mL) was significantly higher (P<.001) than that
by quiescent HCSMC strains (0.34±0.12 ng/mL). This may
explain the upregulation of elastin synthesis and elastin gene
transcripts in quiescent SMCs from moyamoya patients in the absence
of exogenous TGF-ß1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Histopathological investigations on autopsy subjects have demonstrated that the intimal thickening of intracranial arteries in moyamoya patients contains multiple elastic lamina.4 5 6 7 Previous reports have suggested that recurrent microthrombi and subsequent organization may contribute to the layered structures separated by multiple elastic fibers in the thickened intima of moyamoya patients.5 10 30 We recently reported that intimal thickening of superficial temporal arteries is frequently observed in young patients with moyamoya disease but not in young control patients.19 The arteries of moyamoya patients contain strongly stained multilayered elastic fibers in the thickened intima, whereas those from adult control patients show only weakly stained elastic fibers in the thickened intima.19 These findings are essentially the same as those in the thickened intima of intracranial arteries of moyamoya disease patients.4 5 6 7 These results strongly suggest that moyamoya disease is a systemic vascular disease with an etiologic factor that affects both intracranial and extracranial arteries. The present studies demonstrate that quiescent SMCs derived from superficial temporal arteries of young patients with moyamoya disease show significantly more elastin synthesis and higher steady state levels of elastin mRNA than those from age-matched control subjects, suggesting abnormal elastogenesis in vivo.
Recent studies31 have shown that macrophages and T lymphocytes localize in the surface layer of the thickened intima of intracranial arteries of moyamoya disease patients, suggesting a role for chronic inflammatory stimuli in SMC proliferation in the thickened intima. Cytokines inducible by inflammatory stimuli, such as interleukin-1 (IL-1) and TGF-ß, are multifunctional regulators of cellular activity. IL-1 induces TGF-ß1 mRNA expression and TGF-ß1 synthesis by rat aortic SMCs.32 TGF-ß1 (1 ng/mL) upregulates elastin mRNA expression in human skin fibroblasts.33 The incubation of porcine aortic SMCs with TGF-ß (1 to 10 ng/mL) increases elastin production 2- to 3-fold in a dose-dependent manner.27 29 McGowan28 reported that aortic SMCs and lung fibroblasts obtained from neonatal rats exhibit higher steady state levels of elastin mRNA and contain more soluble elastin in their culture medium than cells from adult animals. Cultured cells from neonates tend to secrete more TGF-ß than cells from adults. In the present study, exogenous TGF-ß1 (1 to 10 ng/mL) produced an elevation in the level of elastin mRNA and increased elastin synthesis by 2- to 3-fold in SMCs from both moyamoya and control subjects. However, the levels of elastin mRNA expression and elastin synthesis were significantly higher in SMC strains from moyamoya patients with or without TGF-ß1 than in SMC strains from control subjects. HMSMC strains secreted significantly more TGF-ß1 into the culture medium than HCSMC strains. Therefore, endogenous TGF-ß1 may affect, at least in part, the steady state levels of elastin mRNA and elastin synthesis in quiescent HMSMC, and autocrine regulation may influence the effects of exogenous TGF-ß. Furthermore, the increased response to exogenous TGF-ß1 in moyamoya SMCs suggests that moyamoya SMCs possess a higher potential for elastin synthesis than control SMCs. Endogenous and exogenous TGF-ß1, which are released from SMCs themselves and from inflammatory cells by chronic inflammatory stimuli in moyamoya patients, may modulate elastin gene expression and elastin synthesis by HMSMC. Autocrine secretion of TGF-ß1 and the increased response of elastin synthesis to exogenous TGF-ß1 in moyamoya SMCs may be genetically regulated and explain the increased accumulation of elastic fibers in the thickened intima of moyamoya disease patients.
The causal relation of an increase in elastin synthesis and tropoelastin transcripts in moyamoya SMCs to the early development of intimal thickening in moyamoya disease presently remains unclear. However, elastin is one of the major fibrous proteins of vascular extracellular matrix contributing to neointimal formation after arterial wall injury.34 35 36 The accumulation of matrix proteins in the neointima may depend on the balance between matrix synthesis and degradation.36 Elastin synthesis and tropoelastin transcripts are strictly regulated to increase in neointimal SMCs near the end of the proliferative phase.19 Elastin may also function to induce proliferating SMCs to the quiescent state. An inherited disease of supravalvular aortic stenosis, which has been shown to have mutations in elastic gene, contains excessive SMCs with broken and disorganized elastic fibers in the media of affected vessels.37 38 Furthermore, Kawai et al39 reported a rare case of Williams syndrome complicated by moyamoya disease. Autopsy findings reveal a marked disarray of elastic fibers in the thickened media associated with Williams syndrome and the intimal undulation at the carotid bifurcation associated with moyamoya disease.39 Lack of functional integrity of elastin might be expected to affect the normal repair process of arterial wall injury, leading to a greater amount of elastin accumulation and prolonged neointimal formation in the arterial wall, although no evidence of functional status of elastin has been yet shown in moyamoya disease. As proven for many genes, the transcriptional regulation of elastin gene may vary among different tissues and even different arteries.40 41 42 Further work aimed at the functional status of elastin and the transcriptional regulation of elastin gene is essential and will aid in clarifying the mechanisms of early development of intimal thickening in moyamoya disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants-in-aid for scientific research from the Ministry of Education, Science and Culture, Tokyo, Japan. We thank Dr Margaret Dooley Ohto for reviewing the manuscript.
Received March 31, 1997; revision received May 13, 1997; accepted May 13, 1997.
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