(Stroke. 1997;28:1805-1811.)
© 1997 American Heart Association, Inc.
Articles |
Strain-Related Differences in Susceptibility to Transient Forebrain Ischemia in SV-129 and C57Black/6 Mice
From the Stroke and Neurovascular Regulation Laboratory, Department of Neurosurgery and Neurology (M.F., H.H., W.M., Z.H., M.A.M.), and the Neuropathology Service (J.P.V.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Michael A. Moskowitz, MD, Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, CNY 6403, 149 13th St, Charlestown, MA 02129. Email moskowitz{at}helix.mgh.harvard.edu
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Abstract |
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Background and Purpose We explored susceptibility to injury after global ischemia in SV-129 and C57Black/6 mice, two commonly used background strains in genetically engineered mice.
Methods Mice (n=84) were subjected to 15, 30, or 75 minutes of bilateral common carotid artery (BCCA) occlusion followed by reperfusion for 72 hours. BCCA occlusion was performed under halothane or chloral hydrate anesthesia; in one experiment, mean arterial blood pressure and regional cerebral blood flow (laser Doppler flowmetry) were matched by controlled exsanguination. Baseline absolute blood flow measurements were obtained in both strains using a tracer, N-isopropyl-[methyl 1,3-14C]-p-iodoamphetamine, indicator fractionation technique (n=5 per group). Vascular anatomy of the circle of Willis was visualized by intravascular perfusion of carbon black ink (n=10 per group). Cerebrovascular reactivity was assessed by measuring the diameter of pial vessels (intravital microscopy) to acetylcholine (ACh) superfusion (0.1 to 10 mmol/L) in a closed cranial window preparation (n=29).
Results Resting blood flow values did not differ between groups in striatum, cerebellum, and brain-stem regions. SV-129 mice were less susceptible than C57Black/6 mice to ischemic injury (0.0±0.0 versus 1.3±0.3 damage in hippocampal CA1 region after 30 minutes of ischemia in SV-129 and C57Black/6, respectively; P<.01). Cellular damage (grade 1 to 3 injury) comparable to 30-minute BCCA occlusion was achieved only after 75 minutes of ischemia in SV-129 mice (1.1±0.3). Ischemic damage was also significantly less in SV-129 mice after blood pressure and flow were matched during ischemia in halothane-anesthetized SV-129 mice (0.5±0.3 versus 1.4±0.2, P<.05), or after chloral hydrate anesthesia (0.4±0.2 versus 1.5±0.4, P<.05). Hypoplastic posterior communicating arteries were found in all 10 C57Black/6 mice and may explain the greater susceptibility of these mice to injury after BCCA occlusion. More robust vasodilation to ACh in C57Black/6 mice could also indicate genetic differences in responses to vasoactive substances.
Conclusions C57Black/6 mice exhibit enhanced susceptibility to global cerebral ischemic injury, an incompletely formed circle of Willis, and augmented pial vessel dilation to ACh compared with SV-129 mice. Our findings suggest that strain differences may confound results when genetically engineered mice generated from more than a single background strain are used.
Key Words: cerebral ischemia, transient • mice • genetic engineering • circle of Willis
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Introduction |
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Genetically engineered mice provide a unique opportunity to evaluate the role of single gene products in models of cerebral ischemia. SV-129 and C57Black/6 mice are the most commonly used background strains.1 2 3 4 5 SV-129 mice are the source of the embryonic stem cells that, after successful gene targeting, become implanted in blastocysts of C57Black/6 mice (eg, see endothelial, type III, NOS, and neuronal, type I, NOS knockout mice1 2 ). Differences in genetic background can influence the outcome of cerebral ischemia6 7 and therefore may confound the interpretation of results in genetically engineered mice derived from more than a single parent strain.5
We recently characterized a mouse model of global ischemia in which common carotid and basilar arteries were occluded.4 Although this model clearly established a relationship between type I NOS gene deficiency and resistance to stroke damage,4 mortality was sufficiently high and the preparation technically difficult enough that development and characterization of a more simple model seemed justified. Hence, we searched for a technique that was simple, and highly reproducible, in which the neuropathological changes were consistent. Some of these criteria are fulfilled by reversible BCCA occlusion. Using this model, we determined that C57Black/6 mice were significantly more susceptible to global ischemic injury and that the resistance could not be accounted for by differences in blood pressure or choice of anesthesia, but that it was probably related to the presence of a circle of Willis lacking vascular connections between the anterior and posterior circulations and poor collateral blood flow during BCCA. Vasomotor tone and reactivity to vasoactive substances may also contribute to differences in ischemic susceptibility between the two wild-type strains.
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Methods |
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Animals
Seventy-three SV-129 (18 to 24 g) and 70 C57Black/6 (18 to 24 g) mice were obtained from Taconic Labs (Germantown, NY) and allowed food and water ad libitum.
Global Ischemia
Thirty Minutes of BCCA Occlusion
SV-129 (n=8) and C57Black/6 (n=12) mice were
anesthetized with 2% halothane, maintained with 1% halothane
plus 70% N2O and 30% O2 using a Fluotec 3
vaporizer (Colonial Medical), and kept in a supine position. The
duration of anesthesia was approximately 5 minutes (4
minutes to occlude BCCA and 1 minute to close the suture). Rectal and
scalp temperatures were recorded and maintained at approximately
37°C with a heating pad (Temperature Control; FHC) and heating lamp
(Skytron, Daiichi Shomei). After a ventral midline cervical incision,
the common carotid arteries were exposed and ligated with 6-0 silk
sutures. Immediately after the ligation, anesthesia was
turned off and the animals were assessed for level of consciousness and
pupillary and corneal reflexes. To reperfuse, animals were briefly
reanesthetized with 1% halothane and the ligatures removed.
After observing blood flow return, the incision was closed.
Animals were killed at 72 hours after ischemia by injecting euthanasia solution (50 mg/kg IP pentobarbital; Euthanasia-5 solution, Henry Schein). They were then perfused via the ascending aorta with heparinized physiological saline (2 USP heparin Units/mL, Abbott Laboratories) followed by 10% phosphate-buffered formalin (Poly Scientific). The brains were removed and postfixed in 10% phosphate-buffered formalin for 3 days and then embedded in paraffin. Five-µm coronal sections were stained with hematoxylin and eosin.
Hippocampal CA1, striatum, and cerebral cortex were evaluated in two tissue sections by investigators (H.H., M.S.) naive to the treatment group. Striatal damage was assessed at the level of the globus pallidus and triangular nucleus. Hippocampus and cerebral cortex were evaluated at the level of the subthalamic nucleus. The grading scale was as described by Pulsinelli and Brierley8 : 0=normal, 1=a few (<30%) neurons damaged, 2=many neurons (30% to 70%) damaged, and 3=majority of neurons (>70%) damaged. The mean values of both sides were calculated and used for further analysis.
Matching MABP by Controlled Exsanguination
Because of significant hemodynamic differences
during ischemia under halothane anesthesia (Table 2A
), we next evaluated ischemic damage after withdrawing 200
µL of blood into a heparinized syringe from the femoral artery of
SV-129 mice. Both strains (n=8 per group) were then subjected to
30-minute BCCA occlusion. After reperfusion, approximately 180 µL of
shed blood was returned carefully over about 1 minute in SV-129 mice.
Physiological parameters and
histological outcome were compared at 72 hours.
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Chloral Hydrate Anesthesia
To determine whether the difference in susceptibility to
ischemia was related to anesthetic effects on vascular
resistance as reflected by differences in MABP, chloral hydrate (300
mg/kg IP, Sigma Chemical Co) was used instead of halothane
anesthesia. SV-129 (n=12) and C57Black/6 mice (n=7) were
then subjected to 30 minutes of BCCA occlusion under
physiological monitoring. The change in rCBF was
matched in the two groups. Hence, 5 of 12 SV-129 mice were rejected
because rCBF did not decrease to 25% after BCCA occlusion. Animals
were sacrificed after 72 hours.
Effect of Longer Ischemic Duration on Neuronal Damage in
SV-129 Mice
Because SV-129 mice were less susceptible to the consequences of
30 minutes of BCCA occlusion than C57Black/6 mice, we next determined
whether 75 minutes of BCCA occlusion in SV-129 mice (n=16) would
produce injury equivalent to 15 minutes of ischemia in
C57Black/6 mice (n=13) under 1% halothane anesthesia.
Animals were killed after 72 hours as described above.
Physiological Parameters
MABP, rCBF, arterial blood gases, pH, and rectal and
scalp temperatures were measured. MABP was obtained from the left
femoral artery. rCBF was measured by laser Doppler
flowmetry (Perimed, PF2B) with a flexible 0.8-mm fiberoptic
extension. The tip of the probe was affixed to the intact skull over
the left cortex (2 mm posterior and 6 mm lateral from
bregma). MABP and rCBF were recorded from 10 minutes before
ischemia until 30 minutes after reperfusion.
Arterial blood gases (Pao2, Paco2)
and pH were measured 10 minutes before ischemia and 30 minutes
after induction of ischemia in 30-µL samples (Corning 178;
Ciba-Corning Diagnostics). Scalp temperature was measured
with a needle probe (model BAT-12, Physitemp Instruments) inserted into
the right temporal muscle. Rectal and scalp temperatures were
maintained at approximately 37°C as described above. Parallel groups
of animals were monitored physiologically in
experiments described in "30 Minutes of BCCA Occlusion" above,
whereas direct measurements were obtained in animals described in
experiments "Matching MABP by Controlled Exsanguination" and
"Chloral Hydrate Anesthesia," also described above.
Absolute CBF Measurements
CBF was determined using an indicator fractionation technique
described previously9 10 with some modifications. Animals
(n=5 per group) were anesthetized with 1% halothane as above.
The right femoral artery and jugular vein were cannulated with PE-10
polyethylene tubing. After determining MABP and blood gases,
arterial blood was withdrawn continuously from the femoral
artery at a rate of 0.3 mL/min (Stoelting). One microcurie of
N-isopropyl-[methyl 1,3-14C]-
p-iodoamphetamine (American Radiolabeled Chemicals Inc)
dissolved in 0.1 mL saline was injected into the jugular vein as a
bolus (<1 second). Twenty seconds after injection, the animal was
decapitated and the blood withdrawal terminated
simultaneously. The brain was removed quickly, frozen in
isopentane solution, chilled with dry ice, and then dissected into
right and left hemispheres and subdivided into striatum and remaining
forebrain, cerebellum, and brain-stem regions. After adding scintigest
(Fisher Scientific) and incubating (50°C for 6 hours), scintillation
fluid and H2O2 were added. Twelve hours after
shaking, radioactivity in brain and blood were measured by liquid
scintillation spectrometry (RackBeta 1209, LKB). CBF was calculated
according to the method of Van Uitert and Levy9 and Betz
and Iannotti.10
Carbon Black Perfusion Study
Animals (n=10 per group) were perfused under pentobarbital
anesthesia (50 mg/kg IP) with 10 mL of
physiological saline followed by 2 mL of
concentrated solution of Pelican carbon black ink (Pelican AG, D-3000)
via the left cardiac ventricle until the tissues (eg, tongue, lips, and
gums) turned black. After decapitation, the brains were carefully
removed into 10% buffered formalin for 24 hours before examination.
The vessels of the circle of Willis and their branches were examined
with a Leica-Wild M3Z microscope.
Pial Vessel Diameter and Its Response to ACh
Mice (SV-129, n=11; C57Black/6, n=18) were initially
anesthetized with 2% halothane and intubated. Mice were
artificially ventilated (SAR-830/P) with a mixture of 70%
N2O/30% O2. Alpha-chloralose (1%, 80 to 100
mg/kg) was then injected via the femoral vein, after which
halothane inhalation was discontinued. End-tidal CO2 was
continuously monitored by a microcapnometer (Columbus Instruments).
A stainless steel cranial window ring (8.0 mm in inner diameter, 2.0 mm in height) containing three ports was embedded into a loop of bone wax so as to adhere to the skull. A craniotomy (2.0x1.5 mm) was made in the left parietal bone within the ring of the window. The dura was opened while the brain surface was superfused with aCSF. The volume under the window was approximately 0.1 mL. The composition of aCSF was as follows (in mmol/L): Na+ 156.5, K+ 2.95, Ca2+ 1.25, Mg2+ 0.67, Cl- 138.7, HCO3- 24.6, dextrose 3.7, and urea 0.67. The pH of aCSF was kept at 7.35 to 7.45 by equilibration with 6.5% CO2, 10% O2, and balance N2, and was monitored continuously with a pH meter (Corning Inc). The aCSF was superfused by an infusion pump (0.4 mL/min) via a PE-100 tubing connected to a window port. Intracranial pressure was maintained at 5 to 8 mm Hg by adjusting the outlet tubing to an appropriate height. The temperature of aCSF within the window was maintained at 36.5°C to 37.0°C.
Pial vessels were visualized by an intravital microscope equipped with a video camera. The diameter of a single pial arteriole (20 to 30 µm) was continuously measured (C3161, Hamamatsu Photonics) and recorded using the MacLab data acquisition and analysis system. After obtaining a stable diameter and blood pressure, ACh (0.1, 1, and 10 mmol/L) was sequentially superfused and the change in diameter measured over 3 to 4 minutes.
Statistical Analysis
All data were presented as mean±SEM. For
nonparametric data (eg, histological
grading) Mann-Whitney U test was utilized, whereas ANOVA
followed by Dunnett's test was used to compare
physiological parameters, and Student
t test was used to compare maximum percent change in pial
vessel diameter during ACh superfusion in the two strains. Values of
P<.05 were considered statistically significant.
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Results |
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Resting CBF
Values varied between 125 and 141 mL · 100 g–1 · min–1 in the four brain regions of SV-129 and C57Black/6 mice. They did not differ between sides or between groups (Table 1
). MABP was 93±3
and 74±4 mm Hg for SV-129 and C57 black/6 mice,
respectively.
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Global Ischemia
Thirty Minutes of BCCA Occlusion in SV-129 and C57Black/6
Mice
Histological damage was evident in hippocampus,
striatum, and cerebral cortex in C57Black/6 mice but not in any regions
of SV-129 mice after 30 minutes of BCCA occlusion in
halothane-anesthetized mice (Fig 1A). During ischemia, rCBF
decreased in both strains, although it was more reduced in C57Black/6
mice (Table 2A
). Other
physiological variables (rectal and scalp
temperatures, arterial blood gases) did not differ except
that MABP was lower in C57Black/6 mice at rest and during
ischemia (Table 2A).
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Matching MABP by Controlled Exsanguination
After controlled exsanguination, there were no group differences
in MABP, rCBF, or other physiological
parameters (Table 2B). SV-129 mice remained less
susceptible than C57Black/6 mice at 72 hours after ischemia
(Fig 1B).
Chloral Hydrate Anesthesia
SV-129 mice were also significantly more resistant to
ischemia than C57Black/6 mice under chloral hydrate
anesthesia (Fig 1C). However, unlike the results under
halothane anesthesia, ischemic injury was detected
in both strains, probably as a consequence of the lower MABP and rCBF
after chloral hydrate versus halothane anesthesia. There
were no differences in MABP, rCBF, or other
physiological parameters in these
experiments (Table 2C).
Effect of Longer Ischemic Duration on Neuronal Damage in
SV-129 Mice
In halothane-anesthetized SV-129 mice, 75 minutes of
BCCA occlusion approximated the histological damage
after 30 minutes of ischemia in C57Black/6 mice (Fig 1A).
Hippocampal CA1 (particularly the medial aspect) and CA2 neurons were most frequently damaged, whereas neurons in CA3 and CA4 were well preserved. Dentate gyrus and hilus regions also showed ischemic changes in both groups.
Rostal neostriatum was more susceptible than caudal in both groups. Small- to medium-sized striatal neurons appeared abnormal most frequently, whereas large neurons were relatively preserved. Globus pallidus was remarkably resistant to ischemic injury in this model.
In the cerebral cortex, ischemic changes were limited to layers 2 and 3 and less frequently 5 and 6, whereas changes consistent with ischemia were noted in ventral posteromedial, ventral posterolateral, posterior and mediodorsal thalamic nuclei, and zona incerta.
During ischemia, halothane-anesthetized animals continued to breathe spontaneously and showed reversible signs (loss of corneal reflex, righting reflex, mydriasis) that recovered within 1 hour after reperfusion.
No seizure activity was witnessed after 15 minutes of occlusion in C57Black/6. Tonic and clonic seizure activity such as rolling and rapid running was observed in 43% of C57Black/6 mice after 30 minutes of ischemia and in 13% of SV-129 mice after 75 minutes of BCCA occlusion.
There was no mortality in SV-129 or C57Black/6 mice after 30 minutes of ischemia, whereas after 75 minutes, 25% of SV-129 mice died.
Carbon Black Study
The rostral circle of Willis did not differ between strains at the
level of the anterior and middle cerebral arteries (Fig 2). However, in all 10 C57Black/6 mice,
the posterior communicating artery was hypoplastic on both sides. In
contrast, this vessel was well formed in all 10 SV-129 mice
studied.
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Pial Vessel Diameter and Its Response to ACh
The baseline diameters did not differ between strains
(SV-129, n=11, 24.9±1.5 mm versus C57Black/6, n=18,
22.5±0.8 mm). Topical superfusion of ACh induced dose-dependent
arteriolar dilation in both strains. More robust dilation was observed
at each of three concentrations in C57Black/6 (Fig 3). The values for pHa,
PaCO2, and PaO2 did not
differ between groups (7.26±0.02 versus 7.31±0.02 mm Hg,
35.3±1.9 versus 29.3±0.9 mm Hg, and 104±9 versus 120±8
mm Hg for SV-129 versus C57Black/6, respectively). MABP was higher in
SV-129 mice (96±4 versus 78±2 mm Hg, P<.01).
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Discussion |
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Two murine strains commonly used in genetically engineered mice differ in their susceptibility to brain damage after transient forebrain ischemia. After 30 minutes of BCCA occlusion, ischemic changes were significantly less in SV-129 mice. In fact, 75 minutes of BCCA occlusion in SV-129 mice caused only as much ischemic damage as 30 minutes in C57Black/6 mice. Differences in outcome were observed at both 72 hours and 7 days (SV-129: n=7; C57Black/6: n=8; data not shown). The response to anesthetic may explain some of the strain differences, as rCBF changes after ischemia and MABP were higher in SV-129 mice anesthetized with identical concentrations of halothane. However, C57Black/6 mice were still more susceptible when both MABP and %rCBF decreases were matched by controlled exsanguination. Greater ischemic injury in C57Black/6 mice was probably not due to halothane sensitivity because of the similar results with chloral hydrate anesthesia. Hence, the susceptibility differences between strains were not explained by sensitivity of pial or other vessels to specific anesthetics. The findings are especially interesting because resting CBF values did not differ between strains. Poorly developed vascular connections between the anterior and posterior circle of Willis were the most significant risk factor identified in C57Black/6 mice, which was observed in all 10 animals perfused with carbon black ink. This same anomaly was described in the Mongolian gerbil and makes it particularly useful in ischemia studies.11 Barone et al found a similar anomaly in BALB/C mice.6 An absent posterior communicating artery decreases collateral blood flow between the anterior and posterior circulations. If both carotid arteries and the basilar artery are occluded, possibilities for collateral blood flow between the anterior and posterior circulation are eliminated. In this global ischemia model, ischemic damage does not differ significantly between C57Black/6 and SV-129 mice.4 Hence, the integrity of the circle of Willis appears to be an important risk factor contributing to susceptibility to global ischemia in mice.
Factors other than vascular anatomy may also influence
susceptibility to ischemia. We observed more robust dilation to
topical ACh in pial vessels of C57Black/6 mice. Higher eNOS activity or
the efficiency of ACh receptor coupling may underlie such differences,
but a precise explanation was not identified at this time. We
previously reported that genetically engineered mice deficient in eNOS
exhibit higher vascular resistance (MABP approximately 112 mm Hg)
and show greater ischemic damage after MCA
occlusion.1 12 Our results showing greater dilation to
topical ACh in pial blood arterioles (Fig 3) by
nitro-L-arginine–reversible mechanisms (data not shown)
could reflect upregulation of eNOS activity within vascular
endothelium of C57Black/6 mice, and this speculation
could be examined experimentally. C57Black/6 mice appeared more
susceptible to hypotension after halothane anesthesia
(Table 2A) and were reportedly more susceptible to fatty streak
formation when fed an atherogenic diet.13 Factors such as
the frequency of spreading depression,14 15
seizures,16 NOS1 2 3 4 and superoxide dismutase
activity,17 18 glutamate receptor subtype, and density are
theoretical explanations for differences in selective vulnerability. We
have shown that the density of glutamate receptor subtypes (NMDA, AMPA,
kainate) and muscarinic ACh receptors did not differ between
C57Black/6 and SV-129 mice (unpublished data, Waeber et al, 1997).
Seizure may have contributed to the greater damage in C57Black/6 mice
after 30 minutes of BCCA occlusion; although C57Black/6 mice showed no
overt seizure activity after 15 minutes of BCCA occlusion, they were
more susceptible to ischemic damage.
Several authors have previously reported that mouse strains differ in their susceptibility to focal and global cerebral ischemias. Hara et al3 observed that C57Black/6 mice developed larger lesions than SV-129 mice during focal ischemia/reperfusion, although such differences were not found after permanent focal ischemia.2 Barone et al, the first group to describe BCCA occlusion as a useful model,6 showed that BALB/C mice were more sensitive to focal ischemia than BDF or CFW mice. In addition, the ddY strain showed higher mortality and memory disturbance than the ICR strain after 2 to 30 minutes of BCCA occlusion.19 20 Approximately 35% of CA1 neurons in BALB/C and C57Black/6 mice were ischemic after 30 minutes of BCCA occlusion, and as noted above, both strains have an incomplete circle of Willis.6 Strain differences are also important in rat models of ischemia.14 21
Because SV-129 and C57Black/6 mice together provide the genomic background of many mutant mice,1 2 3 4 5 our results raise questions as to the choice of control groups when using knockout mice with mixed genetic backgrounds. Our data suggest that if wild-type littermates of heterozygote matings are not available, both parent strains must be tested individually. If both parent strains show the same difference (ie, larger or smaller lesions) from the mutant group, additional controls may not be necessary. However, if only one wild-type strain differs from the mutant, then it becomes essential to develop and test wild-type littermates. Alternatively, mutant mice can be backcrossed with a single parent strain for at least 12 generations to ensure homogeneity of genetic background.5 Although laborious, time-consuming, and expensive,5 by doing so, group comparisons become more valid.
Variations in genetic background can lead to erroneous conclusions about the importance of an identified phenotype to a specifically targeted gene. Hence, the results described herein emphasize the need to use proper controls when studying ischemia and cerebrovascular regulation in genetically engineered mice derived from more than a single parent strain.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by Massachusetts General Hospital Interdepartmental Stroke Project Grants (NS10828) and by an unrestricted award in Neuroscience from Bristol-Myers Squibb (M.A.M.). We thank Drs Michael Winking, Christian Waeber, Masao Sasamata, and Cenk Ayata for their helpful assistance.
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Footnotes |
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© 1997 American Heart Association, Inc.
Received April 7, 1997; revision received May 22, 1997; accepted June 6, 1997.
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References |
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 A. Proweller, A. C. Wright, D. Horng, L. Cheng, M. M. Lu, J. J. Lepore, W. S. Pear, and M. S. Parmacek Notch signaling in vascular smooth muscle cells is required to pattern the cerebral vasculature PNAS, October 9, 2007; 104(41): 16275 - 16280. [Abstract] [Full Text] [PDF]
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A. Y. Shih, P. Li, and T. H. Murphy A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral Ischemia In Vivo J. Neurosci., November 2, 2005; 25(44): 10321 - 10335. [Abstract] [Full Text] [PDF]
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R. Helton, J. Cui, J. R. Scheel, J. A. Ellison, C. Ames, C. Gibson, B. Blouw, L. Ouyang, I. Dragatsis, S. Zeitlin, et al. Brain-Specific Knock-Out of Hypoxia-Inducible Factor-1{alpha} Reduces Rather Than Increases Hypoxic-Ischemic Damage J. Neurosci., April 20, 2005; 25(16): 4099 - 4107. [Abstract] [Full Text] [PDF]
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T. W. Kurtz, K. A. Griffin, A. K. Bidani, R. L. Davisson, and J. E. Hall Recommendations for Blood Pressure Measurement in Humans and Experimental Animals: Part 2: Blood Pressure Measurement in Experimental Animals. A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): e22 - e33. [Abstract] [Full Text] [PDF]
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M. G. De Simoni, E. Rossi, C. Storini, S. Pizzimenti, C. Echart, and L. Bergamaschini The Powerful Neuroprotective Action of C1-Inhibitor on Brain Ischemia-Reperfusion Injury Does Not Require C1q Am. J. Pathol., May 1, 2004; 164(5): 1857 - 1863. [Abstract] [Full Text] [PDF]
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C.-Y. Kuan, A. J. Whitmarsh, D. D. Yang, G. Liao, A. J. Schloemer, C. Dong, J. Bao, K. J. Banasiak, G. G. Haddad, R. A. Flavell, et al. A critical role of neural-specific JNK3 for ischemic apoptosis PNAS, December 9, 2003; 100(25): 15184 - 15189. [Abstract] [Full Text] [PDF]
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A. Mitani and K. Tanaka Functional Changes of Glial Glutamate Transporter GLT-1 during Ischemia: An In Vivo Study in the Hippocampal CA1 of Normal Mice and Mutant Mice Lacking GLT-1 J. Neurosci., August 6, 2003; 23(18): 7176 - 7182. [Abstract] [Full Text] [PDF]
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M. J. Ryan, S. P. Didion, D. R. Davis, F. M. Faraci, and C. D. Sigmund Endothelial Dysfunction and Blood Pressure Variability in Selected Inbred Mouse Strains Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 42 - 48. [Abstract] [Full Text] [PDF]
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M. Yamada, K. G. Lamping, A. Duttaroy, W. Zhang, Y. Cui, F. P. Bymaster, D. L. McKinzie, C. C. Felder, C.-X. Deng, F. M. Faraci, et al. Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice PNAS, November 9, 2001; (2001) 251542998. [Abstract] [Full Text] [PDF]
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K. L. Gabrielson, B. A. Hogue, V. A. Bohr, A. J. Cardounel, W. Nakajima, J. Kofler, J. L. Zweier, E. R. Rodriguez, L. J. Martin, N. C. de Souza-Pinto, et al. Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice Am. J. Pathol., October 1, 2001; 159(4): 1507 - 1520. [Abstract] [Full Text]
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S. Amin-Hanjani, N. E. Stagliano, M. Yamada, P. L. Huang, J. K. Liao, M. A. Moskowitz, C. Y. Hsu, and A. Nassief Mevastatin, an HMG-CoA Reductase Inhibitor, Reduces Stroke Damage and Upregulates Endothelial Nitric Oxide Synthase in Mice Editorial Comment Stroke, April 1, 2001; 32(4): 980 - 986. [Abstract] [Full Text] [PDF]
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A. Majid, Y. Y. He, J. M. Gidday, S. S. Kaplan, E. R. Gonzales, T. S. Park, J. D. Fenstermacher, L. Wei, D. W. Choi, C. Y. Hsu, et al. Differences in Vulnerability to Permanent Focal Cerebral Ischemia Among 3 Common Mouse Strains Editorial Comment Stroke, November 1, 2000; 31(11): 2707 - 2714. [Abstract] [Full Text] [PDF]
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Y. AOKI, Z. HUANG, S. S. THOMAS, P. G. BHIDE, I. HUANG, M. A. MOSKOWITZ, and S. A. REEVES Increased susceptibility to ischemia-induced brain damage in transgenic mice overexpressing a dominant negative form of SHP2 FASEB J, October 1, 2000; 14(13): 1965 - 1973. [Abstract] [Full Text]
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S. P. Didion, C. D. Sigmund, F. M. Faraci, and Z. S. Katusic Impaired Endothelial Function in Transgenic Mice Expressing Both Human Renin and Human Angiotensinogen • Editorial Comment Stroke, March 1, 2000; 31(3): 760 - 765. [Abstract] [Full Text] [PDF]
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L. Lang-Lazdunski, K. Matsushita, L. Hirt, C. Waeber, J.-P. G. Vonsattel, M. A. Moskowitz, and W. D. Dietrich Spinal Cord Ischemia : Development of a Model in the Mouse Editorial Comment: Development of a Model in the Mouse Stroke, January 1, 2000; 31(1): 208 - 213. [Abstract] [Full Text] [PDF]
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M. D. Ginsberg On Ischemic Brain Injury in Genetically Altered Mice Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2581 - 2583. [Full Text] [PDF]
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P. Tabrizi, L. Wang, N. Seeds, J. G. McComb, S. Yamada, J. H. Griffin, P. Carmeliet, M. H. Weiss, and B. V. Zlokovic Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model : Studies in tPA-Deficient Mice and Wild-Type Mice on a Matched Genetic Background Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2801 - 2806. [Abstract] [Full Text] [PDF]
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H. Sheng, D. T. Laskowitz, G. B. Mackensen, M. Kudo, R. D. Pearlstein, D. S. Warner, and C. Iadecola Apolipoprotein E Deficiency Worsens Outcome From Global Cerebral Ischemia in the Mouse • Editorial Comment Stroke, May 1, 1999; 30(5): 1118 - 1124. [Abstract] [Full Text] [PDF]
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K. Kitagawa, M. Matsumoto, Y. Tsujimoto, T. Ohtsuki, K. Kuwabara, K. Matsushita, G. Yang, H. Tanabe, J.-C. Martinou, M. Hori, et al. Amelioration of Hippocampal Neuronal Damage After Global Ischemia by Neuronal Overexpression of BCL-2 in Transgenic Mice • Editorial Comment Stroke, December 1, 1998; 29(12): 2616 - 2621. [Abstract] [Full Text] [PDF]
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M. Endres, U. Laufs, Z. Huang, T. Nakamura, P. Huang, M. A. Moskowitz, and J. K. Liao Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase PNAS, July 21, 1998; 95(15): 8880 - 8885. [Abstract] [Full Text] [PDF]
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M. Yamada, K. G. Lamping, A. Duttaroy, W. Zhang, Y. Cui, F. P. Bymaster, D. L. McKinzie, C. C. Felder, C.-X. Deng, F. M. Faraci, et al. Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice PNAS, November 20, 2001; 98(24): 14096 - 14101. [Abstract] [Full Text] [PDF]
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