(Circulation. 2000;101:2532.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Prevention of Rat Cerebral Aneurysm Formation by Inhibition of Nitric Oxide Synthase
From the Department of Neurosurgery (S.F., N.H., K.N., S.K.) and Section of Electron Microscopy Laboratory of Anatomic Pathology (M.K.), Kyoto University Hospital, and the Stroke Care Unit, Department of Medicine (H.N.) and Department of Neurosurgery (I.N., H.K.), National Cardiovascular Center, Osaka, Japan. Dr Fukuda is now at the Department of Neurosurgery, Maizuru Municipal Hospital, and Dr Kondo is now at the Department of Neurosurgery, Tokyo Women’s Medical University Hospital, Japan.
Correspondence to Shunichi Fukuda, MD, PhD, Department of Neurosurgery, Maizuru Municipal Hospital, 150–11 Mizoshiri, Maizuru City, Kyoto 625-0035, Japan.
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Abstract |
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Background—Cerebral saccular aneurysm is a major cause of subarachnoid hemorrhage, one of the cerebrovascular diseases with the highest mortality. The mechanisms underlying the development of aneurysms, however, still remain unclear. We have made a series of reports on an animal model of experimentally induced cerebral aneurysms that resemble human cerebral aneurysms in their location and morphology, suggesting that the arterial wall degeneration associated with aneurysm formation develops near the apex of arterial bifurcation as a result of an increase in wall shear stress. Using the animal model and human specimens, we examined the role of nitric oxide (NO) in the degenerative changes and cerebral aneurysm formation.
Methods and Results—Inducible NO synthase (iNOS) was immunohistochemically located at the orifice of human and rat aneurysms. Nitrotyrosine distribution was also seen in the human aneurysm. Although no iNOS immunostaining was found in normal arteries, iNOS immunoreactivity was observed in parallel with the development of early aneurysmal changes in rats. In contrast, during the early development of aneurysm, endothelial NOS immunostaining in the endothelium was weakened compared with that in the control arteries. An NOS inhibitor, aminoguanidine, attenuated both early aneurysmal changes and the incidence of induced aneurysms. A defibrinogenic agent, batroxobin, which may diminish shear stress by reduction of blood viscosity, prevented iNOS induction as well as early aneurysmal changes.
Conclusions—The evidence suggests that NO, particularly that derived from iNOS, is a key requirement for the development of cerebral aneurysm. The iNOS induction may be caused by an increase in shear stress near the apex.
Key Words: aneurysm • nitric oxide • cerebrovascular disorders • hemodynamics
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Introduction |
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The pathogenesis of cerebral saccular aneurysms still remains unresolved. Our experimentally induced aneurysms in rats and monkeys resemble human cerebral aneurysms in their location and microscopic structure.1 2 They have been accepted as good models for studying the pathogenesis of human aneurysms. In our microscopic studies, the initial changes associated with aneurysm formation were observed mainly at arterial bifurcations, particularly at the distal side of the major branch adjacent to the apex (Figure 1A
).3 The degenerative
changes were localized almost exclusively at the intimal pad and its
neighboring distal portion, the so-called juxta-apical groove
(JAG).
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The mechanism of the arterial wall degeneration at the JAG, however, is still unclear. Nitric oxide (NO) is one of the possible contributors to the arterial wall degeneration.4 5 We show here that NO synthesized by inducible NO synthase (iNOS) may serve to damage the arterial wall and lead to aneurysm formation. Distributions of iNOS and nitrotyrosine in human and rat cerebral aneurysms were studied immunohistochemically. The association between tissue damage and induction of iNOS and endothelial NOS (eNOS) during the early development of aneurysm was also examined immunohistochemically. The NOS inhibitor aminoguanidine (AG) was used to confirm whether NOS inhibition prevents both the early aneurysmal changes and the formation of aneurysms in rats.6
We also examined the mechanism of iNOS induction in the development of aneurysms. Clinical and epidemiological evidence suggests that the heightened hemodynamic stress due to an increase in blood flow may be an important factor underlying aneurysm development.7 8 Aneurysms in our model develop at several sites along the circle of Willis, where blood flow is increased in compensation for unilateral common carotid artery ligation and experimental hypertension.9 The data suggest that the hemodynamic stress and hypertension are of primary importance. Our hemorheological studies in rat aneurysms showed that in early aneurysm development, the wall shear stress was increased and highest at the distal end of the JAG, the distal end of the aneurysmal orifice.10 11 Moreover, the initial dilatation and degeneration of the arterial wall invariably developed in the same area.3 Other investigators have also indicated that the wall shear stress is the highest at the aneurysmal end.12 13 The data suggest that the increase in shear stress is associated with the formation of aneurysm. An increase in shear stress is known to induce the production of various mediators, including NO.14 Thus, we hypothesized that iNOS may be induced by an increase in shear stress. A defibrinogenic agent, batroxobin (BX), was used to decrease wall shear stress.15 16
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Methods |
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Cerebral Aneurysm–Inducing Surgery in Rats
For aneurysm induction, 147 male Sprague-Dawley rats 6 to 8 weeks old were subjected to ligations of the right common carotid artery and the posterior branches of both renal arteries after pentobarbital anesthesia (50 mg/kg IP). One week after the operation, 0.5% saline was substituted for drinking water.
Treatment of Rat Induced Aneurysms With BX and AG
To clarify the effect of BX and AG on early aneurysmal
changes, from the day after the surgery, the animals received an
injection of 100 mg · kg-1 ·
d-1 AG IP (Sigma) (n=6), 200 mg ·
kg-1 · d-1 AG
(n=6), 100 mg · kg-1 ·
d-1 AG plus 300 mg ·
kg-1 · d-1
L-arginine (Sigma) (n=10), 60 U ·
kg-1 · d-1 BX
(Tobishi Pharmaceutical Co and Nippon Chemiphar Co) (n=16), or an
equivalent volume of physiological saline (n=27)
for 14 consecutive days. To examine the effect of AG on mature
aneurysm formation, the animals received 100 mg ·
kg-1 · d-1 AG
(n=13) or physiological saline (n=8) for 90
consecutive days. The animals were then anesthetized with 1.5
mL/min halothane. The MABP was recorded. The CBF was monitored at
the left parietofrontal cortex with a laser Doppler flowmeter.
Electron Microscopy for Early Aneurysmal Changes and Light
Microscopy for Aneurysm Formation in Rats
The animals were deeply anesthetized and perfused with
0.5% glutaraldehyde in 0.1 mol/L cacodylate buffer for
electron microscopy or 4% paraformaldehyde in 0.1
mol/L PBS for light microscopy. The brains were immersion-fixed with
3% paraformaldehyde, 0.5%
glutaraldehyde, and 0.01% tannic acid for electron
microscopy or 4% paraformaldehyde for light
microscopy. Arteries of the circle of Willis were embedded in epoxy
resin. For early aneurysmal changes, ultrathin sections of
bifurcations of the left anterior cerebral artery and olfactory artery
were examined with a Hitachi H-600 electron microscope. Light
microscopy was used for mature aneurysm formation after serial
sections 1 µm thick were cut and stained with toluidine blue.
"Aneurysm," as defined here, refers to an outward bulging
of the arterial wall detected by light microscopy. The
assessments were done by 3 examiners in a blinded manner.
Preparation of Rat Tissue for Immunohistochemistry
Tissues were fixed with Zamboni’s fixative by the same methods
as described above. The tissues at the apex areas obtained 2 weeks
after the surgery were cut off from the bifurcations as shown in Figure 1B
and were put in 0.4% Triton-X (Sigma) in PBS. The tissues
were immunostained without embedding, and the inner wall of
the tissues was opened and placed on a glass slide (Figure 1B).
The mature aneurysmal tissues obtained 3 months after the
surgery were embedded in paraffin, and sections 4 µm thick were
cut.
Preparation of Human Tissue for Immunohistochemistry
A human cerebral aneurysm was obtained from a
69-year-old woman during brain surgery. The large aneurysm was
resected out from the right middle cerebral artery, followed by
arterial bypass surgery. The specimens were immediately
fixed in formalin and embedded in paraffin, and sections 4 µm
thick were cut.
Immunohistochemistry in Human and Rat Specimens
After the inactivation of intrinsic peroxidase with 0.3%
H2O2 in methanol and
blocking with 15% normal goat serum, either a rabbit antibody against
mouse iNOS (Upstate Biotechnology) (1:500), a monoclonal antibody
against bovine eNOS (Calbiochem-Novabiochem Corp) (1:500), or a
monoclonal anti-nitrotyrosine antibody (1:50)17 was
applied overnight (NOS antibodies) or for 18 hours (nitrotyrosine
antibody) at 4°C, followed by application of the immunoperoxidase
technique using ABC kits (Vector Laboratories). The specificity of the
immunostaining was confirmed by replacing the primary
antibody with either nonimmune rabbit IgG, nonimmune mouse IgG, or an
anti-nitrotyrosine antibody in the presence of 10 mmol/L
nitrotyrosine. The anti-nitrotyrosine antibody recognizes nitrotyrosine
in the human tissue.17 The anti-iNOS and anti-eNOS
antibodies recognize human and rat iNOS and rat eNOS, respectively, and
do not cross-react with other NOS isoforms.18 19
Effect of BX on Fibrinogen Concentration
The animals received 60 U ·
kg-1 · d-1 BX
(n=5) or physiological saline (n=5). Their blood
was collected just before and 1, 3, 6, 10, and 24 hours after the
injection, and the fibrinogen concentration was measured by the
modified weight method.15
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Results |
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iNOS and Nitrotyrosine Immunoreactivities in Cerebral Aneurysms
iNOS immunoreactivity could be demonstrated in smooth muscle cells (SMCs) at the distal end of the neck of the rat cerebral aneurysm (Figure 2A
), whereas no
such immunoreactivity was found at the control bifurcations (Figure 2B). No nitrotyrosine immunoreactivity was seen in rat
specimens.
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In the human aneurysm, iNOS and nitrotyrosine distributions
were observed in SMCs of the aneurysmal orifice (Figure 3A and 3B).
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Effects of BX and AG on Early Aneurysmal Changes in
Rats
Damage to endothelial cells (ECs) and SMCs at the
JAG was classified into 5 grades according to electron microscopic
pathological changes as follows: grade 1 (Figure 4A), no EC or SMC damage; grade 2 (Figure 4B), mild EC damage, such as a wavy rippling of plasma membrane,
in the majority of ECs without SMC damage; grade 3 (Figure 4C),
moderate EC damage, such as some vacuoles in the cytoplasm without SMC
damage; grade 4 (Figure 4D), severe EC damage, such as cell
deformation and/or many vacuoles in the cytoplasm and nucleus without
SMC damage; and grade 5 (Figure 4E), severe EC damage in
association with SMC damage.
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Although no damage was seen in the nonsurgical group, severe damage to
ECs and SMCs was observed in the saline group (Table 1). BX ameliorated EC and SMC
damage (Table 1). AG at 100 and 200 mg ·
kg-1 · d-1
diminished EC and SMC damage. AG plus L-arginine, however,
did not decrease the damage. The grade of damage in the AG plus
L-arginine group was higher than that in the 100-mg
· kg-1 · d-1 AG
group. There was no significant difference in cerebral blood flow (CBF)
or mean arterial blood pressure (MABP) in any group
compared with the saline group. MABP in the AG plus
L-arginine group was significantly lower than that in the
100-mg/kg AG group. SMC damage without severe EC damage was not seen in
any group.
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iNOS and eNOS Immunoreactivities in Early Aneurysmal
Changes in Rats
In the nonsurgical group, eNOS immunoreactivity was seen in all
arterial endothelium examined (Figure 5A). In particular, eNOS staining was
stronger at the area around the JAG than any other area (Figure 5A). In the saline group, eNOS immunoreactivity at the area
around the JAG, in which mild tissue damage could be seen, was weakened
compared with that in the nonsurgical group, leading to
homogeneous eNOS distribution in the arterial
wall (Figure 5B). eNOS staining was no longer observed at the
JAG where severe damage was observed.
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In contrast with eNOS, neither iNOS immunoreactivity nor tissue damage
was seen in the nonsurgical group. In 6 of 8 animals of the saline
group, iNOS immunostaining was seen in the
arterial wall of the JAG and the intimal pad near the apex,
with severe tissue damage (Figure 5D). The tissue damage was
severe not at the apex, but rather in the areas surrounding the apex,
especially at the JAG, in parallel with the iNOS immunoreactivity.
There was no apparent iNOS immunoreactivity with mild tissue damage in
2 animals of the saline group.
To clarify whether reduction of shear stress with BX results in
prevention of iNOS induction, we also examined the correlation between
iNOS immunoreactivity and tissue damage in the BX group. iNOS
immunoreactivity was not seen in any animal of the BX group with any
tissue damage in light microscopy (4 animals) (Figure 5C) or
with very mild tissue damage (4 animals). There was no significant
difference in MABP or CBF among the groups.
Effects of AG on Incidence of Induced Aneurysm Formation
in Rats
In the saline group, aneurysm formation was common (Table 2). In the AG group, the frequency of
aneurysm formation was significantly below that in the saline
group. MABP in the AG group was significantly higher than that in the
saline group. CBF remained the same in the 2 groups.
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Effect of BX on Fibrinogen Concentration
The fibrinogen concentration in the BX group was significantly
lower than that in the saline group 1, 3, 6, 10, and 24 hours after the
BX treatment (Figure 6).
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Discussion |
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We have demonstrated that aneurysmal changes are initiated by endothelial degenerative changes and that aneurysmal alterations progress from the luminal toward the abluminal side of the arterial wall.3 20 In our rat model,
3 months was usually needed for mature
aneurysms to develop. Two weeks after the
aneurysm-inducing surgery, severe damage first to ECs and in
time to SMCs at the JAG was observed, whereas no damage was seen in the
nonsurgical group (Table 1). The EC and SMC damage thus reflects
the early changes of aneurysm development, which are compatible
with the findings of the early phases of development in previous
studies.20
iNOS was immunohistochemically demonstrated in the aneurysmal
orifice, whereas there was no iNOS immunoreactivity in control arteries
(Figures 2 and 3). iNOS distribution was also observed at
the JAG during the development of early aneurysmal changes in
parallel with the tissue damage (Figure 5). iNOS, which does not
ordinarily exist in the vascular wall, is induced by various stimuli in
both ECs and SMCs and synthesizes a large amount of NO, which appears
to be involved in various types of EC and SMC injury and degenerative
changes.4 5 17 Thus, iNOS induction in the
arterial wall may contribute to tissue damage and the
development of aneurysm. This hypothesis is further supported
by experiments that showed that the NOS inhibitor AG
suppressed both the early aneurysmal changes and the incidence
of aneurysm formation in rats (Tables 1 and 2).
Neither MABP nor CBF in the AG groups was lower than those in the
saline groups. Although AG has other pharmacological
actions,21 22 the suppression of aneurysm
development by AG may not be attributable to these other actions,
because this ameliorating effect could be antagonized by
L-arginine (Table 1). The effect may be mediated by
L-arginine–NO pathways. AG is a relatively selective
inhibitor for iNOS.6 MABP in the AG group 3
months after the surgery, however, was significantly higher than that
in the saline group (Table 2), suggesting that AG also inhibited
eNOS at least partially. To evaluate whether eNOS is also involved in
aneurysm formation, we observed eNOS immunoreactivity during
the early development of aneurysm. In contrast with iNOS, eNOS
immunostaining at the JAG was weakened as the
aneurysmal changes developed (Figure 5). Therefore, eNOS
downregulation and iNOS induction were observed in parallel with the
development of early aneurysmal changes, suggesting that eNOS
has little effect on aneurysm development. Moreover, the amount
of NO derived from eNOS is much less than that of NO synthesized by
iNOS, too little to damage ECs and SMCs.23 Thus, NO
derived from iNOS, but not from eNOS, may be a key requirement for
tissue damage and degenerative changes in the arterial wall
and the formation of cerebral aneurysms from the early phases
of development. Although the ideal experiment to more clearly define
the role of iNOS in the formation of aneurysm may be one that
shows that iNOS is not induced with an increase in
hemodynamic stress in mice lacking iNOS, an
experimental induction of aneurysms in mice has never been
successful, probably because of their small size. This may need further
investigation in the future.
A question may be raised here as to the mechanism of iNOS induction in
the development of aneurysm. One likely explanation is that
iNOS is induced in response to an excessive increase in wall shear
stress. We have shown that the wall shear stress at the distal end of
the JAG is highest during the early development of
aneurysms10 11 and that the initial dilatation of
the arterial wall develops at this area.3 BX
had a significant amelioration of EC and SMC damage (Table 1).
Although whole blood is a non-Newtonian liquid, at high shear stresses
it behaves as a Newtonian liquid,24 in which the wall
shear stress is the product of shear rate and Newtonian viscosity.
The shear rate depends on the flow rate and the arterial
diameter. A major factor determining whole blood viscosity is the
hematocrit, with a secondary determinant being fibrinogen
concentration.24 BX is used clinically as a defibrinogenic
agent for humans.15 16 BX at a dose of 60 U ·
kg-1 · d-1 in rats
decreases fibrinogen concentration and lowers the whole-blood viscosity
without any influences on inflammatory events.16 25 A dose
of 60 U/kg BX significantly reduced the fibrinogen concentration in
rats for 24 hours (Figure 6). BX did not reduce CBF or MABP
(Table 1). In the cerebral circulation, when both CBF and MABP
are the same, cerebral arterial tonus may be kept the same
by means of cerebral autoregulation. The arterial diameter,
therefore, is also likely to be the same. Thus, BX probably reduced the
overall blood viscosity without a corresponding change in the shear
rate. The tissue damage at the JAG was probably ameliorated by a
decrease in the wall shear stress resulting from the reduction of
whole-blood viscosity by BX, although it still remains possible that
some other effect of BX caused the reduction of tissue damage, because
we did not directly measure the wall shear stress in the BX-treated
animals. The data suggest that the increase in wall shear stress may be
involved in the mechanisms of early aneurysm development.
Moreover, iNOS immunoreactivity was attenuated in parallel with the
reduction of tissue damage by BX treatment, suggesting that a decrease
in the level of shear stress by BX treatment may prevent iNOS induction
during the period of aneurysm development. The increase in wall
shear stress may play an important role in iNOS induction.
The mechanism of iNOS induction in response to high shear stress is not
clear. The promoter of human iNOS contains a shear-stress–responsive
element,26 and nuclear factor-
B, which is required for
iNOS gene expression, is activated by shear
stress.27 An increase in shear stress may directly promote
iNOS induction, or high shear stress may induce functional tissue
damage and then the functional damage may lead to iNOS induction. In
addition to ECs directly exposed to blood flow, SMCs are also exposed
and can respond to shear stress due to interstitial flow
derived from transmural pressure gradients even in intact
arteries.28 Endothelial denudation caused
by endothelial injury may lead to an exposure of SMCs
to higher levels of fluid shear stress. iNOS is not induced in SMCs in
response to shear stress on the order of 1.1 to 25
dyn/cm2 in a short time, up to 24
hours.29 Maximum shear stresses on the wall of human
cerebral aneurysms are estimated to be 50
dyn/cm2.13 iNOS may be induced by
exposure to higher magnitudes of shear stress in a longer time.
NO-related cell injury was evaluated with an anti-nitrotyrosine
antibody as a marker of peroxynitrite (Figure 3). Peroxynitrite,
which is a reaction product of NO and superoxide, is a potentially
cytotoxic agent.4 17 Both iNOS and nitrotyrosine
immunoreactivities were found in the medial layer of the human
aneurysm (Figure 3), suggesting that the NO synthesized
by iNOS may damage the arterial wall at least partly by
producing peroxynitrite. We tested the anti-nitrotyrosine antibody at
dilutions from 1:5 to 1:100 and could get the best contrast
immunohistochemical images using the antibody at a dilution of 1:50.
Some investigators reported good results using a higher dilution of the
antibody.17 The difference may be a result of differences
in procedure and/or specimens.
The results all suggest the importance of enhanced wall shear stress, iNOS induction, and the subsequent NO synthesis as the mechanism for aneurysm development. Although the present experiments were performed mainly on animals with experimental aneurysms, the results may also shed light on the mechanisms of human cerebral aneurysms, because the iNOS immunoreactivity was also demonstrated in the human cerebral aneurysm.
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Acknowledgments |
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These experiments were done in part at the Department of Bioengineering, University of California San Diego. We thank Dr Geert W. Schmid-Schönbein, Professor in the Department, for his permission to do the experiments in the laboratory. We are grateful to Dr Joseph S. Beckman, Department of Anesthesiology, University of Alabama at Birmingham, for providing the anti-nitrotyrosine antibody; to Tobishi Pharmaceutical Co, Ltd, Tokyo, Japan, for providing batroxobin (Defibrase, DF-512) and unpublished data about the effect of batroxobin on fibrinogen concentration; to the late Dr Benjamin W. Zweifach and Dr Hiroshi Mitsuoka, Department of Bioengineering, University of California San Diego; Dr Louis E. Leff, St Francis Medical Center, Pittsburgh, Pa; and Dr Shobu Namura, National Cardiovascular Center, Japan, for their valuable advice; and to Augustus P. Lestick for editorial assistance and Yukiko Uemizo for a line drawing.
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Footnotes |
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Reprint requests to Nobuo Hashimoto, MD, PhD, Department of Neurosurgery, Kyoto University Hospital, 54 Kawahara-cho, Shougoin, Sakyo-ku, Kyoto 606-8507, Japan.
Received August 9, 1999; revision received November 30, 1999; accepted December 6, 1999.
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S. Tateshima, K. Tanishita, H. Omura, J.P. Villablanca, and F. Vinuela Intra-Aneurysmal Hemodynamics during the Growth of an Unruptured Aneurysm: In Vitro Study Using Longitudinal CT Angiogram Database AJNR Am. J. Neuroradiol., April 1, 2007; 28(4): 622 - 627. [Abstract] [Full Text] [PDF]
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M.A. Castro, C.M. Putman, and J.R. Cebral Computational fluid dynamics modeling of intracranial aneurysms: effects of parent artery segmentation on intra-aneurysmal hemodynamics. AJNR Am. J. Neuroradiol., September 1, 2006; 27(8): 1703 - 1709. [Abstract] [Full Text] [PDF]
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Y. Mineharu, K. Inoue, S. Inoue, S. Yamada, K. Nozaki, K. Takenaka, N. Hashimoto, and A. Koizumi Association Analysis of Common Variants of ELN, NOS2A, APOE and ACE2 to Intracranial Aneurysm Stroke, May 1, 2006; 37(5): 1189 - 1194. [Abstract] [Full Text] [PDF]
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T. Moriwaki, Y. Takagi, N. Sadamasa, T. Aoki, K. Nozaki, and N. Hashimoto Impaired Progression of Cerebral Aneurysms in Interleukin-1{beta}-Deficient Mice Stroke, March 1, 2006; 37(3): 900 - 905. [Abstract] [Full Text] [PDF]
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 E. Lopez-Rivera, T. R. Lizarbe, M. Martinez-Moreno, J. M. Lopez-Novoa, A. Rodriguez-Barbero, J. Rodrigo, A. P. Fernandez, A. Alvarez-Barrientos, S. Lamas, and C. Zaragoza Matrix metalloproteinase 13 mediates nitric oxide activation of endothelial cell migration PNAS, March 8, 2005; 102(10): 3685 - 3690. [Abstract] [Full Text] [PDF]
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 S. Yamada, M. Utsunomiya, K. Inoue, K. Nozaki, S. Inoue, K. Takenaka, N. Hashimoto, and A. Koizumi Genome-Wide Scan for Japanese Familial Intracranial Aneurysms: Linkage to Several Chromosomal Regions Circulation, December 14, 2004; 110(24): 3727 - 3733. [Abstract] [Full Text] [PDF]
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 S. Rudin, Z. Wang, I. Kyprianou, K. R. Hoffmann, Y. Wu, H. Meng, L. R. Guterman, B. Nemes, D. R. Bednarek, J. Dmochowski, et al. Measurement of Flow Modification in Phantom Aneurysm Model: Comparison of Coils and a Longitudinally and Axially Asymmetric Stent--Initial Findings Radiology, April 1, 2004; 231(1): 272 - 276. [Abstract] [Full Text] [PDF]
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N. Sadamasa, K. Nozaki, and N. Hashimoto Disruption of Gene for Inducible Nitric Oxide Synthase Reduces Progression of Cerebral Aneurysms Stroke, December 1, 2003; 34(12): 2980 - 2984. [Abstract] [Full Text] [PDF]
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V. G. Khurana, Y. R. Sohni, W. I. Mangrum, R. L. McClelland, D. J. O'Kane, F. B. Meyer, and I. Meissner Endothelial Nitric Oxide Synthase T-786C Single Nucleotide Polymorphism: A Putative Genetic Marker Differentiating Small Versus Large Ruptured Intracranial Aneurysms Stroke, November 1, 2003; 34(11): 2555 - 2559. [Abstract] [Full Text] [PDF]
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S. Tateshima, Y. Murayama, J. P. Villablanca, T. Morino, K. Nomura, K. Tanishita, and F. Vinuela In Vitro Measurement of Fluid-Induced Wall Shear Stress in Unruptured Cerebral Aneurysms Harboring Blebs Stroke, January 1, 2003; 34(1): 187 - 192. [Abstract] [Full Text] [PDF]
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M. Morimoto, S. Miyamoto, A. Mizoguchi, N. Kume, T. Kita, and N. Hashimoto Mouse Model of Cerebral Aneurysm: Experimental Induction by Renal Hypertension and Local Hemodynamic Changes Stroke, July 1, 2002; 33(7): 1911 - 1915. [Abstract] [Full Text] [PDF]
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 J.-B. Michel Contrasting Outcomes of Atheroma Evolution: Intimal Accumulation Versus Medial Destruction Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1389 - 1392. [Full Text] [PDF]
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J. K. Lee, M. Borhani, T. L. Ennis, G. R. Upchurch Jr, and R. W. Thompson Experimental Abdominal Aortic Aneurysms in Mice Lacking Expression of Inducible Nitric Oxide Synthase Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1393 - 1401. [Abstract] [Full Text] [PDF]
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 W. Gosgnach, D. Messika-Zeitoun, W. Gonzalez, M. Philipe, and J.-B. Michel Shear stress induces iNOS expression in cultured smooth muscle cells: role of oxidative stress Am J Physiol Cell Physiol, December 1, 2000; 279(6): C1880 - C1888. [Abstract] [Full Text] [PDF]
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