Exaggerated Hypotensive Effect of Vascular Endothelial
Growth Factor in Spontaneously Hypertensive Rats
Renhui Yang, Annie K. Ogasawara, Thomas F. Zioncheck, Zhen Ren, Guo-Wei He,
Geralyn G. DeGuzman, Nicolas Pelletier, Ben-Quan Shen, Stuart Bunting, Hongkui Jin
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Abstract—Vascular endothelial growth factor (VEGF) induces hypotension in normotensive subjects, which is considered
to be a major side effect for treatment of ischemic diseases. However, the hypotensive effect of VEGF has not been
investigated in the setting of hypertension. This study determined effects of VEGF on hemodynamics, pharmacokinetics,
and release of NO and prostaglandin I2 (PGI2) in vivo and on vasorelaxation of mesentery artery rings in vitro in
spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Intravenous infusion of VEGF for 2
hours produced a dose-related decrease in arterial pressure, which was enhanced in conscious SHR compared with WKY
(P⬍0.01), and an increase in heart rate in WKY but not in SHR. In response to similar doses of VEGF, compared with
WKY, SHR had a higher plasma VEGF level and lower VEGF clearance (P⬍0.01). Circulating NO and PGI2 levels
after VEGF administration were not increased in SHR versus WKY, and VEGF-induced vasorelaxation was blunted in
SHR versus WKY in vitro, suggesting endothelial dysfunction in SHR. One-week VEGF infusion also caused greater
hypotension (P⬍0.05) in the absence of tachycardia in SHR compared with WKY controls. Thus, despite blunted
vasorelaxation in vitro because of endothelial dysfunction, SHR exhibited exaggerated hypotension without tachycardia
in response to VEGF, which was independent of NO and PGI2. The exaggerated hypotensive response to VEGF in SHR
may be owing to impaired baroreflex function and reduced VEGF clearance. The data may also suggest that more
caution should be taken when VEGF is administered in patients with hypertension. (Hypertension. 2002;39:815-820.)
Key Words: growth substances 䡲 rats, spontaneously hypertensive 䡲 hemodynamics 䡲 hypotension
䡲 blood pressure
V
in vitro, which is diminished in spontaneously hypertensive
rats (SHR) compared with normotensive Wistar-Kyoto rats
(WKY).23 The present study was designed to determine the
effects of VEGF on mean arterial pressure (MAP), heart rate
(HR), and release of NO and prostaglandin I2 (PGI2) in
conscious SHR and to compare the levels to those in WKY
controls. Furthermore, pharmacokinetic responses to VEGF
were examined in SHR versus WKY. In addition, we also
examined the in vitro vasorelaxant effects of VEGF in
isolated mesentery arteries of SHR and WKY. Our results
showed that compared with WKY, SHR exhibited an enhanced hypotensive response to VEGF in vivo, which may be
caused by impaired baroreflex function and reduced VEGF
clearance, despite a blunted vasorelaxant response to VEGF
in vitro due to endothelial dysfunction.
ascular endothelial growth factor (VEGF) is a unique
mitogen specific for vascular endothelial cells.1– 4 As a
fundamental mediator of normal and pathological angiogenesis, VEGF has been shown to induce a strong angiogenic
response in vitro5,6 and in vivo.2,3,7–9 Animal studies have
demonstrated that administration of VEGF produces beneficial angiogenic effects in peripheral vascular ischemia10 –12
and in coronary ischemia.13–16
VEGF has been shown to induce endothelium-dependent
vasorelaxation in normal animals in vitro.17–19 Because of its
vasodilatory effect, VEGF induces hypotensive and tachycardic responses in vivo in normotensive animals, including
rats, rabbits, and pigs,14,21 and the hypotensive effect is
mediated, at least in part, by NO.20,21 In humans, intracoronary administration of VEGF caused a hypotensive effect that
was dependent on VEGF infusion rate.22 Although hypotensive effects of VEGF have been characterized in normotensive subjects, these effects have not been investigated in the
setting of hypertension.
Our previous studies have demonstrated that VEGF induces endothelium-dependent vasorelaxation in aortic rings
Methods
Male SHR and WKY age 12 weeks were obtained from Charles
River Breeding Laboratories (Wilmington, Mass). The experimental
procedures were approved by the Institutional Animal Care and Use
Committee of Genentech.
Received October 30, 2001; first decision November 15, 2001; revision accepted January 9, 2002.
From the Departments of Cardiovascular Research (R.Y., A.K.O., S.B., H.J.) and Clinical and Experimental Pharmacology (T.F.Z., G.G.D., N.P.,
B-Q.S.), Genentech Inc, South San Francisco, Cal; Cardiovascular Research, Starr Academic Center, St Vincent Hospital (Z.R., G-W.H.), Portland, Org;
and Department of Surgery, The Chinese University of Hong Kong (G-W.H.), Hong Kong.
Correspondence to Hongkui Jin, MD, Department of Cardiovascular Research, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080. E-mail
[email protected]
© 2002 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
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March 2002
Measurements of MAP and HR
After anesthesia with intraperitoneal injection of ketamine 80 mg/kg
and xylazine 10 mg/kg, catheters were implanted into the right
femoral artery and vein.20 MAP and HR were measured in conscious
unrestrained SHR (n⫽53) and WKY (n⫽51) 1 day after catheterization with a pressure transducer coupled to a polygraph.20 VEGF
(recombinant human VEGF165, Genentech Inc) was infused intravenously at 0.3, 1.5, or 4.5 ␮g/kg per min in normal saline (5 ␮L/min)
for 2 hours.
Plasma NO Assessment
Blood (0.2 to 0.25 mL) was collected from the arterial catheter
before and 2 hours after intravenous infusion of VEGF (1.5 ␮g/kg
per min) in SHR and WKY (n⫽9 in each group). Serum nitrates
were measured by capillary electrophoresis.24
Pharmacokinetic Study
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Blood (300 ␮L) was collected in 6 SHR and 6 WKY before and after
intravenous infusion of VEGF at 1.5 ␮g/kg per min for 120 minutes.
Plasma rhVEGF was measured using a dual monoclonal antibodybased enzyme-linked immunosorbent assay (ELISA). This assay
utilizes a capture antibody MAb 3.5 F8 that binds to the VEGF
heparin-binding domain (amino acid Nos. 111 to 165) and a
detecting antibody, MAb A 4.6.1 that binds to the KDR-binding
region (amino acid Nos. 82, 84, and 86). A noncompartmental
method was used to calculate VEGF pharmacokinetic parameters.
Plasma PGI2 Assay
The levels of 6-ketoprostaglandin F1␣, a nonenzymatically hydrated
product from PGI2, in the plasma samples were measured by using an
EIA kit from Cayman Chemicals according to the manufacture’s
instructions. The amount of 6-ketoprostaglandin F1␣ (pg/mL) was
calculated based on a standard curve.
Chronic Administration of VEGF
An Alzet pump was implanted for infusion of saline or VEGF into
the right jugular vein at the dose of 0.16, 0.32, or 0.42 ␮g/kg per min
for 7 days in 28 SHR and 28 WKY. Six days after the continuous
infusion, the arterial catheter was implanted. One day later, MAP and
HR were measured in conscious rats.
Microarterial Preparation and Mounting In Vitro
The mesentery arteries were dissected and cut into cylindrical rings
under a microscope. A pair of a stainless steel wires (diameter, 40
␮m) was guided through the lumen of each ring. One wire was fixed
tightly on a jaw in a 2-channel myograph (Model 500A, J.P.
Trading), and another wire was anchored to another jaw of the same
chamber. The measurement was performed as described
previously.23
Statistical Analysis
Results are expressed as mean⫾SEM. One-way ANOVA was
performed to assess differences in parameters under the same
condition between groups and to compare changes over time within
each group. Two-way ANOVA was used to compare parameters in
response to chronic VEGF infusion. Significant differences were
then subjected to posthoc analyses using the Newman-Keuls method.
P⬍0.05 was considered to be statistically significant.
An expanded Methods section can be found in an online data
supplement available at http://www.hypertensionaha.org.
Results
Figure 1. A and B, Effects of acute intravenous VEGF infusion
on MAP (A) and HR (B) in SHR and WKY. Values are
mean⫾SEM of 10 to 13 animals in each group. *P⬍0.05,
**P⬍0.01 vs the respective WKY group; #P⬍0.05, ##P⬍0.01 vs
the vehicle (0 dose) group; and ⫹P⬍0.05 vs the 0.3 ␮g/kg per
min dose. C and D, Effects of chronic intravenous VEGF infusion
at 0.32 ␮g/kg per min for 7 days MAP (C) and HR (D) in SHR
and WKY (6 animals in each group). **P⬍0.01 vs the vehicle
group in the same strain; #P⬍0.05, ##P⬍0.01 vs the respective
WKY group.
however, was observed in WKY at the 3 doses but not in SHR
at any doses studied (Figure 1, bottom). For example,
following 2-hour infusion at the same dose (1.5 ␮g/kg per
min), the maximal hypotensive response was exaggerated by
2.5-fold in SHR compared with WKY controls (P⬍0.01)
(Figure 1A). In contrast, this dose of VEGF significantly
increased HR in WKY (P⬍0.01) but not in SHR (Figure 1B).
Effects of VEGF on Plasma NO and PGI2
Because of a very short half-life, NO gets converted rapidly
to nitrites and nitrates, and nitrites also get converted to
nitrates in the presence of oxygen. Accordingly, plasma
nitrate concentration was used as an indicator of NO release
in vivo. After 2-hour infusion of VEGF at the same dose (1.5
␮g/kg per min), the plasma level of nitrates (an indicator of
NO) was elevated by 28% in WKY (P⬍0.01) and by 25% in
SHR (P⫽0.068) (Figure 2A). The VEGF-induced increase in
plasma nitrates was not significantly different between the 2
strains (P⫽0.314). There is no difference in plasma levels of
6-ketorostaglandin F1␣, an indicator of PGI2, before and after
VEGF administration between SHR and WKY (Figure 2B).
Hemodynamic Responses to Acute Infusion of VEGF
Intravenous administration of VEGF for 2 hours caused a
dose-related reduction in MAP in both SHR and WKY
(Figure 1A). The reduction in MAP was significantly greater
in SHR than in WKY. A concomitant increase in HR,
Pharmacokinetic Responses to VEGF
Intravenous infusion of VEGF at 1.5 ␮g/kg per min produced
substantially higher plasma levels of VEGF in SHR than
WKY (P⬍0.01) (Figure 2C). Areas under the curve (pg/mL
Yang et al
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Figure 2. Effects of acute intravenous VEGF infusion at 1.5
␮g/kg per min on plasma nitrate (A, 9 animals in each group),
plasma 6-ketoprostaglandin F1␣ (B, 6 animals in each group),
plasma VEGF concentration/time profile (C, 6 animals in each
group), and VEGF clearance (D, 6 animals in each group) in
SHR and WKY. Values are mean⫾SEM. A, **P⬍0.01 vs basal
level in the WKY group; ⫹P⫽0.068 vs the basal level in the SHR
group. C and D, **P⬍0.01 vs the SHR and WKY group.
per min) in SHR were 2-fold larger than those in WKY
(P⬍0.01). This was associated with a 57% decrease in VEGF
clearance in SHR compared with WKY controls (P⬍0.01)
(Figure 2D).
Hemodynamic Responses to Chronic Intravenous
Infusion of VEGF
Intravenous infusion of VEGF at 0.16 ␮g/kg per min for 7
days did not produce a significant change in MAP in
conscious SHR and WKY (data not shown). VEGF at 0.32
␮g/kg per min, however, resulted in a 27% reduction in MAP
in SHR (P⬍0.01) but only a small decrease in MAP in WKY
(P⫽NS) (Figure 1C). In contrast, the chronically infused
VEGF at this dose increased HR by 45% in WKY (P⬍0.01)
but did not altered HR in SHR (Figure 1D). Further, VEGF at
0.42 ␮g/kg per min caused a marked fall in MAP (⫺36% in
WKY and ⫺46% in SHR compared with the respective
vehicle-treated controls), with a 50% mortality rate in each
group.
VEGF-Induced Relaxation of the Mesentery
Artery In Vitro
The mean internal diameter of the rings at an equivalent
transmural pressure of 100 mm Hg (D100) was 432.5⫾1.15
␮m as determined from the normalization procedure. When
the mesentery microartery rings were set at a resting diameter
of 90% D100, the equivalent transmural pressure was
Hypotensive Effect of VEGF in SHR
817
Figure 3. VEGF-induced relaxation of the mesentery artery in
WKY (top) and SHR (middle) and a comparison between SHR
and WKY (bottom). Data are mean⫾SEM of 7 animals in each
group. Control indicates treatment with VEGF alone; L-NNA,
pretreatment with N␻-nitro-L-arginine (a specific inhibitor of NO
synthase); and E-denuded, pretreatment with removing endothelium. **P⬍0.01 vs control group; ##P⬍0.01 vs the SHR and
WKY group.
58.7⫾0.6 mm Hg, and the resting force was 6.21⫾0.31 mN.
There was no significant difference in the internal diameter,
resting force, and U46619-induced precontraction force between groups.
In both the WKY and SHR groups, VEGF induced relaxation in a concentration-dependent manner in the mesentery
microartery rings (Figure 3, top and middle). The VEGFinduced vasorelaxation was significantly attenuated by pretreatment with N␻-nitro-L-arginine (300 ␮mol/L, P⬍0.01)
and completely abolished by removing endothelium in both
strains. However, the relaxation induced by VEGF was
significantly blunted in SHR compared with WKY (P⬍0.01)
(Figure 3, bottom).
Discussion
The present study showed that acute and chronic administration of VEGF resulted in a dose-related reduction in MAP in
both conscious SHR and WKY. The VEGF-induced reduction in MAP was significantly greater in the hypertensive
SHR than in normotensive animals (Figure 1A). This is the
first report documenting that systemic administration of
VEGF induces exaggerated hypotension in the setting of
hypertension.
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Hypertension
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Interestingly, our in vitro experiments demonstrated that
VEGF induced an endothelium-dependent vasorelaxation in
the mesentery microartery rings, which was significantly
blunted in the SHR group compared with the WKY group
(Figure 3). This finding is consistent with our previous
observation that SHR exhibits a diminished vasorelaxant
response to VEGF in aortic rings.23 Furthermore, the basal
level of plasma NO before VEGF administration was decreased by 27% in SHR compared with WKY. Intravenous
infusion of VEGF at 1.5 ␮g/kg per min for 2 hours significantly increased the plasma NO level in WKY (P⬍0.01),
whereas the same dose of VEGF tended to increase the NO
level in SHR (P⫽0.068). This is despite the fact that an
increase in circulating VEGF concentration induced by the
VEGF infusion was significantly greater in SHR than WKY
(see below). Our findings are consistent with previous studies, which have shown that chronic hypertension is associated
with endothelial dysfunction.25–31 SHR has been shown to
exhibit impairment in endothelium-dependent vasorelaxation.
Recently, Brovkovych et al32 demonstrated that in hypertensive SHR, endothelial dysfunction is associated with decreased endothelial NO release compared with normotensive
rats, which is likely owing to a higher production of O2⫺ from
oxygen in SHR. Endothelial dysfunction, however, would be
expected to reduce the hypotensive response to VEGF in
SHR, and apparently cannot account for the exaggerated
hypotension in response to VEGF observed in the hypertensive animals.
The present study suggests 2 mechanisms that may contribute to the enhanced hypotensive effect of VEGF in SHR.
First is a decrease in VEGF clearance. Our pharmacokinetic
study revealed that intravenous administration of VEGF at
the same dose produced a significantly higher plasma level of
VEGF and a significantly lower VEGF clearance in SHR than
in WKY (Figure 2C and 2D). It has been suggested by renal
transplantation studies that an intrinsic defect in the kidney
plays an important role in the development and maintenance
of hypertension in SHR.33 Renal dysfunction identified in
SHR includes reduced renal excretory function, low renal
plasma flow, reduced glomerular filtration rate, and reduced
renal interstitial hydrostatic pressure.34 –37 These abnormalities in renal function would result in a decrease in VEGF
clearance in SHR. Although the higher plasma level of VEGF
after infusion did not induce a higher circulating level of NO
in SHR compared with WKY because of endothelial dysfunction, factors other than NO could mediate the VEGF-induced
hypotension, because pretreatment with specific inhibitors of
NO synthase only partially attenuated vasorelaxant responses
to VEGF in both SHR and WKY (Figure 3). Recent in vitro
studies suggest that in addition to NO, VEGF also stimulates
synthesis of PGI2 that may be involved in VEGF-induced
vasodilation.38,39 Our results, however, showed there was no
difference in plasma PGI2 before and after VEGF infusion
between SHR and WKY, suggesting that the exaggerated
hypotensive effect of VEGF in SHR is not attributed to PGI2.
Second is a defect in baroreflex function. The hypotensive
response to VEGF is accompanied by an increase in HR in
conscious normal animals.20 VEGF, however, does not alter
HR in the isolated heart preparation,20 suggesting that VEGF-
induced tachycardia may be caused by a reflex response to a
decrease in arterial pressure, which is primarily through the
baroreflex, rather than a direct effect on the cardiac pacemaker. This is a compensatory mechanism that prevents a
further decrease in arterial pressure. The present study demonstrated that both acute and chronic infusion of VEGF
caused a concomitant increase in HR in WKY but not in SHR
(Figure 1B and 1D). It is known that SHR exhibits damage to
the baroreflex function,40 – 47 and the baroreflex control of HR
was diminished in SHR compared with WKY. The defect of
baroreflex would lead to a complete lack of the tachycardic
response to a fall in arterial pressure induced by VEGF,
thereby contributing to the exaggerated hypotension.
The hypotension induced by acute administration of VEGF
is transient or lasts a short time, and usually can be tolerated
in normal animals. The side effect of VEGF, however, could
be life threatening in the setting of severe heart diseases when
given by bolus injection. Hariawala et al14 have reported that
intracoronary administration of VEGF (2 mg) as a single
bolus injection improves myocardial blood flow but produces
severe hypotension, incurring a 50% chance of death (4 in 8)
in pigs with chronic myocardial ischemia. We have previously demonstrated that although the hypotensive response to
VEGF is attenuated when given by intravenous infusion
compared with bolus injection, a dose-related reduction in
arterial pressure is still observed after VEGF infusion.48 The
present study shows that in response to VEGF infusion, the
hypertensive animals exhibit exaggerated hypotension compared with that of normotensive controls. In addition, we also
found chronic infusion of VEGF at a higher dose for 7 days
caused severe hypotension with a 50% mortality rate in both
SHR and WKY, suggesting that chronic, continuous infusion
of VEGF at higher doses should be avoided even in normotensive subjects. In contrast to administration of the VEGF
protein that induces hypotension, however, gene therapy with
VEGF DNA may avoid this side effect. Clinical studies
indicate that gene transfer of VEGF DNA produces beneficial
effects without evidence of hypotension in patients with
coronary artery disease.49 –50 Further clinical trials in a large
number of patients are needed to confirm the benefits of the
gene therapy.
In conclusion, despite the in vitro observations that VEGF
induced a blunted vasorelaxation in SHR compared with
WKY because of endothelial dysfunction, both acute and
chronic administration of VEGF resulted in an exaggerated
hypotension with no tachycardia in conscious SHR. The
exaggeration of the hypotensive response to VEGF may be
owing to damaged baroreflex function and reduced VEGF
clearance in SHR. Our data suggest that more precautions
may be necessary when VEGF is systemically administered
in patients with hypertension and/or renal dysfunction. Further studies may be needed to determine whether local
administration of VEGF reduces the dose required and thus
the hypotensive effect observed.
Acknowledgments
We are grateful to Lea Berleau for her technical assistance and to
Stephen Eppler for pharmacokinetic analyses.
Yang et al
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Exaggerated Hypotensive Effect of Vascular Endothelial Growth Factor in Spontaneously
Hypertensive Rats
Renhui Yang, Annie K. Ogasawara, Thomas F. Zioncheck, Zhen Ren, Guo-Wei He, Geralyn G.
DeGuzman, Nicolas Pelletier, Ben-Quan Shen, Stuart Bunting and Hongkui Jin
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Hypertension. 2002;39:815-820
doi: 10.1161/hy0302.105398
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