(Stroke. 1997;28:822-829.)
© 1997 American Heart Association, Inc.
Articles |
Gene Transfer to Cerebral Blood Vessels After Subarachnoid Hemorrhage
From the Departments of Surgery (Division of Neurosurgery), Internal Medicine, and Pharmacology, University of Iowa College of Medicine; the Howard Hughes Medical Institute (M.J.W.); and the Veterans Administration Medical Center, Iowa City, Iowa.
Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Background and Purpose Vasospasm remains a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. One step toward gene therapy to prevent spasm of cerebral vessels is to determine whether subarachnoid blood prevents transgene expression.
Methods Vasospasm was induced in mongrel dogs using the double-hemorrhage intracranial-injection model. Diameter of the basilar artery was assessed by angiography, and profound vasospasm (>50% decrease in diameter) was demonstrated at 4 and 7 days. Recombinant adenovirus expressing nuclear-targeted ß-galactosidase (reporter gene) under the control of the cytomegalovirus promoter was injected into the cisterna magna at the same time as (n=9) or 2 days after (n=4) injection of blood for induction of vasospasm. Brains were removed and examined histochemically for expression of nuclear ß-galactosidase.
Results At 2 to 7 days, ß-galactosidase was expressed in leptomeninges over the brain stem, cortex, cerebral arteries, in small vessels in the cerebrum and brain stem, and in the ependymal lining of the ventricles. Transgene expression was observed in adventitia of blood vessels but not in vascular muscle or endothelium. Transgene expression was observed after simultaneous injection of virus and blood or when virus was injected 2 days after blood.
Conclusions The findings indicate that intracisternal injection of recombinant adenovirus can be used for gene transfer to cerebral blood vessels and overlying meninges, even in the presence of cisternal blood. We speculate that transfer of genes using recombinant viral vectors that encode for enzymes with vasodilator function to cerebral blood vessels and perivascular tissues may be useful for prevention or treatment of cerebral vasospasm after subarachnoid hemorrhage.
Key Words: gene therapy • subarachnoid hemorrhage • vasospasm • dogs
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Vasospasm remains a major cause of morbidity and mortality in patients with SAH.1 2 Some therapeutic approaches are promising,3 4 5 6 but none has been shown to completely ameliorate vasospasm or the ischemic deficit associated with vasospasm. The present study, which involves gene transfer to cerebral blood vessels, represents a potentially novel approach to treatment of vasospasm after SAH.
Proteins and peptides have been delivered into the brain parenchyma with a variety of vectors that are injected directly into the central nervous system.7 8 9 Transgenes introduced into the CSF or central nervous system by replication-deficient adenovirus also can be expressed in a wide variety of recipient cell types, including neurons, glia, and the ependymal cells lining the ventricles.10 11 12 13 14 Gene transfer to cerebral blood vessels is very difficult, however, because most approaches to vascular gene transfer require that blood flow is stopped.15
The vascular wall has been a target organ for cardiovascular gene therapy in previous studies.16 17 18 19 We have obtained evidence that genes can be transferred into the meninges and adventitia overlying normal cerebral vessels after injection of adenovirus into CSF.20 Gene transfer to intracranial vessels or vessels in spasm after SAH has not been accomplished previously.
In this study, we tested the hypothesis that during vasospasm induced by SAH, adenovirus can be used to transfer genes to cerebral blood vessels. A major concern was that the presence of subarachnoid blood might prevent access of adenovirus to vessels and thus prevent transgene expression. Angiography and studies of vascular reactivity were performed to confirm that vasospasm was induced in dogs.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Experimental Groups
All experiments were performed using procedures approved by the University of Iowa animal care and recombinant DNA committees. Adult mongrel dogs of both sexes (n=21, 15 to 25 kg) were used. Four groups of animals were studied. In group 1 (n=6), the double-hemorrhage model of canine vasospasm was used to demonstrate that vasospasm was produced in the experimental model.21 22 23 In group 2 (n=9), blood and adenovirus expressing a reporter gene were injected simultaneously into the cisterna magna. In group 3 (controls, n=2), control adenovirus containing an irrelevant transgene was injected into the cisterna magna. In group 4 (n=4), adenoviral vectors were injected 2 days after injection of blood to determine whether tissue could be transduced in the presence of subarachnoid blood.
Experimental SAH Technique (Group 1)
All procedures were performed after dogs were
anesthetized with pentobarbital (25 mg/kg IV). The trachea was
intubated, and ventilation was controlled with a respirator. End-tidal
CO2 was maintained at 40±2 mm Hg, and
anesthesia was maintained with room air and 1% halothane.
Arterial blood gas levels were measured immediately before
angiography was performed. Values (mean±SE) were pH 7.37±0.01,
PaCO2 39.8±0.7 mm Hg, and
PaO2 78±2 mm Hg. There were no
significant changes during the experiment.
A catheter was inserted through the femoral artery to the vertebral artery, and angiography of the basilar artery and circle of Willis was performed in the anterior-posterior plane. Under aseptic conditions, a 20-gauge spinal needle was inserted into the cisterna magna. The animal was maintained in a head-down position (superior plane of the parietal bone was tilted forward by 30°) for 30 minutes to facilitate contact of autologous blood with the base of the brain. Two days after the initial injection of blood, dogs were anesthetized again, and venous blood was again injected into the cisterna magna. On days 4 and 7 after intracisternal injection of blood, angiograms were obtained to determine the incidence and degree of chronic cerebral vasospasm. Diameters of the rostral, middle, and caudal thirds of the basilar arteries were measured (using a scaled loupe), and values from days 4 and 7 were compared with values from day 0.
Reactivity and Endothelial Function of Vessels
In Vitro
Dogs after double blood injection (n=6) and dogs without SAH
(n=3) were anesthetized with 30 mg/kg IV sodium pentobarbital,
and brains were removed and placed in cold modified Krebs-Ringer
bicarbonate solution with the following composition (mmol/L): 118.3
NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 25.0
NaHCO3, 0.026 calcium-ethylenediaminetetraacetic acid, and
11.1 glucose. Rings of branches of the basilar artery 2 to 3 mm in
length were dissected and mounted on stainless-steel hooks. Tension was
recorded with a linear force transducer (Gould Inc). Over 1 hour,
the resting force was gradually increased until the optimal tension (1
g) for generating force during isometric contraction was reached. The
vessels remained at this resting tension throughout the remainder of
the study. Krebs-Ringer solution was circulated over the vessels, and
temperature was maintained at 37±0.5°C. Experiments were performed
in the presence of 10-5 mol/L
indomethacin.
Responses to sodium nitroprusside, bradykinin, and arginine vasopressin were examined during contraction with UTP (10-5 to 10-6 mol/L). Responses to serotonin and UTP were also examined. Studies were performed to compare vessels from normal dogs and dogs that received intracisternal injection of blood.
Adenoviral Vectors
The adenoviral vectors, based on adenovirus serotype 2, were
constructed as described previously.24 These
replication-deficient adenoviral vectors have been deleted of sequences
in the E1A and E1B regions, which impairs replication in nonpermissive
cells. The vector contains an expression cassette encoding the
Escherichia coli ß-galactosidase gene (lacZ) downstream
from a nuclear-targeting signal. The immediate early promoter of CMV
was used to drive transcription of lacZ with a simian virus 40
polyadenylation sequence cloned downstream from this reporter, forming
the vector Ad/CMV-ßgal. The control adenovirus used was Ad/CMV-CFTR,
which carried CMV promoter and cDNA for CFTR. The viral titer was
determined as infectious units per milliliter, using anti-adenovirus
antibody in a titration assay. The ratio of particles (measured by
spectrophotometer) to infectious units is approximately 100 in our
experiments. The virus was suspended in 3% sucrose and stored at
-80°C until used.
In Vivo Gene Transfer (Groups 2 Through 4)
Five mL of autologous venous blood was injected slowly (over 10
minutes) into the cisterna magna, immediately followed by injection of
1 mL of Ad/CMV-ßgal (1.2 to 3.8x1010 infectious units)
in group 2. Two dogs received 1 mL of control adenovirus (Ad/CMV-CFTR,
1.4x1010 infectious units, group 3). In group 4, 1 mL of
Ad/CMV-ßgal (2.6x1010 infectious units) was injected
into the cisterna magna 2 days after injection of 5 mL of autologous
venous blood. In all groups, a volume of CSF equal to the that of
injectate was removed before injection of blood and viral suspension to
avoid an increase in intracranial pressure. Rectal temperature was
measured daily, and aspirin was given if temperature was >38.0°C.
Animals that were injected with adenovirus were not studied with
angiography. The animals were killed on days 2, 4, 6, or 7. Brains were
removed, cut into serial sections, and stained for
ß-galactosidase.
X-Gal Histochemical Staining
Brain sections were placed in plastic vials and fixed for 10
minutes in fixative (PBS, pH 7.4, 2% paraformaldehyde,
and 0.025% glutaraldehyde) at room temperature. The
samples were rinsed well in PBS and then immersed in X-Gal stain [PBS:
20 mmol/L K4Fe(CN)6·3H2O,
20 mmol/L K3Fe(CN)6, 2 mmol/L
MgCl2, and 1 mg/mL in DMSO of X-Gal stain; Gibco BRL Life
Technologies, Inc] for 2 hours at room temperature. After a rinsing in
PBS, the samples were fixed for approximately 16 hours in 4%
formaldehyde. The samples were embedded in paraffin and thin-sectioned
(6 to 8 µm) with a microtome, then counterstained with nuclear
fast red. The sections were evaluated to determine whether
ß-galactosidase was expressed in blood vessels and brain tissue (blue
staining). The basilar, anterior, middle, and posterior cerebral
arteries; cerebral hemisphere (including lateral ventricles and
subarachnoid space between gyri); mid pons; and medulla were
cut into sections. The blood vessels (adventitia, muscle,
endothelium) were examined under a microscope.
Statistical Analysis
In group 1, baseline diameter of the basilar artery was compared
with diameters measured at days 4 and 7 using the paired-samples
t test with Bonferroni corrections for multiple comparisons.
A value of P<.05 was considered significant. Reactivity of
vessels in vitro was compared between normal dogs and dogs with SAH
using an unpaired t test.
In groups 2 through 4, five tissue sections from each vessel or region of cerebrum were analyzed. ß-Galactosidase staining was estimated with a three-point scale: 0, no stain; +, mild staining (approximately 1% to 25% of nuclei stained blue); ++, moderate staining (approximately 26% to 75% of nuclei stained blue); and +++, diffuse staining (>75% of nuclei stained blue).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Effects of Blood in the CSF (Group 1)
After injection of blood in the cisterna magna, approximately one half of the dogs appeared normal. Some dogs exhibited conjunctival hemorrhage or lethargy and ate little food. All dogs appeared to be pain-free throughout the experiment.
Basilar artery diameter decreased approximately 50% at days 4 and 7
after injection of blood, indicating profound vasospasm (Fig 1
, Table 1). Vasospasm was greater by day
7 (compared with day 4) in all dogs.
|
|
Contraction to UTP (Fig 2) and relaxation to bradykinin
and sodium nitroprusside (Fig 3) were similar in normal
dogs and dogs with vasospasm. Arginine vasopressin relaxed the basilar
artery of normal dogs, and the response was impaired after SAH
(P<.05, Fig 3). Serotonin had little effect on
normal vessels and caused contraction in vessels exposed to SAH (Fig 2).
|
|
In Vivo Gene Transfer (Group 2)
Systemic effects of CSF replacement with blood and Ad/CMV-ßgal
were similar to those in group 1 (which received intracisternal blood
but not virus), except that temperature increased from 38.1±0.2°C at
baseline to 40.0±0.3°C at day 1. The temperature always returned to
normal after administration of 325 mg aspirin PO. We did not attempt to
quantify the inflammatory response, but we did not detect differences
in the inflammatory responses in the subarachnoid space in dogs
that received intracisternal blood alone compared with dogs that
received intracisternal blood plus recombinant adenovirus.
After 2 to 7 days, ß-galactosidase was expressed in the basilar
artery; small arteries on the brain stem; and the anterior, middle, and
posterior cerebral arteries (Table 2, Fig 4). Transgene expression was also observed in ependymal
lining of the lateral ventricle, floor of the fourth ventricle,
pia-arachnoid over the brain stem, and in tissue within the
subarachnoid space between the hemisphere gyri. On gross
examination, there was diffuse staining of the basal surface of the
brain, lining of the ventricles, and the cerebral arteries in all dogs.
This diffuse staining represented gene transfer primarily
within the pia-arachnoid. On microscopic examination, approximately two
thirds of four sections from each dog of basilar, anterior, middle, and
posterior cerebral artery had some expression of ß-galactosidase in
the adventitia. Virtually all sections of pons, medulla, ependymal
lining of ventricle, and hemisphere sections had some expression of
ß-galactosidase.
|
|
In large cerebral vessels, there was blue staining in the nucleus of
cells in adventitia and pia-arachnoid surrounding the vessels (Fig 4
).
Occasionally, a cell within the muscularis layers expressed
ß-galactosidase, but generally there was minimal transduction of
vascular muscle. No endothelial cells expressed
transgene.
Injection of Control Virus (Group 3)
Cerebrum and vessels from control dogs that received control
adenovirus (Ad/CMV-CFTR) were negative for ß-galactosidase activity
(Table 2). Systemic effects of treatment were similar to those of group
2.
Injection of Virus After SAH (Group 4)
Dogs that received Ad/CMV-ßgal 2 days after injection of blood
were killed 7 days after the first injection of blood. Patterns of
transgene expression were similar to those in group 2. Expression of
ß-galactosidase was observed in the basilar artery; small arteries on
the brain stem; and the anterior, middle, and posterior cerebral
arteries. Expression was also found in ependymal lining of the lateral
ventricle and pia-arachnoid over the brain stem (Table 3). Microscopically, there was transgene expression in
basilar, anterior, middle, and posterior cerebral artery sections in
the adventitial layer.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The major new finding in this study is that gene transfer to cerebral blood vessels and perivascular tissue can be accomplished after injection of adenovirus into the cisterna magna in the presence of subarachnoid blood. The findings suggest that an adenoviral vector can be used to transiently transfect cerebral blood vessels after SAH. The time frame of transgene expression from this viral construct may be appropriate for gene therapy, in which a short burst of expression is desirable. This study is the first to report gene transfer to cerebral blood vessels and perivascular tissues during spasm from SAH.
Consideration of the Model
The canine double-hemorrhage model of cerebral vasospasm
was used in this study because spasm is produced
consistently.21 22 23 Vascular reactivity was studied
to ensure that vessels exposed to subarachnoid blood reacted
similarly to vessels in other studies after SAH. Other studies have
reported similar effects of SAH on responses to vasopressin, sodium
nitroprusside, bradykinin, and serotonin,21 25
although responses to sodium nitroprusside and bradykinin may be
impaired in a different model.22 26 We therefore confirmed
by angiography that vasospasm was induced using the canine
double-hemorrhage model, demonstrated that vascular responses
were similar to those in previous studies, and used the same model for
gene transfer to vessels in spasm.
The major finding in this study was that the presence of subarachnoid blood does not appear to interfere with adenovirus-mediated gene transfer to vessels in spasm. In most animals, there were thrombi in close proximity to vessels, and these thrombi did not seem to interfere with gene transfer.
This model has several limitations. First, the target of gene transfer is not cerebral tissue, but gene transfer nevertheless occurred to the surface of brain, as well as to blood vessels. Therefore, gene transfer is not specific for cerebral blood vessels, and all cells exposed to the subarachnoid space become potential targets of the adenovirus. Second, transfer of the reporter gene to endothelium was not observed. However, this may not detract from the ability to transfer therapeutic genes to vessels. X-Gal staining likely underestimates (up to 1/10) the number of cells that have been transduced.24 Also, transduction of adventitial cells and perivascular cells may be sufficient to alter vessel function. Periadventitial delivery of drugs and bioactive substances, including growth hormone and antisense oligonucleotide, can alter vascular function in vivo.27 28 29 Therefore, it is likely that transduction of adventitial cells and perivascular cells that encode enzymes, which produce highly diffusible substances, will affect functions of underlying vascular smooth muscles. Thus, perivascular tissue may be a useful target when genes that express diffusible substances are transferred.
Gene Transfer to Vessels
Several investigators have accomplished adenovirus-mediated gene
transfer to endothelium and smooth muscle cells in both
intact and balloon-injured arteries by an intravascular approach in
vivo.18 30 31 However, efficient gene transfer seems to
require increased intraluminal pressure that may cause damage to the
vessels.32 Our study differed from those studies in that
we approached the vessel from the adventitia, rather than from the
luminal side. This approach also avoids the need to stop flow in the
vessel and allows longer contact of the virus with the vessel wall.
Direct In Vivo Gene Transfer to Central Nervous System
The central nervous system is relatively inaccessible to
circulating proteins and peptides because of the presence of a
blood-brain barrier. Several years ago, an alternative method to
deliver therapeutic protein/peptides directly into the central nervous
system was developed. This approach involves the use of several vectors
for gene transfer to produce proteins in the CSF and
brain.7 8 9 33
Replication-deficient adenoviruses, which are promising vectors for gene transfer to the CNS, can deliver genes to many cell types. Injection of adenovirus carrying ß-galactosidase into brain parenchyma results in extensive expression of the reporter gene in neurons or glia in the injection site and in ependymal cells of the ventricles.10 12 13 34 35 36 The transgene was also expressed in ependyma after intraventricular injection, but effects on cerebral vessels were not described.11 14 34 Recently, we injected adenoviral vectors in the cisterna magna or lateral ventricle of rats and observed that genes can be transferred to the adventitia and perivascular tissues overlying cerebral blood vessels.20 However, it was not clear whether subarachnoid blood would interfere with access of viral vectors to the vessels and expression of transgene.
Future Directions
The present study indicates that genes can be transferred to
perivascular tissue and adventitia of cerebral blood vessels during
blood-induced vasospasm with an adenoviral vector injected into the
cisterna magna. Transfer of genes with therapeutic potential, such as
genes that encode enzymes that produce vasodilatation, may be useful.
The vasoactive substance may need to be highly diffusible because gene
transduction does not occur consistently in vascular muscle.
Substances such as nitric oxide synthase, which produces nitric oxide
(which is highly diffusible), or calcitonin gene–related peptide may
exert vasomotor effects when they are released from perivascular tissue
or adventitia. The similar time frame for onset of vasospasm after SAH
(3 to 10 days) and onset of protein synthesis after gene transfer makes
gene transfer to the vessel wall an attractive alternative in the
search for effective prevention or treatment of cerebral vasospasm.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This research was supported by National Institutes of Health grants NS-24621, HL-16066, HL-14388, AG-10269, and HD-33531 and research funds from the Veterans Administration. B.L. Davidson is a fellow of the Roy J. Carver Charitable Trust, and M.J. Welsh is an investigator of the Howard Hughes Medical Institute. The authors thank Richard D. Anderson and Lisa DeBerg for preparation of the adenovirus, William Barnhart for assistance with angiography, Pamela Tompkins for assistance with X-Gal staining and thin sectioning, Donna G. Martin and Kristen Rummelhart for help with studies of vessel reactivity, Dr James Torner for assistance with statistical analysis, Dr Frank Faraci for review of this manuscript, and Dr Alan E. Smith, Genzyme, for the gift of Ad/CMV-ßgal and Ad/CMV-CFTR.
Received September 9, 1996; revision received December 27, 1996; accepted January 16, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Kiwak KJ, Heros RC. Cerebral vasospasm after subarachnoid hemorrhage. Trend Neurosci. 1987;10:89-92.
2.
MacDonald RL, Weir BKA. A review of hemoglobin
and the pathogenesis of cerebral vasospasm. Stroke. 1991;22:971-982.
3. Shinyama H, Uchida T, Kido H, Hayashi K, Watanabe M, Matsumura Y, Ikegawa R, Takaoka M, Morimoto S. Phosphoramidon inhibits the conversion of intracisternally administered big endothelin-1 to endothelin-1. Biochem Biophys Res Commun. 1991;178:24-30. [Medline] [Order article via Infotrieve]
4. Egeman N, Turker RK, Sanlidilek U, Zorlutuna A, Blilgic S, Baskaya M, Unlu A, Caglar S, Spetzler RF, McCormick JM. The effect of intrathecal sodium nitroprusside on severe chronic vasospasm. Neurol Res. 1993;15:310-315. [Medline] [Order article via Infotrieve]
5.
Juul R, Aakhus S, Bjornstad K, Gisvold SE, Brubakk AO,
Edvinsson L. Calcitonin gene-related peptide (human 
-CGRP)
counteracts vasoconstriction in human subarachnoid
haemorrhage. Neurosci Lett. 1994;170:67-70. [Medline]
[Order article via Infotrieve]
6. Kajita Y, Suzuki Y, Oyama H, Tanazawa T, Takayasu M, Shibuya M, Sugita K. Combined effects of L-arginine and superoxide dismutase on the spastic basilar artery after subarachnoid hemorrhage in dogs. J Neurosurg. 1994;80:476-483. [Medline] [Order article via Infotrieve]
7.
Rosenberg MB, Friedmann T, Robertson RC, Tuszynski M,
Wolff JA, Breakefield XO, Gage FH. Grafting genetically modified
cells to the damaged brain: restorative effects of NGF
expression. Science. 1988;242:1575-1578.
8. Dobson AT, Margolis TP, Sedarati F, Stevens JG, Feldman LT. A latent, nonpathogenetic HSV-1 derived vector stably expresses ß-galactosidase in mouse neurons. Neuron. 1990;5:353-360. [Medline] [Order article via Infotrieve]
9.
Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH,
Blaese RM. In vivo gene transfer with retroviral vector-produced
cells for treatment of experimental brain tumors.
Science. 1992;256:1550-1552.
10. Lal B, Cahan MA, Couraud P-O, Goldstein GW. Development of endogenous ß-galactosidase and aurofluorescence in rat brain microvessels: implication for cell tracking and gene transfer studies. J Histochem Cytochem. 1994;42:953-956. [Abstract]
11. Bajocchi G, Feldman SH, Crystal RG, Mastrangeli A. Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors. Nat Genet. 1993;3:229-234. [Medline] [Order article via Infotrieve]
12. Davidson BL, Allen ED, Kozarsky KF, Wilson JM, Roessler BJ. A model system for in vivo gene transfer into the central nervous system using adenoviral vector. Nat Genet. 1993;3:219-223. [Medline] [Order article via Infotrieve]
13. Akli S, Caillaud C, Vigne E, Stratford-Perricaudet LD, Poenaru L, Perricaudet M, Kahn A, Peschanski MR. Transfer of a foreign gene into the brain using adenovirus vectors. Nat Genet. 1993;3:224-228. [Medline] [Order article via Infotrieve]
14. Betz AL, Yang G-Y, Davidson BL. Attenuation of stroke size in rats using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist in brain. J Cereb Blood Flow Metab. 1995;15:547-551. [Medline] [Order article via Infotrieve]
15.
Heistad DD, Faraci FM. Gene therapy for cerebral
vascular disease. Stroke. 1996;27:1688-1693.
16.
Yao SN, Wilson JM, Nabel EG, Kurachi S, Hachiya HL,
Kurachi K. Expression of human factor IX in rat capillary
endothelial cells: toward somatic gene therapy
for hemophilia B. Proc Natl Acad Sci U S A. 1991;88:8101-8105.
17.
Dichek D, Nerville RF, Zwiebel JA, Freeman SM, Leon MB,
Anderson WF. Seeding of intravascular stents with genetically
engineered endothelial cells.
Circulation. 1989;80:1347-1353.
18.
Lemarchand P, Jones M, Yamada I, Crystal RG. In
vivo gene transfer and expression in normal uninjured blood vessels
using replication-deficient recombinant adenovirus vectors.
Circ Res. 1993;72:1132-1138.
19.
Morishita R, Gibbons GH, Kaneda Y, Ogihara T, Dzau
VJ. Novel in vitro gene transfer method for study of local
modulators in vascular smooth muscle cells.
Hypertension. 1993;21:894-899.
20.
Ooboshi H, Welsh MJ, Rios CD, Davidson BL, Heistad
DD. Adenovirus-mediated gene transfer in vivo to cerebral blood
vessels and perivascular tissue. Circ Res. 1995;77:7-13.
21.
Katusic ZS, Milde JH, Cosentino F, Mitrovic BS.
Subarachnoid hemorrhage and endothelial
L-arginine pathway in small brain stem arteries in
dogs. Stroke. 1993;24:392-399.
22. Kim P, Sundt TMJ, Vanhoutte PM. Alterations in endothelium-dependent responsiveness of the canine basilar artery after subarachnoid hemorrhage. J Neurosurg. 1988;69:239-246. [Medline] [Order article via Infotrieve]
23. Varsos VG, Liszczak TM, Han DH, Kistler JP, Vielma J, Black PM, Heros RC, Zervas NT. Delayed cerebral vasospasm is not reversible by aminophylline, nifedipine, or papaverine in a `two-hemorrhage' canine model. J Neurosurg. 1983;58:11-17. [Medline] [Order article via Infotrieve]
24. Zabner J, Couture LA, Smith AE, Welsh MJ. Correction of cAMP-stimulated fluid secretion in cystic fibrosis airway epithelia: efficacy of adenoviral-mediated gene transfer in vitro. Hum Gene Ther. 1994;5:585-593. [Medline] [Order article via Infotrieve]
25.
Hatake K, Wakabayashi I, Kakishita E, Hishida S.
Impairment of endothelium-dependent relaxation in human
basilar artery after subarachnoid hemorrhage.
Stroke. 1992;23:1111-1117.
26. Sobey CG, Heistad DD, Faraci FM. Effect of subarachnoid hemorrhage on dilatation of rat basilar artery in vivo. Am J Physiol. 1996;40:H126-H132.
27. Simons M, Edelman ER, DeKeyser J, Langer R, Rosenberg RD. Antisense c-myb oligonucleotides inhibit arterial smooth muscle cell accumulation in vivo. Nature. 1992;359:67-70. [Medline] [Order article via Infotrieve]
28.
Edelman ER, Nugent MA, Karnovsky MJ.
Perivascular and intravenous administration of basic
fibroblast growth factor: vascular and solid organ deposition.
Proc Natl Acad Sci U S A. 1993;90:1513-1517.
29. Villa AE, Guzman LA, Chen W, Golomb G, Levy RJ, Topol EJ. Local delivery of dexamethasone for prevention of neointimal proliferation in a rat model of balloon angioplasty. J Clin Invest. 1994;93:1243-1249.
30.
Lee SW, Trapnell BC, Rade JJ, Virmani R, Dichek
DA. In vitro adenoviral vector–mediated gene transfer into
balloon-injured rat carotid arteries. Circ Res. 1993;73:797-807.
31.
Schulick AH, Dong G, Newman KD, Virmani R, Dichek
DA. Endothelium-specific in vivo gene
transfer. Circ Res. 1995;77:475-485.
32.
Rome JJ, Shayani V, Flugelman MY, Newman KD, Farb A,
Virmani R, Dichek D. Anatomic barriers influence the
distribution of in vivo gene transfer into the arterial
wall: modeling with microscopic tracer particles and verification with
a recombinant adenoviral vector. Arterioscler
Thromb. 1994;14:148-161.
33. Ono T, Fujino Y, Tsuchiya T, Tsuda M. Plasmid DNAs directly injected into mouse brain with lipofectin can be incorporated and expressed by brain cells. Neurosci Lett. 1990;117:259-263. [Medline] [Order article via Infotrieve]
34. Davidson BL, Doran SE, Shewach DS, Latta JM, Hartman JW, Roessler BJ. Expression of Escherichia coli ß-galactosidase and rat HPRT in the CNS of Macaca mulatta following adenoviral mediated gene transfer. Exp Neurol. 1994;125:258-267. [Medline] [Order article via Infotrieve]
35. Badie B, Hunt K, Economou JS, Black KL. Stereotactic delivery of a recombinant adenovirus into a C6 glioma cell line in a rat brain tumor model. Neurosurgery. 1994;35:910-916. [Medline] [Order article via Infotrieve]
36. Kojima H, Inuzuka S, Miwa T, Furukawa S, Hayashi K, Kanegae Y, Saito I, Ohishi N, Takamori M, Yagi K. Construction and characterization of adenoviral vector expressing biologically active brain-derived neurotrophic factor. Biochem Biophys Res Commun. 1995;212:712-717. [Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  T. Ogawa, S. Ono, T. Ichikawa, S. Arimitsu, K. Onoda, K. Tokunaga, K. Sugiu, K. Tomizawa, H. Matsui, and I. Date Novel Protein Transduction Method by Using 11R: An Effective New Drug Delivery System for the Treatment of Cerebrovascular Diseases Stroke, April 1, 2007; 38(4): 1354 - 1361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Watanabe and D. D. Heistad Targeting cerebral arteries for gene therapy Exp Physiol, May 1, 2005; 90(3): 327 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yamaguchi, C. Zhou, D. D. Heistad, Y. Watanabe, and J. H. Zhang Gene Transfer of Extracellular Superoxide Dismutase Failed to Prevent Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage Stroke, November 1, 2004; 35(11): 2512 - 2517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Yenari, M. Minami, G. H. Sun, T. J. Meier, D. M. Kunis, J. R. McLaughlin, D. Y. Ho, R. M. Sapolsky, and G. K. Steinberg Calbindin D28K Overexpression Protects Striatal Neurons From Transient Focal Cerebral Ischemia Stroke, April 1, 2001; 32(4): 1028 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ooboshi, S. Ibayashi, J. Takada, H. Yao, T. Kitazono, and M. Fujishima Adenovirus-Mediated Gene Transfer to Ischemic Brain : Ischemic Flow Threshold for Transgene Expression Stroke, April 1, 2001; 32(4): 1043 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Toyoda, F. M. Faraci, Y. Watanabe, T. Ueda, J. J. Andresen, Y. Chu, S. Otake, and D. D. Heistad Gene Transfer of Calcitonin Gene-Related Peptide Prevents Vasoconstriction After Subarachnoid Hemorrhage Circ. Res., October 27, 2000; 87(9): 818 - 824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.’i. Sato, T. Mohacsi, A. Noel, C. Jost, P. Gloviczki, G. Mozes, Z. S. Katusic, T. O’Brien, and W. G. Mayhan In Vivo Gene Transfer of Endothelial Nitric Oxide Synthase to Carotid Arteries From Hypercholesterolemic Rabbits Enhances Endothelium-Dependent Relaxations • Editorial Comment Stroke, April 1, 2000; 31(4): 968 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Toyoda, F. M. Faraci, A. F. Russo, B. L. Davidson, and D. D. Heistad Gene transfer of calcitonin gene-related peptide to cerebral arteries Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H586 - H594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Gutterman Adventitia-dependent influences on vascular function Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1265 - H1272. [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Kullo, R. D. Simari, and R. S. Schwartz Vascular Gene Transfer : From Bench to Bedside Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 196 - 207. [Full Text] [PDF]
|
|
|
|
|
|
H. Onoue, M. Tsutsui, L. Smith, A. Stelter, T. O'Brien, Z. S. Katusic, and F. M. Faraci Expression and Function of Recombinant Endothelial Nitric Oxide Synthase Gene in Canine Basilar Artery After Experimental Subarachnoid Hemorrhage • Editorial Comment Stroke, September 1, 1998; 29(9): 1959 - 1966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Christenson, K. D. Lake, H. Ooboshi, F. M. Faraci, B. L. Davidson, D. D. Heistad, and S. P. Finklestein Adenovirus-Mediated Gene Transfer In Vivo to Cerebral Blood Vessels and Perivascular Tissue in Mice • Editorial Comment Stroke, July 1, 1998; 29(7): 1411 - 1416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. Y. Chen, S.-W. Jiang, T. B. Crotty, M. Tsutsui, L. A. Smith, T. O'Brien, and Z. S. Katusic Effects of in vivo adventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries PNAS, November 11, 1997; 94(23): 12568 - 12573. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||