Vol. 276, Issue 5, C1148-C1153, May 1999
VEGF increases permeability of the blood-brain barrier via a
nitric oxide synthase/cGMP-dependent pathway
William G.
Mayhan
Department of Physiology and Biophysics, University of Nebraska
Medical Center, Omaha, Nebraska 68198-4575
 |
ABSTRACT |
It appears that
the expression of vascular endothelial growth factor (VEGF) is
increased during brain injury and thus may contribute to disruption of
the blood-brain barrier (BBB) during cerebrovascular trauma. The first
goal of this study was to determine the effect of VEGF on permeability
of the BBB in vivo. The second goal was to determine possible cellular
mechanisms by which VEGF increases permeability of the BBB. We examined
the pial microcirculation in rats using intravital fluorescence
microscopy. Permeability of the BBB [clearance of FITC-labeled
dextran of molecular mass 10,000 Da (FITC-dextran-10K)] and
diameter of pial arterioles were measured in absence and presence of
VEGF (0.01 and 0.1 nM). During superfusion with vehicle (saline),
clearance of FITC-dextran-10K from pial vessels was minimal and
diameter of pial arterioles remained constant. Topical application of
VEGF (0.01 nM) did not alter permeability of the BBB to
FITC-dextran-10K or arteriolar diameter. However, superfusion with VEGF
(0.1 nM) produced a marked increase in clearance of FITC-dextran-10K
and a modest dilatation of pial arterioles. To determine a potential
role for nitric oxide and stimulation of soluble guanylate cyclase in
VEGF-induced increases in permeability of the BBB and arteriolar
dilatation, we examined the effects of
NG-monomethyl-L-arginine
(L-NMMA; 10 µM) and
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1.0 µM), respectively.
L-NMMA and ODQ inhibited
VEGF-induced increases in permeability of the BBB and arteriolar
dilatation. The findings of the present study suggest that VEGF, which
appears to be increased in brain tissue during cerebrovascular trauma, increases the permeability of the BBB via the synthesis/release of
nitric oxide and subsequent activation of soluble guanylate cyclase.
fluorescein isothiocyanate-dextran; cerebral venules; pial
arterioles; soluble guanylate cyclase; NG-monomethyl-L-arginine; vascular
endothelial cell growth factor
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INTRODUCTION |
VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), also called
vascular permeability factor, is an endothelial cell-specific mitogen (25). In addition to its mitogenic effect, VEGF has been shown to
increase the permeability of the peripheral circulation and endothelial
cell monolayers (2, 3, 7, 10, 20, 26, 30). Mechanisms that account for
the effects of VEGF on vascular and endothelial cell permeability in
the peripheral circulation are varied but appear to involve an increase
in endothelial cell calcium influx (3), synthesis/release of nitric
oxide (20, 28, 30) with subsequent activation of guanylyl cyclase (30) and protein kinase G (30), increased synthesis of platelet-activating factor (26), and/or an increased release of products via activation of
the cyclooxygenase pathway (20). Thus it appears that VEGF is an
important regulator of vascular permeability in the peripheral circulation.
VEGF also appears to play an important role in the cerebral
circulation. VEGF mRNA is expressed in normal brain tissue (18), and
the expression of VEGF increases during brain injury (21, 23) and in
brain tumors (4, 8, 9, 24). Thus it is possible that VEGF may
contribute to disruption of the blood-brain barrier (BBB) during brain
injury and may be responsible for tumor angiogenesis and tumor-related
increases in permeability of the BBB. Investigators have examined the
effects of VEGF on permeability of cultured endothelium from brain
microvessels (29, 31). These investigators (29, 31) report that VEGF
produced an increase in the transport of small molecules (sucrose and
fluorescein) across cerebral endothelium. However, mechanisms by which
VEGF increases permeability of the BBB were not examined in these
previous studies (29, 31).
No studies have used in vivo methodologies to directly examine the
permeability of the BBB to VEGF and the role of a nitric oxide/cGMP-dependent pathway in alterations in permeability of the BBB
in response to VEGF. Thus the first goal of this study was to determine
the in vivo effect of VEGF on permeability of the BBB. The second goal
of this study was to examine potential cellular mechanisms that may
account for VEGF-induced increases in permeability of the BBB.
Specifically, we examined the role of synthesis/release of nitric oxide
and stimulation of soluble guanylate cyclase in VEGF-induced increases
in permeability of the BBB in vivo.
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METHODS |
Preparation of animals.
Male Wistar-Furth rats (n = 24) were
anesthetized (Inactin; thiobutabarbital 100 mg/kg ip), and a
tracheotomy was performed. The rats were mechanically ventilated with
room air and supplemental oxygen. A catheter was placed in a femoral
artery for the measurement of systemic blood pressure and to obtain
blood samples. A catheter was placed in a femoral vein for injection of
the intravascular tracer FITC-dextran (mol mass 10,000 Da;
FITC-dextran-10K). All procedures were carried out following
Institutional Animal Care and Use Committee approval.
To visualize the cerebral microcirculation, a cranial window was
prepared over the parietal cortex using methods we have described previously (14-16). An incision was made in the skin to expose the
skull. The skin was retracted with sutures and served as a "well"
for the suffusion fluid. Inlet and outlet ports were made in the skin
to allow for the constant flow of suffusate across the cerebral (pial)
microcirculation. Finally, a craniotomy was performed, the dura was
incised, and the cerebral microcirculation was exposed. The suffusion
fluid (artificial cerebrospinal fluid) was heated (37 ± 1°C)
and bubbled continuously with 95% nitrogen and 5% carbon dioxide to
maintain gases within normal limits. Blood gases were also monitored
and maintained within normal limits. At the end of the experiment, all
anesthetized rats were killed with an injection of saturated potassium chloride.
Permeability of the BBB.
The permeability of the BBB was evaluated by calculating the clearance
of FITC-dextran-10K (10
6
ml/s) by the area of parietal cortex
exposed by the craniotomy, as we have described previously
(14-16). Briefly, the suffusate fluid was collected in glass test
tubes with the aid of a fraction collector, and we determined the
concentration of FITC-dextran-10K in the suffusate fluid during topical
application of vehicle (saline), VEGF (0.01 and 0.1 nM), VEGF (0.1 nM)
in the presence of
NG-monomethyl-L-arginine
(L-NMMA; 10 µM), and VEGF (0.1 nM) in the presence of
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ; 1.0 µM). FITC-dextran-10K was infused intravenously (40 mg/ml at 0.06 ml/min), and arterial blood samples (~60 µl/sample) were drawn at various intervals throughout the experimental period. To
quantitate the concentration of FITC-dextran-10K in the suffusate fluid
and plasma samples, standard curves for concentration of FITC-dextran-10K vs. percent transmission were obtained with a spectrophotofluorometer (Perkin-Elmer model LS30). The standard (FITC-dextran-10K) was prepared on a weight-per-volume basis. The
suffusate concentration was used as background, a standard curve was
generated for each experiment, and each curve was subjected to linear
regression analysis. The percent transmission for unknown samples
(suffusate and plasma) was measured on the spectrophotofluorometer, and
the concentration was calculated from the standard curve. The clearance
of FITC-dextran-10K was calculated by multiplying the
suffusate-to-plasma concentration ratio by the suffusate flow rate
(14-16).
Pial arteriolar diameter.
Diameter of pial arterioles was measured online using a video image
shearing device (model 908, Instrumentation for Physiology and
Medicine). We measured the diameter of the largest pial arteriole exposed by the craniotomy before and during application of vehicle, VEGF, VEGF in the presence of
L-NMMA, and VEGF in the presence of ODQ. We report the maximum change in diameter of cerebral
arterioles, which appeared to occur 40 min after the start of
superfusion with VEGF. In addition, we also examined the effects of ODQ
on nitroglycerin-induced responses of pial arterioles to determine the
efficacy of ODQ on cGMP-mediated vasodilatation.
Experimental protocol.
The first group of rats served as time controls
(n = 5). Two hours after the
preparation of the craniotomy, a constant injection of FITC-dextran-10K
(40 mg/ml at 0.06 ml/min) was started. Thirty minutes after starting
infusion of FITC-dextran-10K, we started a continuous suffusion of
vehicle (saline) over the cerebral microcirculation. The clearance of
FITC-dextran-10K was determined for the next 60 min during suffusion
with vehicle. Diameter of pial arterioles was determined immediately
before and 5 and 10 min after the start of suffusion with vehicle and
every 10 min thereafter.
In a second group (n = 4) and third
group (n = 5) of rats, we examined the
effects of VEGF (0.01 and 0.1 nM, respectively) on the permeability of
the BBB to FITC-dextran-10K and reactivity of cerebral arterioles. The
protocol followed was similar to the one described above, with the
exception that the cranial window preparation was suffused with VEGF
instead of vehicle. Clearance of FITC-dextran-10K and diameter of
cerebral arterioles were determined as described above.
In a fourth group (n = 4) of rats, we
examined the role of nitric oxide in VEGF-induced increases in
permeability of the BBB and reactivity of cerebral arterioles. In these
studies, we suffused the cranial window preparation with
L-NMMA (10 µM) 60 min before a
topical application of VEGF (0.1 nM) and continued
L-NMMA suffusion during VEGF
application. Thus clearance of FITC-dextran-10K was determined while
the preparation was suffused with VEGF in the presence of a continuous
suffusion of L-NMMA. Diameter of
cerebral arterioles was measured under control conditions, during
topical application of L-NMMA,
and during topical application of VEGF in the presence of
L-NMMA.
In a fifth group (n = 6) of rats, we
examined the role of soluble guanylate cyclase in VEGF-induced
increases in permeability of the BBB and reactivity of cerebral
arterioles. In these studies, the protocol followed was similar to that
outlined for L-NMMA, with the
exception that ODQ (1.0 µM) was suffused over the cranial window
preparation. Clearance of FITC-dextran-10K and diameter of cerebral
arterioles were determined as described above. In addition, to
determine the efficacy of ODQ for soluble guanylate cyclase, we
examined responses of cerebral arterioles to nitroglycerin before and
after treatment with ODQ (1.0 µM).
Statistical analysis.
ANOVA with Fisher's test for significance was used to compare
clearance of FITC-dextran-10K and diameter of cerebral arterioles during suffusion with vehicle to those during suffusion with VEGF, VEGF
in the presence of L-NMMA, and
VEGF in the presence of ODQ. A paired
t-test was used to compare dilatation
of cerebral arterioles in response to nitroglycerin before and after
treatment with ODQ. P 
0.05 was
considered to be significant.
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RESULTS |
Response to VEGF.
Clearance of FITC-dextran-10K remained relatively constant during
suffusion with vehicle (Fig.
1). Clearance of
FITC-dextran-10K also was not significantly increased by suffusion with
the low dose (0.01 nM) of VEGF (Fig. 1). In contrast, there was a
marked increase in clearance of FITC-dextran-10K during suffusion with the 0.1 nM concentration of VEGF (Fig. 1). The increase in clearance of
FITC-dextran-10K in response to VEGF occurred rapidly, i.e., within
8-10 min after the start of suffusion with VEGF, and continued to
increase during the time course of the experiment. During suffusion with VEGF, we observed that extravasation of FITC-dextran-10K appeared
to be localized around cerebral venules and veins.
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Fig. 1.
Clearance of 10,000-Da FITC-dextran (FITC-dextran-10K), in
106 ml/s, during suffusion
with vehicle, 0.01 nM vascular endothelial growth factor (VEGF), or 0.1 nM VEGF. Values are means ± SE.
* P < 0.05 vs. response during
suffusion with vehicle.
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As to arteriolar diameter, we report values at 40 min after the start
of superfusion with vehicle or VEGF. This time appeared to be the time
of the maximum change in arteriolar diameter in response to VEGF.
Application of vehicle did not alter diameter of cerebral arterioles
(Fig. 2; baseline diameter 30 ± 1 µm). In addition, application of VEGF (0.01 nM) did not alter
diameter of cerebral arterioles (Fig. 2; baseline diameter 47 ± 3 µm). However, superfusion with VEGF (0.1 nM) produced a modest but significant increase in arteriolar diameter (Fig. 2; baseline 32 ± 5 µm).
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Fig. 2.
Percent change in diameter of cerebral arterioles in response to
vehicle, VEGF (0.01 and 0.1 nM), and VEGF (0.1 nM) in presence of
NG-monomethyl-L-arginine
(L-NMMA; 10 µM) or
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ; 1.0 µM). Values shown are maximum changes in diameter in
response to VEGF that occurred 40 min after start of suffusion with
VEGF. Values are means ± SE.
* P < 0.05 vs. response to
vehicle.  P < 0.05 vs.
response to VEGF (0.1 nM).
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Thus it appears that suffusion with VEGF (0.1 nM) produces a marked
increase in permeability of the BBB to FITC-dextran-10K and a modest
but significant increase in diameter of pial arterioles.
Response to VEGF in the presence of
L-NMMA and ODQ.
L-NMMA (10 µM) and ODQ (1.0 µM) significantly inhibited the clearance of FITC-dextran-10K during
application of VEGF (0.1 nM; Fig. 3). The
clearance of FITC-dextran-10K during suffusion with VEGF (0.1 nM) in
the presence of L-NMMA was
similar in magnitude to that reported during suffusion with vehicle
(P > 0.05; Fig. 1).
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Fig. 3.
Clearance of FITC-dextran-10K
(106 ml/s) during suffusion
with VEGF (0.1 nM) and VEGF (0.1 nM) in presence of
L-NMMA or ODQ. Values are means ± SE. * P < 0.05 vs.
response in presence of L-NMMA
or ODQ.
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Topical application of L-NMMA
(10 µM) produced a modest but significant constriction of pial
arterioles (11 ± 2%; baseline diameter 60 ± 4 µm)
before suffusion with VEGF. In addition,
L-NMMA significantly inhibited
dilatation of pial arterioles in response to VEGF (0.1 nM; Fig. 2;
baseline diameter 53 ± 4 µm). Topical application of ODQ (1.0 µM) also produced a modest (7 ± 3%) decrease in
baseline diameter (47 ± 3 µm) of cerebral arterioles. However, unlike that reported for L-NMMA,
this change in baseline diameter in response to ODQ failed to reach
statistical significance (P > 0.05).
In addition, topical application of ODQ significantly inhibited
dilatation of cerebral arterioles in response to VEGF (Fig. 2; baseline
diameter 44 ± 2 µm) and significantly inhibited dilatation of cerebral arterioles in response to nitroglycerin (Fig.
4; baseline diameter 47 ± 3 µm).
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Fig. 4.
Percent change in diameter of cerebral arterioles in response to
nitroglycerin (1.0 µM) in absence and presence of ODQ (1.0 µM).
Values are means ± SE. * P < 0.05 vs. response before suffusion with ODQ.
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Thus it appears that the synthesis/release of nitric oxide or a nitric
oxide-containing compound with subsequent activation of soluble
guanylate cyclase plays a significant role in VEGF-induced increases in
permeability of the BBB and dilatation of rat pial arterioles.
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DISCUSSION |
The main findings of the present study are that in vivo application of
VEGF to the cerebral microcirculation produces an increase in
permeability of the BBB to a molecule of moderate size
(FITC-dextran-10K) and produces a modest dilatation of cerebral
arterioles. In addition, this increase in permeability of the BBB and
dilatation of cerebral arterioles in response to VEGF could be
inhibited by application of
L-NMMA, an enzymatic inhibitor
of nitric oxide synthase, or ODQ, a novel inhibitor of soluble
guanylate cyclase. Thus it appears that the actions of VEGF on the
cerebral microcirculation involve the synthesis/release of nitric oxide
with a subsequent activation of soluble guanylate cyclase.
Consideration of methods.
The permeability of the BBB was evaluated by calculating the clearance
of FITC-dextran-10K by the area of brain exposed by the craniotomy.
This methodology has been used by our laboratory in many previous
studies to evaluate the permeability characteristics of the BBB
(14-16). No extravasation of FITC-dextran-10K was observed from
the dura, skin, or bone during suffusion with vehicle and/or VEGF, and
we suggest that increases in clearance of FITC-dextran-10K during
topical application of VEGF represent changes in permeability that are
occurring in pial vessels.
We evaluated changes in permeability of the BBB in response to two
concentrations of VEGF (0.01 and 0.1 nM). Although studies have shown
that VEGF mRNA is expressed by normal brain tissue (18) and that brain
injury increases the expression of VEGF (21, 23), no studies to our
knowledge have examined the concentration of VEGF produced during brain
injury. Thus it is not possible for us to determine whether the
concentrations of VEGF used in the present study actually represent
that observed during brain injury. The choice of concentrations of VEGF
used in the present study was based on previous studies that have
examined the effects of VEGF on permeability of the peripheral
circulation and/or monolayers of endothelium from the peripheral
circulation (2, 3, 7, 10, 20, 26, 30) and in vitro studies that have
examined the effects of VEGF on permeability of cerebral endothelium
(29, 31).
We used L-NMMA to examine the
role of nitric oxide in permeability of the BBB and dilatation of pial
arterioles following topical application of VEGF. The concentration of
L-NMMA (10 µM) used in the
present study has been shown to be specific and efficacious in
inhibition of the effects of nitric oxide or a nitric oxide-containing compound on cerebral arterioles (6, 11, 17), disruption of the BBB
during acute hypertension (12), or disruption of the BBB during topical
application of histamine (13). Thus we suggest that the concentration
of L-NMMA used in the present
study is appropriate for examining the effects of nitric oxide on the cerebral microcirculation.
We also examined the role of activation of soluble guanylate cyclase in
disruption of the BBB in response to VEGF and dilatation of cerebral
arterioles in response to VEGF and nitroglycerin by using ODQ. It
appears that relaxation of vascular smooth muscle in response to nitric
oxide is accomplished by activation of soluble guanylate cyclase and
the production of cGMP (19, 22, 27). However, recent evidence suggests
that nitric oxide may also affect blood vessels via a soluble guanylate
cyclase-independent mechanism (1, 5). In the present study, we found
that ODQ, which is a specific inhibitor of soluble guanylate cyclase in
cerebral arterioles (27), significantly inhibited dilatation of rat
cerebral arterioles in response to VEGF and nitroglycerin. Thus we
suggest that endogenous (produced in response to VEGF) and exogenous
(produced in response to nitroglycerin) effects of nitric oxide on
cerebral vessels are mediated predominantly by activation of soluble
guanylate cyclase.
Consideration of previous studies.
Several previous studies have examined the effect of VEGF on the
permeability of the peripheral circulation. These previous studies have
shown that VEGF increases the permeability of isolated perfused
microvessels of the coronary (30) and mesenteric (2, 3, 26)
circulations, of the skin (20), of the trachea, bronchi, and pancreas
(26), and of endothelial cell cultures (10, 26). Mechanisms that
contribute to changes in vascular permeability of the peripheral
circulation in response to VEGF are varied. Murohara et al. (20)
suggested that VEGF-induced increases in permeability are related to
the synthesis/release of nitric oxide, since inhibitors of nitric oxide
synthase attenuate the VEGF-induced increase in vascular permeability.
Wu et al. (30) also reported that inhibitors of nitric oxide synthase attenuate VEGF-induced increase in venular permeability of the coronary
circulation. In addition, these investigators (30) found that
inhibitors of guanylate cyclase and protein kinase G also prevent
VEGF-induced increases in coronary venular permeability. Thus it
appears that VEGF may modulate changes in vascular permeability of the
coronary microcirculation via a pathway involving synthesis/release of
nitric oxide with subsequent stimulation of guanylate cyclase and
protein kinase G. Others have suggested that VEGF may increase vascular
permeability via the release of prostaglandins (20), synthesis of
platelet-activating factor (26), an increase in the flux of calcium
across the endothelium (3), and/or a direct effect of VEGF on vascular
endothelium (10). The present study extends these previous findings by
examining the effects of VEGF on the permeability and reactivity of the
cerebral microcirculation using in vivo methodologies.
Although previous studies have shown that VEGF is expressed by brain
tissue under physiological (18) and pathophysiological (21, 23)
conditions, few studies have examined the effects of VEGF on
permeability of the BBB. Two studies have examined the effects of VEGF
on the transport of small molecules across endothelium derived from
brain microvessels (29, 31). Wang et al. (29) found that VEGF increased
the permeability of cerebral endothelium to
[14C]sucrose. In
addition, these investigators report that the increase in transport of
sucrose across cerebral endothelium was greater when VEGF was applied
to the basolateral side of the endothelial membrane than when it was
applied to the apical side (29). However, mechanisms by which VEGF
increased the flux of sucrose across cerebral endothelium were not
investigated in this previous study (29). A more recent study by Zhao
et al. (31) examined the flux of carboxyfluorescein (mol wt 376) across
endothelial cells derived from brain capillaries during stimulation
with VEGF. These investigators report that VEGF, when applied to the
abluminal side of cerebral endothelium, produced an increase in the
flux of carboxyfluorescein (31). However, mechanisms by which VEGF increased the flux of carboxyfluorescein across cerebral endothelium were not examined by these investigators (31). The findings of the
present study complement the results of these two previous studies (29,
31). We report that VEGF increases the permeability of the BBB to a
moderately sized molecule (FITC-dextran-10K). In addition, the findings
of the present study extend those of previous studies (29, 31) by
examining the in vivo effects of VEGF on the BBB and arteriolar
diameter and by examining potential cellular mechanisms by which VEGF
increases the permeability of the BBB and cerebral arteriolar diameter.
In summary, we found that VEGF, when applied topically to the cerebral
microcirculation, produces an increase in the permeability of the BBB
to FITC-dextran-10K and dilates cerebral arterioles. The increase in
permeability of the BBB and dilatation of cerebral arterioles in
response to VEGF appear to involve a mechanism dependent on the
synthesis/release of nitric oxide or a nitric oxide-containing compound
and stimulation of soluble guanylate cyclase. We suggest that the
production of VEGF may contribute to the pathogenesis of disruption of
the BBB and the development of cerebral edema during brain injury.
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ACKNOWLEDGEMENTS |
This study was supported by National Institutes of Health Grants
HL-40781 and AA-11288, American Heart Association Grants-in-Aid 9607851S (Nebraska Affiliate) and 96006160 (National Affiliate), a
Grant-in-Aid from the American Diabetes Association, and Smokeless Tobacco Research Council Grant 0668-02.
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FOOTNOTES |
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: W. G. Mayhan,
Dept. of Physiology and Biophysics, 984575 Nebraska Medical Center,
Omaha, NE 68198-4575 (E-mail: wgmayhan{at}unmc.edu).
Received 30 November 1998; accepted in final form 10 February
1999.
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ABSTRACT
INTRODUCTION
