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1 Departments of Anesthesiology and Pharmacology, and 2 Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota 55905
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Our previous ex vivo
and in vivo studies reported that expression of the recombinant
endothelial nitric oxide (NO) synthase (eNOS) gene in adventitial
fibroblasts recovers NO production in arteries without endothelium in
response to bradykinin. The present study was designed to characterize
subtypes of bradykinin receptors on adventitial fibroblasts coupled to
the activation of recombinant eNOS. Endothelium-denuded segments of
canine basilar arteries were transduced with 
-galactosidase
(-Gal) gene or eNOS gene ex vivo, using a replication-defective
adenoviral vector (1010 plaque-forming units/ml) for 30 min
at 37°C. Twenty-four hours later, isometric force recording or cGMP
measurement was carried out. B1 bradykinin receptor agonist
(des-Arg9-bradykinin,
10
10-108
mol/l) did not significantly affect vascular tone in control or -Gal
gene-transduced canine basilar arteries without endothelium. In
contrast, this agonist caused concentration-dependent relaxations in
recombinant eNOS gene-transduced arteries without endothelium. Relaxations to B1 receptor agonist in the eNOS arteries
were abolished by B1 receptor antagonist
(des-Arg9-[Leu8]bradykinin, 6 × 109 mol/l) but not by
B2 receptor antagonist (Hoe-140, 5 × 108 mol/l). Bradykinin did not
significantly alter vascular tone in control or -gal arteries
without endothelium, whereas this peptide
(1011-108
mol/l) induced concentration-dependent relaxations, as well as an
increase in cGMP formation in endothelium-denuded eNOS-transduced arteries. Stimulatory effects of bradykinin were prevented in the
presence of a B2 receptor antagonist but not in the
presence of a B1 receptor antagonist. B1 and
B2 receptor antagonists had no effect on relaxations to
substance P, confirming the selectivity of the compounds. Our results
suggest that B1 and B2 bradykinin receptors are
coupled to activation of recombinant eNOS expressed in adventitial fibroblasts.
des-Arg9-[Leu8]bradykinin; Hoe-140; gene transfer
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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BRADYKININ is a vasodilator nonapeptide synthesized in the blood vessel wall and the blood from kininogen precursors by kallikreins (3, 22, 26). This peptide acts on two receptor subtypes named B1 and B2 (3, 22). The deduced amino acid sequences indicate that both receptors belong to the G protein-coupled superfamily of receptors with seven transmembrane domains. The B1 receptor has a higher affinity for the bradykinin metabolite des-Arg9-bradykinin than it does for bradykinin itself and can be blocked by the selective antagonist des-Arg9-[Leu8]bradykinin. The B2 receptor has a higher affinity for bradykinin than it does for des-Arg9-bradykinin and is blocked by the potent and selective B2 receptor antagonist Hoe-140.
Nitric oxide (NO) possesses a powerful vasodilator effect (4, 13, 19, 20), and it inhibits vascular smooth muscle cell proliferation (11), platelet aggregation (21), and leukocyte adhesion (14). All of these effects might be beneficial in the prevention and/or treatment of cardiovascular disorders. Gene transfer of recombinant endothelial NO synthase (eNOS) offers potential for altering vessel wall physiology and intervening in diseased blood vessels. We previously reported successful transfer and functional expression of recombinant eNOS gene in the adventitia of canine cerebral arteries ex vivo (7, 23, 25) and in vivo (6). Interestingly, perivascular eNOS gene delivery restored NO production in arteries without endothelium and induced the endothelium-independent, adventitia-dependent relaxations in response to bradykinin. Immunogold labeling and electron microscopy indicated that recombinant eNOS protein was predominantly expressed in adventitial fibroblasts, supporting a novel concept that fibroblasts in the adventitia may play a role in the regulation of vascular tone after successful transfer and expression of recombinant eNOS gene. The present study was designed to characterize subtypes of bradykinin receptors on adventitial fibroblasts coupled to activation of recombinant eNOS.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Adenoviral vectors. The adenoviral vector encoding an eNOS gene
driven by the cytomegalovirus immediate early promoter was generated
through homologous recombination. These vectors, based on serotype 5 wild adenovirus, have been made replication deficient by a deletion of
the early region 1, which was replaced by a cDNA sequence encoding
bovine aortic endothelial cell eNOS (kindly provided by Dr. David G. Harrison, Emory University, Atlanta, GA). The generation, propagation,
purification, and evaluation of the adenoviral vector containing eNOS
gene were described in detail previously (7). The recombinant
adenoviral vector encoding -galactosidase (-Gal) gene driven by
cytomegalovirus promoter, used in all experiments as a control, was a
kind gift of Dr. James M. Wilson (University of Pennsylvania,
Philadelphia, PA).
Gene transfer. All procedures were in accordance with Institutional Animal Care and Use Committee guidelines of Mayo Clinic. Rings (3 mm long) of basilar artery were taken from mongrel dogs (18-27 kg) intravenously anesthetized with 30 mg/kg pentobarbital sodium. Arterial rings were gently rinsed with Krebs-Ringer bicarbonate solution (in mmol/l: 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25.0 NaHCO3, 0.0026 calcium EDTA, and 11.1 glucose) to remove blood. In all rings of basilar arteries, endothelium was removed mechanically. The surface of the needles (19-22 gauge) was made rough with sandpaper, and the needles were fixed for denudation in a dish filled with Krebs-Ringer bicarbonate solution. Endothelial removal was accomplished by sliding an arterial segment over the needle with two pairs of fine forceps under a microscope (6, 23, 25). After this procedure, the rings were randomly assigned for gene transfer. Arterial rings were transduced with an adenoviral vector in minimum essential medium (MEM) (with Earle's salts, containing 0.1% BSA, 100 U/ml penicillin, and 100 µg/ml streptomycin) for 30 min at 37°C and then transferred to fresh MEM and incubated for 24 h at 37°C in a CO2 incubator (5% CO2-95% air) (Forma Scientific, Marietta, OH) (6, 23, 25). Control arteries (nontransduced arteries) were incubated in MEM for 24 h in the same manner.
Vascular reactivity. Twenty-four hours after gene transfer,
arterial rings were connected to isometric force-displacement transducers (Grass Instruments, Quincy, MA) and suspended in organ chambers filled with 25 ml of Krebs-Ringer bicarbonate solution (pH
7.4, 37°C) gassed with 94% O2-6% CO2.
Isometric force was recorded continuously. Arteries were allowed to
stabilize for 1 h. The rings were then stretched progressively to
optimal force (~3 g), determined by repeated stimulation with
105 mol/l UTP (1).
Concentration-response curves to des-Arg9-bradykinin
(1010-108
mol/l), bradykinin (1011-3 × 109 mol/l) or substance P
(1011-3 × 109 mol/l) were cumulatively obtained
during submaximal contractions with median effective concentration
(EC50) of UTP (3 × 106-5 × 105 mol/l). To inhibit cyclooxygenase
activity, all experiments were performed in the presence of
indomethacin (105 mol/l). The incubation
time with indomethacin or
NG-nitro-L-arginine methyl ester
(L-NAME) was 30 or 15 min, respectively. The incubation
times with B1 antagonist
des-Arg9-[Leu8]bradykinin and
B2 antagonist Hoe-140 were both 25 min. The relaxations were expressed as a percentage of maximal relaxations induced by
papaverine (3 × 104 mol/l). In all
experiments, arterial rings taken from the same dogs were studied in parallel.
Intracellular cGMP levels. A radioimmunoassay technique was
used to determine the levels of cGMP, as reported previously (23, 24).
Twenty-four hours after gene transfer,
105 mol/l indomethacin and
103 mol/l 3-isobutyl-1-methylxanthine
were added to the incubation medium for 30 min at 37°C to inhibit
cyclooxygenase activity and the degradation of cGMP by
phosphodiesterases, respectively. Arteries were incubated in the
presence of B1 antagonist
des-Arg9-[Leu8]bradykinin or
B2 antagonist Hoe-140 for 25 min, respectively. During the
last 2 min of the 30-min incubation period, certain rings were
stimulated with 109 mol/l bradykinin.
Rings were then removed from the medium and quickly frozen in liquid
nitrogen. After homogenization, cGMP levels were measured by a cGMP RIA
kit (Amersham, Arlington Heights, IL). Total protein levels were
determined by the Lowry et al. (15) method. Arterial rings taken from
the same dogs were studied in parallel.
Drugs. The following agents were used: bradykinin, des-Arg9-[Leu8]bradykinin, substance P, indomethacin, UTP, papaverine hydrochloride, L-NAME, 3-isobutyl-1-methylxanthine (Sigma Chemical, St. Louis, MO), des-Arg9-bradykinin, Hoe-140 (Phoenix Pharmaceuticals, Mountain View, CA), fetal bovine serum, MEM, and penicillin-streptomycin (GIBCO BRL, Grand Island, NY). Indomethacin was dissolved with equal molar concentrations of Na2CO3. All concentrations are expressed as final molar concentration in medium or solution.
Statistical analysis. The results are expressed as means ± SE. In each set of experiments, n refers to the number of animals studied. Statistical evaluation of the data was performed by ANOVA, followed by Bonferroni-Dunn's post hoc test (16). A value of P < 0.05 was considered to be statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of B1 bradykinin receptor agonist.
B1 receptor agonist des-Arg9-bradykinin did not
significantly affect vascular tone in control or -Gal
gene-transduced canine basilar arteries without endothelium (Fig.
1A). In contrast, in recombinant
eNOS gene-transduced arteries without endothelium,
des-Arg9-bradykinin
(1010-108
M) caused concentration-dependent relaxations (P < 0.05)
(Fig. 1A). The presence of endothelium did not affect the
relaxations to des-Arg9-bradykinin in the eNOS arteries
(Table 1). The relaxant effect of
des-Arg9-bradykinin was abolished by a NOS inhibitor
L-NAME (3 × 104 mol/l)
(P < 0.05) (Table 2). Relaxations
to des-Arg9-bradykinin in the eNOS arteries were
antagonized by B1 receptor antagonist
des-Arg9-[Leu8]bradykinin (6 × 109 mol/l) (P < 0.05)
but not by B2 receptor antagonist Hoe-140 (5 × 108 mol/l) (Fig. 1B).
B1 receptor antagonist had little effect on relaxations to
substance P in control (Fig. 2A)
and eNOS gene-transduced arteries with endothelium (data not shown),
confirming the selectivity of the compound.
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Effect of bradykinin. Bradykinin did not significantly alter
vascular tone in control or -Gal arteries without endothelium, whereas this peptide
(1011-108
mol/l) induced concentration-dependent relaxations in eNOS arteries without endothelium (P < 0.05) (Fig.
3A). The stimulatory effect of
bradykinin was prevented in the presence of B2 receptor
antagonist Hoe-140 (5 × 108 mol/l)
(P < 0.05) but not in the presence of B1 receptor
antagonist des-Arg9-[Leu8]bradykinin (6 × 109 mol/l) (Fig. 3B).
The selectivity of B2 receptor antagonist was confirmed by
the fact that it did not affect relaxations to substance P in
control (Fig. 2B) and eNOS gene-transduced (data not
shown) arteries with endothelium.
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Cellular cGMP levels. Bradykinin significantly enhanced
intracellular cGMP formation in eNOS arteries without endothelium (P < 0.05), which was prevented by pretreatment with
B2 receptor antagonist Hoe-140 (5 × 108 mol/l) (P < 0.05) but not
with B1 receptor antagonist
des-Arg9-[Leu8]bradykinin (6 × 109 mol/l) (Fig.
4). Those antagonists did not change basal
cGMP levels (Fig. 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Our previous ex vivo (23) and in vivo (6) studies demonstrated that genetically engineered adventitial fibroblasts transduced with recombinant eNOS gene restore production of NO in arteries without endothelium in response to bradykinin. The major new findings of the present study are that B1 and B2 bradykinin receptors on adventitial fibroblasts are coupled to activation of recombinant eNOS and that stimulatory effect of bradykinin on NO formation appears to be mediated by activation of B2 receptors.
It is well established that competitive B1 receptor antagonist des-Arg9-[Leu8]bradykinin and noncompetitive B2 receptor antagonist Hoe-140 are highly selective (3, 22). In the present study, pretreatment with des-Arg9-[Leu8]bradykinin virtually prevented B1 agonist-elicited relaxations in eNOS arteries, whereas that with Hoe-140 was without effect. Moreover, des-Arg9-[Leu8]bradykinin and Hoe-140 did not affect other receptor-mediated relaxations (substance P-evoked relaxations), confirming the selectivity of these compounds under the present experimental conditions.
We have recently demonstrated the adventitial fibroblast-dependent relaxations of canine basilar arteries transduced with recombinant eNOS gene (25). Serum, substance P, angiotensin II, and bradykinin, all of which are known to increase intracellular calcium concentrations in fibroblasts, evoke significant concentration-dependent relaxations in eNOS arteries without endothelium. More importantly, chemical (ethanol treatment) or mechanical (adventitial rubbing) disruption of adventitial cell function significantly attenuated relaxations induced by those substances in the endothelium-denuded eNOS arteries (25). In the present study, B1 agonist-stimulated relaxations in eNOS arteries were almost identical in the presence and the absence of endothelial cells, further supporting our conclusion that observed relaxations in eNOS arteries are dependent on activation of adventitial fibroblasts.
B2 bradykinin receptor is constitutively expressed in
different cell types and tissues (3, 22). Although constitutive expression of B1 bradykinin receptor has been shown in the
dog coronary system and in the cat pulmonary vascular bed,
B1 receptor is in general thought to be induced under
certain pathological conditions such as tissue injury or inflammation
(3, 22). Adenoviral-mediated gene transfer itself appears not to induce B1 receptor in endothelial cells, because in arteries with
endothelium transduction with -Gal gene did not cause
endothelium-dependent relaxations in response to stimulation of
B1 receptor (M. Tsutui and Z. S. Katusic, unpublished
observations). It remains to be elucidated whether or not
adenoviral-mediated transduction of the recombinant eNOS gene might
induce B1 receptor in fibroblasts of basilar artery adventitia.
Bradykinin is formed within the arterial wall from kininogen by kallikreins (3, 22). High activity of angiotensin-converting enzyme, which not only transforms angiotensin I into angiotensin II but also converts bioactive bradykinin to inactive peptide (26), has been detected in human vascular adventitia (27). Further studies are certainly needed to determine whether under physiological or pathological conditions the locally released bradykinin can indeed activate recombinant eNOS protein expressed in adventitial fibroblasts following in vivo eNOS gene transfer.
B1 and B2 bradykinin receptors exist in
fibroblasts, as indicated by the fact that cloning of both receptors
was carried out by using a fibroblast cell line (12, 17). Activation of
bradykinin receptors on fibroblasts leads to elevation of cellular
calcium concentrations through extracellular calcium influx and
intracellular calcium release (2, 5). After ex vivo and in vivo eNOS
gene transfer into cerebral arteries, electron microscopy immunogold labeling demonstrated that recombinant eNOS enzyme is localized in
caveolae of adventitial fibroblasts (9, 10, 18). Stimulation with
bradykinin has been shown to recruit and sequester B2
bradykinin receptors, and the receptor-coupled G protein 
-subunits
G-q and G-i in caveolae (8) and
activation of bradykinin receptors in caveolae might promote eNOS
depalmitoylation, which could lead to the release and translocation of
eNOS from caveolae to the cytosol (18). Thus the adventitial
fibroblasts may be well equipped with machinery for bradykinin
receptor-mediated, caveolae-associated activation of recombinant eNOS enzyme.
In summary, the present study has demonstrated the coupling of B1 and B2 bradykinin receptors with NO formation in fibroblasts expressing recombinant eNOS enzymatic activity. Adventitial fibroblasts may be optimal target cells for delivery of recombinant eNOS in protocols designed to restore or increase NO production in cerebral arteries.
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ACKNOWLEDGEMENTS |
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The authors thank Janet Beckman for preparing the paper.
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FOOTNOTES |
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This work was supported in part by National Heart, Lung, and Blood Institute Grant HL-53524 and National Institute of Neurological Disorders and Stroke Grant NS-37491, funds from the Bruce and Ruth Rappaport Program in Vascular Biology, Mayo Clinic Molecular Medicine Program, and the Mayo Foundation.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: Z. S. Katusic, Dept. of Anesthesiology and Pharmacology, Mayo Clinic, 200 First St., SW, Rochester, MN 55905 (E-mail: Katusic.Zvonimir{at}mayo.edu).
Received 21 May 1999; accepted in final form 26 August 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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