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Stroke. 1997;28:1733-1738

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(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

Mari Yamamoto, PhD; Masaru Aoyagi, MD; Shingo Tajima, MD; Hiroshi Wachi, PhD; Naomi Fukai, MD; Yoshiharu Matsushima, MD; Kiyotaka Yamamoto, PhD

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


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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 TableDown). 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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  		Table 1. Established Strains of Arterial Smooth Muscle Cells Derived From Moyamoya Disease and Control Subjects

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 {approx}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).


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
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 1aDown, 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 1bDown).



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  		Figure 1. Tropoelastin synthesis in cultured SMCs from moyamoya patients (HMSMC) and control subjects (HCSMC). a, Equal amounts of protein obtained from quiescent SMCs were analyzed by immunoblotting with an antibody against tropoelastin. Lanes 1 and 2, HCSMC strains. Lanes 3 and 4, HMSMC strains. b, Bands corresponding to 70-kD tropoelastin were scanned with a densitometer. Columns show the mean and SD of three separate experiments. *P<.01, compared with cells from control subjects by independent Student's t test.

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 2aDown and 3aDown). The amounts of intracellular elastin synthesized by HMSMCs were also increased to the same degree (3.0-fold, Fig 3bDown). 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 3aDown). 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 2bDown and 3Down). 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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  		Figure 2. Effects of TGF-ß1 on elastin production in the culture medium of HMSMC and HCSMC strains. Confluent cultures were treated in the absence (a) or presence (b) of TGF-ß1 (10 ng/mL) for 48 hours and labeled with 3H-valine for the final 6 hours. Labeled proteins obtained from the culture medium were resolved on 4% to 15% SDS-polyacrylamide gels and subjected to fluorography. The arrow shows the migration of tropoelastin. Lanes 1 through 4, HCSMC strains. Lanes 5 through 10, HMSMC strains.



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  		Figure 3. Relative levels of elastin production in the culture medium (a) or cell layer (b). Confluent cultures were treated with TGF-ß1 (0 to 10 ng/mL) for 48 hours and labeled with 3H-valine for the final 6 hours. Labeled proteins obtained from the culture medium or cell layer were resolved on 4% to 15% SDS-polyacrylamide gels and subjected to fluorography. Densitometric scanning was performed to compare the relative levels of the 70-kD tropoelastin band. Columns show the means and SDs for HCSMC (n=4) and HMSMC (n=6). *P<.004, **P<.0001, compared with cells from control subjects with the use of independent Student's t test. **P<.0001 on panels a and b.

The level of elastin mRNA was measured by Northern blot analysis (Fig 4Down). 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 3Up) and correlate with histological observations in the superficial temporal arteries in patients with moyamoya disease.19



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  		Figure 4. Northern blot analysis of elastin mRNA levels in HCSMC and HMSMC strains. a, RNA (15 µg) isolated from cells treated with or without TGF-ß1 (10 ng/mL) for 48 hours, resolved by 1% agarose gel electrophoresis, and blotted onto nitrocellulose membranes. The membranes were hybridized with elastin cDNA probes as described in "Materials and Methods" and subjected to autoradiography. The loading of the gels was determined by visualizing the 28S rRNA band using ethidium bromide (28S). Lanes 1 through 3, HCSMC strains. Lanes 4 through 6, HMSMC strains. b, Autoradiograms were scanned with a densitometer. Columns show the means and SDs for HCSMC and HMSMC strains. *P<.03, **P<.002 compared with cells from control subjects by independent Student's t test.

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 5Down, 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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  		Figure 5. Production of TGF-ß1 in the medium of cultured HCSMC and HMSMC. SMCs grown to confluence were incubated in MEM containing 0.5% FBS at 37°C for 48 hours. The medium was collected, and the TGF-ß1 secreted into the medium was measured with a TGF-ß1 ELISA kit. Columns show the means and SDs for HCSMC and HMSMC strains. *P<.001, compared with cells from control subjects by independent Student's t test.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
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.


*    Selected Abbreviations and Acronyms
 
DMEM = Dulbecco's modified Eagle's medium
FBS = fetal bovine serum
HCSMC = arterial SMC strains from Japanese control subjects
HMSMC = arterial SMC strains from Japanese patients with moyamoya disease
MEM = minimum essential medium
SDS = sodium dodecyl sulfate
SMC(s) = smooth muscle cell(s)
TGF-ß = transforming growth factor-ß


*    Acknowledgments
 
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.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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