![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 284, Issue 1, 103-110, 1998
Departments of Cardiovascular Research (R.Y, S.B., A.K., N.F., H.J.) and Pharmacokinetics and Metabolism (B.A.K., N.B.M., T.F.Z.), Genentech, Inc., South San Francisco, California
 |
Abstract |
|---|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Vascular endothelial growth factor (VEGF) produces beneficial angiogenesis in animal models of coronary and peripheral ischemia. However, intravenous bolus injection of Chinese hamster ovary cell (CHO)-derived VEGF produces adverse effects on hemodynamics. The present study examined pharmacokinetic and hemodynamic responses to Escherichia coli-derived VEGF, which will be used in clinical patients, compared with responses to CHO-derived VEGF, and tested whether intravenous infusion of E. coli-derived VEGF attenuates the hemodynamic responses compared with the responses observed with intravenous bolus injection. Hemodynamic parameters were measured before and after administration of VEGF in conscious, instrumented rats. Intravenous injection of both CHO- and E. coli-derived VEGF produced a similar maximal reduction in arterial pressure, although E. coli-derived VEGF exhibited less of a depressor effect in the initial phase after injection. Either infusion or injection of E. coli-derived VEGF caused hypotension, tachycardia and reduced cardiac output and stroke volume, which were significantly attenuated when given by infusion compared with injection. The maximal hypotensive and tachycardic responses to infusion were decreased by 50 to 60% compared with those responses observed after injection. Cardiac output was maximally reduced by 34% after injection, but only 18% after infusion. A sustained elevation in systemic vascular resistance observed after injection was avoided after infusion. Thus, the hemodynamic side effects of VEGF administration can be substantially attenuated by controlling the rate of VEGF infusion. The data indicate that infusion, instead of bolus injection, is a more appropriate regimen for VEGF administration.
| |
Introduction |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Vascular
endothelial growth factor is a heparin-binding mitogen specific for
micro- and macrovascular endothelial cells (Ferrara and Henzel, 1989
;
Connolly et al., 1989; Keck et al., 1989; Leung et al., 1989; Plouet et al., 1989; Conn et
al., 1990). VEGF promotes angiogenesis in vitro (Pepper
et al., 1992; Nicosia et al., 1995) and induces a
strong angiogenic response in a variety of in vivo models
(Connolly et al., 1989; Keck et al., 1989; Plouet
et al., 1989; Phillips et al., 1994; Tolentino
et al., 1996). Four different homodimeric species of VEGF
have been identified, each monomer having 121, 165, 189 or 206 amino
acids, respectively (Leung et al., 1989; Tischer et
al., 1991; Houck et al., 1991). The primary amino acid
structure of all four isoforms includes a putative N-linked
glycosylation site with the consensus sequence,
asparagine-isoleucine-threonine, at amino acids 75-77 (Claffey
et al., 1995). Two different recombinant forms of human
VEGF165 have been used for preclinical studies: glycosylated VEGF165 produced by CHO (CHO-derived
VEGF) and nonglycosylated VEGF165 produced by
E. coli (E. coli-derived VEGF). CHO-derived VEGF
has been shown to exert beneficial angiogenic effects in a rabbit model
of limb ischemia by systemic injection (Pu et al., 1993;
Takeshita et al., 1994; Bauters et al., 1995) and
in a pig model of coronary ischemia by intracoronary (Banai et
al., 1994; Hariawala et al., 1996) or intramyocardial
administration (Pearlman et al., 1995). Recent in
vitro and in vivo studies have demonstrated that
E. coli-derived VEGF has similarly favorable effects on
angiogenesis (Walter et al., 1996).
Systemic injection of CHO-derived VEGF, however, results in significant
hypotensive and tachycardic responses in rats, rabbits and pigs (Yang
et al., 1996; Horowitz et al., 1995). The
depressor effect observed in these studies is caused by vasodilation,
which is most likely mediated by nitric oxide (Yang et al.,
1996; Horowitz et al., 1995). In addition, our previous
studies on cardiac function have demonstrated that intravenous
injection of CHO-derived VEGF at a dose similar to that used in a
rabbit hindlimb ischemic model to stimulate angiogenesis produces a
significant reduction in cardiac output and stroke volume (Yang
et al., 1996). Furthermore, it has been reported that
intracoronary administration of CHO-derived VEGF as a single bolus
improves myocardial blood flow but produces severe hypotension
incurring a 50% death in the pig with chronic myocardial ischemia
(Hariawala et al., 1996). These preclinical studies suggest
that the adverse effects of VEGF on hemodynamics, including
hypotension, tachycardia and reductions in cardiac output and stroke
volume, may limit clinical use of VEGF when given by bolus injection.
However, the effects of E. coli-derived VEGF, the molecule
that will be used for clinical patients, on hemodynamics and cardiac
function has not been investigated.
The first purpose of the present study was to compare the pharmacokinetic and hemodynamic effects of E. coli-derived VEGF versus CHO-derived VEGF. The results demonstrated that intravenous injection of both molecules at the same dose induced a similar maximal hypotensive response. Because of the hemodynamic effects of VEGF given by bolus injection, alternate regimens of therapy, including systemic infusion or local application at lower doses, should be considered. The second purpose of the present study was to examine the effects of E. coli-derived VEGF given as intravenous infusion on pharmacokinetics, hemodynamics and cardiac function, and to compare these effects with the effects of E. coli-derived VEGF given as a bolus at the same doses in conscious animals. We show that the hemodynamic responses to VEGF are substantially attenuated when given by intravenous infusion compared with injection.
| |
Methods |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Male Sprague-Dawley rats aged 8 weeks were obtained from Charles River Breeding Laboratories, Wilmington, MA. One week after arrival, implantations of catheters and flowprobes were performed for measurements of hemodynamic parameters. The experimental procedures, which were approved by Genentech's Institutional Animal Care and Use Committee, conform to the guiding principles of the American Physiological Society.
VEGF.
As described previously (Ferrara and Henzel, 1989;
Leung et al., 1989; Walter et al., 1996; Ferrara
et al. 1991), a nonglycosylated form of the recombinant
human VEGF165 (E. coli-derived VEGF) was purified and
refolded from E. coli. The glycosylated form of VEGF165 (CHO-derived VEGF) was purified from media conditioned by CHO cells.
The volume was 5 µl/min for intravenous infusion and 150 to 200 µl
for intravenous injection. In a pilot study, the intravenous infusion
(5 µl/min for 4 hr) or injection (200 µl) of vehicle alone did not
affect MAP, HR and cardiac output. Each animal received only a single
administration of VEGF.
Measurements of arterial pressure and heart rate.
MAP and HR
were measured by catheterization as described previously (Yang et
al., 1996). After anesthesia with intraperitoneal injection of 80 mg/kg ketamine (Aveco Co., Inc., Fort Dodge, IA) and 10 mg/kg xylazine
(Rugby Laboratories, Inc., Rockville Center, NY), catheters (PE-10
fused with PE-50) filled with heparin-saline (50 U/ml) were implanted
into the abdominal aorta via the right femoral artery for
measurement of MAP and HR, and into the right femoral vein for VEGF
administration.
;
Walter et al., 1996).
To examine the responses of MAP and HR to intravenous infusion of
E. coli-derived VEGF in the separate groups, rats received intravenous infusion of VEGF at 0.50, 1.04, 2.75 and 5.50 µg/kg/min in normal saline (5 µl/min) for 4 hr. The total dose was 120, 250, 660 or 1320 µg/kg, and the total volume infused was 1.2 ml. To
compare the responses to E. coli-derived VEGF given by
infusion versus injection, an intravenous 150- to 200-µl
bolus of E. coli-derived VEGF was given at the same doses
(120, 250, 660 or 1320 µg/kg). MAP and HR were monitored before and
after administration of VEGF.
Assessment of cardiac function.
Cardiac output was measured
by an ultrasonic probe as described previously (Yang et al.,
1996). After anesthesia and cannulation of the femoral artery and vein
as described above, rats were intubated via a tracheotomy
and ventilated with a respirator (Harvard Apparatus model 683, South
Natick, MA). Through a right-sided thoracotomy, the ascending aorta was
exposed and gently separated from the pulmonary artery. The ultrasonic
perivascular flowprobe (no. 2S165, Transonic Systems Inc., Ithaca, NY)
was placed around the ascending aorta and sterile K-Y jelly injected
into the space between the vessel and the flowprobe. The flowprobe
cable was exteriorized at the back of the neck, and the cable connector
sutured and fixed in place. The chest was closed and the tracheal
incision sutured after extubation.
Blood collection for pharmacokinetics.
To avoid influence of
blood loss on hemodynamics, blood collections were performed in
separate groups of rats. Samples were collected at predose and at 0.5, 1, 3, 5, 10, 20, 40, 60, 90, 120, 180 and 240 min after the VEGF bolus
injection. Blood (0.2-0.25 ml) was collected from the arterial
catheter into siliconized polypropylene tubes containing
ethylenediaminetetraacetic acid (pH = 8) on ice before and after
intravenous injection of CHO-derived or E. coli-derived VEGF
at the same dose (220 µg/kg), and before and after intravenous
infusion of E. coli-derived VEGF at the four doses. Samples
were centrifuged at 13,000 rpm, and plasma was stored at 
70°C for
measurement of VEGF levels by an ELISA assay specific for VEGF.
Pharmacokinetic analyses.
After intravenous bolus injection,
CHO- and E. coli-derived VEGF plasma concentration
versus time data for individual animals were analyzed by a
noncompartmental analysis according to the following relation:
clearance = dose/area under the curve (AUC). For comparison,
nonlinear regression analysis was also examined by use of a
two-compartment model (PCNONLIN, Statistical Consultants, Lexington,
KY). The initial (
) and terminal (
) half-lives and plasma
clearance were calculated by standard pharmacokinetic methods (Gibaldi
and Perrier, 1982). After intravenous infusion of VEGF, a
noncompartmental method was used to estimate the plasma clearance. The
plasma clearance was estimated as the ratio of the infusion rate
versus the steady-state VEGF plasma concentration.
ELISA assay.
A dual monoclonal ELISA was modified from that
described previously (Keyt et al., 1996) for the
quantitation of VEGF. The coated antibody was an anti-VEGF165
monoclonal antibody 5F8. A VEGF165 standard curve ranging from 0.1 to
10 ng/ml was used. A neutralizing anti-VEGF murine monoclonal antibody
A4.6.1 was used for capture (Kim et al., 1992); signal was
generated with horseradish peroxidase-conjugated goat IgG specific for
murine IgG and developed with ortho-phenylenediamine. Signal was
detected via the absorbance measured at 492 nm on a
microplate reader (Molecular Devices, Sunnyvale, CA). The concentration
of VEGF165 was quantitated by interpolation of a standard curve with
nonlinear regression analysis.
Statistical analysis. Results are expressed as mean ± S.E.M. One-way analysis of variance was performed to assess differences in parameters at the same time point between groups and to compare changes over time within each group. P < .05 was considered to be statistically significant.
| |
Results |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Pharmacokinetic and hemodynamic responses to intravenous bolus of
CHO- and E. coli-derived VEGF.
Intravenous
administration of either CHO- or E. coli-derived VEGF at 220 µg/kg resulted in high plasma concentrations of 2.4 ± 0.2 µg/ml at the initial time point, 30 sec after injection (fig.
1). The initial volume of distribution
for both CHO- and E. coli-derived VEGF (91 ml/kg), estimated
by the ratio of dose versus initial plasma concentration,
approximated plasma volume. Clearance was evaluated by the ratio of
dose versus the area under the curve derived from the
concentration versus time data in figure 1. Both forms of
VEGF were rapidly cleared from plasma with similar rates for CHO- and
E. coli-derived VEGF (6.3 ± 0.8 and 6.6 ± 0.2 ml/min/kg, respectively). Bi-exponential equations were fitted to the
data for plasma concentration versus time profiles for both
forms of VEGF. Clearance of CHO-derived VEGF exhibited an - and
-phase with calculated half-lives of 1.1 ± 0.3 and 32 ± 3 min, respectively. E. coli-derived VEGF exhibited an
initial phase of less than 0.5 min and a terminal phase of 37 ± 4 min. In the initial distribution phase, E. coli-derived VEGF
exhibited significantly reduced plasma levels during the first 30 min
compared with those observed with CHO-derived VEGF. At later times
(1-4 hr), E. coli-derived VEGF appeared to achieve slightly
greater plasma concentrations than CHO-derived VEGF (fig. 1).
|
|
Pharmacokinetic and hemodynamic responses to intravenous infusions of E. coli-derived VEGF. E. coli-derived VEGF was administered to rats as an intravenous infusion for 4 hr at rates which varied from 0.5 to 5.5 µg/min/kg. A steady elevation in plasma VEGF was observed during the first 3 hr of infusion at the lower dose groups (fig. 3, top). Steady-state levels of plasma VEGF were achieved with all dosing regimens during the 4-hr infusion. Clearance was calculated as the ratio of the infusion rate versus the plasma VEGF concentration at steady state. A dose-dependent saturation of clearance appeared with increasing infusion rates (fig. 3, bottom). At 0.5 µg/min/kg infusion of VEGF, the clearance was 18.6 ml/min/kg. However, at 5.5 µg/min/kg, the rate of clearance decreased approximately 3.5-fold to a value of 5.2 ml/min/kg. Saturation of plasma clearance was half-maximal at 2 µg/min/kg in the rat. These data indicate that the bolus doses of VEGF (300 µg/kg) were in fact saturating the VEGF clearance process in vivo.
|
13 mmHg at 4 hr. However, no
decreases in MAP greater than this level were seen with doses up to 5.5 µg/kg/min during 4 hr (fig. 4, top).
|
Effects of intravenous infusion of E. coli-derived VEGF on cardiac function. Intravenous infusion of E. coli-derived VEGF resulted in a dose-related reduction in cardiac output and stroke volume, which was significant between the dose of 0.5 and 1.04 µg/kg/min or between 0.5 and 5.5 µg/kg/min, but not between 1.04 and 5.5 µg/kg/min (fig. 5, top and middle). Actually, a transient elevation in cardiac output and stroke volume, which was not statistically significant, was seen almost immediately after infusion. A significant reduction (P < .05) in cardiac output in response to the VEGF began at 30 to 40 min after infusion, reached a nadir at 50 to 60 min and remained at this plateau during the subsequent 4 hr. The reduction in cardiac output was paralleled by the decrease in stroke volume.
|
Comparison of hypotensive and tachycardic responses to infusion versus injection of E. coli-derived VEGF. There were no significant differences in basal levels of MAP and HR before administration of the VEGF between the infusion and injection groups (table 1).
|
|
Comparison of responses of cardiac function to infusion versus injection of E. coli-derived VEGF. No significant differences in the pretreatment levels of cardiac output, stroke volume and systemic vascular resistance were found between the infusion and injection groups (table 1).
Intravenous injection of E. coli-derived VEGF at the doses of 250 or 1320 µg/kg resulted in a transient increase in cardiac output and stroke volume, which was not statistically significant, almost immediately after injection. The cardiac output and stroke volume returned to the basal line at 3 to 5 min, began to decline at 5 to 7 min, reached a nadir at 15 min and remained decreased during the observed 60 min. The decline in stroke volume appeared to be dose-dependent when given by injection but not by infusion (fig. 7, bottom). The reduction in cardiac output and stroke volume was substantially less in the animals receiving infusion versus injection (fig. 7, top and bottom). Cardiac output was maximally reduced by 34% after injection, but only 18% after infusion at the same dose (250 µg/kg).
|
|
| |
Discussion |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Native VEGF is a glycoprotein because of the presence of an
N-linked glycosylation site at Asn-75 (Leung et al., 1989).
Two recombinant forms of human VEGF165 have been
purified: CHO-derived VEGF, which is glycosylated, and E. coli-derived VEGF, which is nonglycosylated (Walter et
al., 1996). Previous studies have shown that bolus injection of
CHO-derived VEGF induces beneficial angiogenesis in animal models of
myocardial and peripheral ischemia, but may be associated with adverse
effects on hemodynamics and cardiac function because of nitric
oxide-mediated vasodilation and vascular hyperpermeability. Because
VEGF expressed in E. coli is currently being used for
clinical trials, and because deglycosylation may influence the
bioactivity of VEGF, it is important to investigate the biological
effect of E. coli-derived VEGF, including the angiogenic and
hemodynamic effect. The present study demonstrated that there was no
difference in the maximal hypotensive and tachycardic responses to
E. coli-derived versus CHO-derived VEGF in
conscious animals. This finding is consistent with the observation of
Walter and colleagues (1996), who showed that the angiogenic effect is
similar for E. coli-derived and CHO-derived VEGF in
vitro and in vivo. The data suggest that the potential
for VEGF to induce both angiogenic and maximal hemodynamic responses
persists unaltered in the nonglycosylated state.
Although the maximal hypotensive response to both forms of VEGF was
similar, E. coli-derived VEGF had a smaller depressor effect
than CHO-derived VEGF in the initial phase after injection at the
same dose. In conjunction with the transient difference in the
depressor effect, the plasma level of VEGF was also lower in the
initial phase after injection of E. coli-derived VEGF than CHO-derived VEGF. In vitro studies suggest that E. coli-derived VEGF binds heparin with higher affinity than
CHO-derived VEGF. Thus, it has been postulated that the difference in
pharmacokinetic behavior between the VEGF produced in different host
cells is related to differences in interactions with endogenous HSPG
(DeGuzman et al., 1997). It is likely that the smaller
depressor effects of E. coli-derived VEGF in the initial
phase of clearance may be because more is associated with its
low-affinity HSPG binding sites rather than its high-affinity
receptors.
One of the most notable findings of the present study is substantially attenuated hemodynamic responses to VEGF as given by infusion versus bolus injection The maximal hypotensive effect was markedly decreased by 50 to 60% in animals receiving intravenous infusion compared with those receiving injection of E. coli-derived VEGF at the same doses. A gradual decrease in MAP was observed at an infusion rate of 1.04 µg/kg/min (total dose, 250 µg/kg), which reached a maximal reduction of approximately 15% at the end of the infusion. However, no decreases in MAP greater than this were seen with doses up to 5.5 µg/kg/min during 4 hr (total dose, 1320 µg/kg). This contrasts with the hypotensive effect after bolus injection, where the decrease in MAP was dose-dependent and was greater (by 36%) at the highest dose (1320 µg/kg) tested.
Both intravenous infusion and injection of E. coli-derived
VEGF also results in a increase in HR, which was dose-dependent after
infusion but not after injection. In contrast, the decrease in MAP was
dose-depend after injection but not after infusion. Our previous
studies have demonstrated that VEGF-induced tachycardia in conscious
animals may be a reflex response to a decrease in arterial pressure
rather than a direct action on the cardiac pacemaker, because VEGF did
not alter HR in the isolated heart preparation (Yang et al.,
1996). This reflex response to a decrease in arterial pressure is
primarily through the baroreflex which is actually a compensatory
mechanism preventing a further decrease in arterial pressure by
tachycardia and vasoconstriction. It is likely that after infusion of
VEGF, a gradual, smaller decrease in MAP could initiate the
dose-dependent reflex response, thereby inhibiting the further decrease
in MAP at the higher doses. After injection of VEGF, however, a maximal
reflex response to a rapid, larger reduction in MAP was already reached
at the lower dose, so that the depressor response to the higher doses
of VEGF would be increased when the reflex mechanism was limited.
VEGF is also known as vascular permeability factor because of its
ability to promote extravasion (Connolly et al., 1989; Keck et al., 1989) or to increase microvascular permeability
(Senger et al., 1983, 1986). We have previously shown that
VEGF given as a bolus causes reductions in cardiac output and stroke
volume probably because of a decline in venous return caused by
vascular hyperpermeability rather than a direct effect on myocardial
contractility (Yang et al., 1996). The present study
demonstrated that the E. coli-derived VEGF-induced reduction
in stroke volume and cardiac output was substantially attenuated when
given by intravenous infusion compared with injection. Cardiac output
was maximally reduced by 34% after injection, but only 18% after
infusion at the same dose (250 µg/kg). In addition, a sustained
elevation in systemic vascular resistance observed in the later phase
after injection, which may be secondary to a reflex response to a
remarkable decline in cardiac output, was avoided after infusion.
In summary, the hemodynamic effects of E. coli-derived VEGF are basically similar to those of CHO-derived VEGF. The side effects of E. coli-derived VEGF given as a bolus on hemodynamics and cardiac function can be substantially attenuated by infusion, which indicates that infusion, instead of bolus injection, is an appropriate regimen for VEGF administration.
| |
Acknowledgments |
|---|
We are grateful to Lea Berleau for her technical assistance and to Stephen Eppler for pharmacokinetic analyses.
| |
Footnotes |
|---|
Accepted for publication September 12, 1997.
Received for publication May 28, 1997.
Send reprint requests to: Hongkui Jin, M.D., Department of Cardiovascular Research, Genentech, Inc., 460 Point San Bruno Blvd., South San Francisco, CA 94080.
| |
Abbreviations |
|---|
VEGF, vascular endothelial growth factor; CHO, Chinese hamster ovary cell; MAP, mean arterial pressure; HR, heart rate; HSPG, heparan sulfate proteoglycans; ELISA, enzyme-linked immunosorbent assay.
| |
References |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
This article has been cited by other articles:
|
|
 |
|
  J. O. Curwen, H. L. Musgrove, J. Kendrew, G. H.P. Richmond, D. J. Ogilvie, and S. R. Wedge Inhibition of Vascular Endothelial Growth Factor-A Signaling Induces Hypertension: Examining the Effect of Cediranib (Recentin; AZD2171) Treatment on Blood Pressure in Rat and the Use of Concomitant Antihypertensive Therapy Clin. Cancer Res., May 15, 2008; 14(10): 3124 - 3131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Trousdale, S. V. Pollak, J. Klein, L. Lobel, Y. Funahashi, N. Feirt, and J. W. Lustbader Single-Chain Bifunctional Vascular Endothelial Growth Factor (VEGF)-Follicle-Stimulating Hormone (FSH)-C-Terminal Peptide (CTP) Is Superior to the Combination Therapy of Recombinant VEGF plus FSH-CTP in Stimulating Angiogenesis during Ovarian Folliculogenesis Endocrinology, March 1, 2007; 148(3): 1296 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Jin, R. Yang, W. Li, A. K. Ogasawara, R. Schwall, D. A. Eberhard, Z. Zheng, D. Kahn, and N. F. Paoni Early Treatment with Hepatocyte Growth Factor Improves Cardiac Function in Experimental Heart Failure Induced by Myocardial Infarction J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 654 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Li, A. K. Ogasawara, R. Yang, W. Wei, G.-W. He, T. F. Zioncheck, S. Bunting, A. M. de Vos, and H. Jin KDR (VEGF Receptor 2) Is the Major Mediator for the Hypotensive Effect of VEGF Hypertension, June 1, 2002; 39(6): 1095 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-H. Liu, H. Jin, H. S. Floten, Z. Ren, A. P.C. Yim, and G.-W. He Vascular endothelial growth factor-mediated, endothelium-dependent relaxation in human internal mammary artery Ann. Thorac. Surg., March 1, 2002; 73(3): 819 - 824. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Lin, J. LeCouter, J. Kowalski, and N. Ferrara Characterization of Endocrine Gland-derived Vascular Endothelial Growth Factor Signaling in Adrenal Cortex Capillary Endothelial Cells J. Biol. Chem., March 1, 2002; 277(10): 8724 - 8729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Yang, A. K. Ogasawara, T. F. Zioncheck, Z. Ren, G.-W. He, G. G. DeGuzman, N. Pelletier, B.-Q. Shen, S. Bunting, and H. Jin Exaggerated Hypotensive Effect of Vascular Endothelial Growth Factor in Spontaneously Hypertensive Rats Hypertension, March 1, 2002; 39(3): 815 - 820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. LECOUTER, R. LIN, and N. FERRARA The Role of EG-VEGF in the Regulation of Angiogenesis in Endocrine Glands Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 217 - 222. [Abstract] [PDF]
|
|
|
|
|
|
M.-H. Liu, H.-K. Jin, H. S. Floten, Q. Yang, A. P. C. Yim, A. Furnary, T. F. Zioncheck, S. Bunting, and G.-W. He Vascular Endothelial Growth Factor-Mediated Endothelium-Dependent Relaxation Is Blunted in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 473 - 477. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. Jin, R. Yang, T. A. Awad, F. Wang, W. Li, S.-P. Williams, A. Ogasawara, B. Shimada, P. M. Williams, G. de Feo, et al. Effects of Early Angiotensin-Converting Enzyme Inhibition on Cardiac Gene Expression After Acute Myocardial Infarction Circulation, February 6, 2001; 103(5): 736 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. SCALIA, G. BOOTH, and D. J. LEFER Vascular endothelial growth factor attenuates leukocyte–endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide FASEB J, June 1, 1999; 13(9): 1039 - 1046. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
