Maternal plasma vascular endothelial growth factor

concentrations in normal and hypertensive pregnancies

and their relationship to peripheral vascular resistance
Paul M. Bosio, MD,a Timothy Wheeler, DM,c Frederick Anthony, PhD,c Ronan Conroy, BA,b
Colm OHerlihy, MD,a and Peter McKenna, MDa
Dublin, Ireland, and Southampton, United Kingdom
OBJECTIVE: The aim of this study was to measure maternal plasma vascular endothelial growth factor concentrations during normal and hypertensive pregnancies and examine their relationship with maternal total
peripheral resistance values.
STUDY DESIGN: Plasma concentrations of total immunoreactive vascular endothelial growth factor and total
peripheral resistances were measured serially throughout pregnancy in 20 women with preeclampsia, 24
women with gestational hypertension, and 26 normotensive control women. One-way analysis of variance
and a regression model were used to analyze the vascular endothelial growth factor levels in the groups and
the relationship between vascular endothelial growth factor concentration and total peripheral resistance.
RESULTS: At 10 to 14 weeks gestation plasma vascular endothelial growth factor concentrations in all subjects were 4 to 5 times greater than the levels measured post partum (P < .0001). Mean vascular endothelial
growth factor concentrations were similar in the control and gestational hypertension groups; in both groups
levels remained stable until 34 to 36 weeks gestation, when levels increased a further 1.3-fold (P < .01).
In comparison, vascular endothelial growth factor concentrations in subjects in the preeclampsia group were
greater at 28 to 32 weeks gestation (P = .002) and at 34 to 36 weeks gestation (P < .001). Vascular endothelial growth factor concentrations were also increased during the 4 weeks that preceded the diagnosis of
preeclampsia (P < .05). Vascular endothelial growth factor concentrations were associated with the elevated
total peripheral resistance observed during the clinical disorder in the preeclampsia group but not in the
other groups.
CONCLUSION: Maternal plasma vascular endothelial growth factor concentrations increased before the clinical onset of preeclampsia and were further elevated during the vasoconstricted state observed in this disorder. We speculate that the hyperdynamic circulation that characterizes the latent phase of preeclampsia
causes vascular shear stress, which in turn increases the levels of circulating vascular endothelial growth
factor. Because vascular endothelial growth factor normally acts as a vasodilator, its increase may represent
an unsuccessful vascular rescue response. (Am J Obstet Gynecol 2001;184:146-52.)

Key words: Hypertensive pregnancy, peripheral resistance, preeclampsia, vascular endothelial

growth factor

Preeclampsia continues to be one of the leading

causes of maternal death and a major contributor to
both maternal and fetal morbidity. Dysfunction of the
vascular endothelium is now thought to be the primary
event that explains the variable expression of this disor-

From the Rotunda Hospital,a the Department of Epidemiology, Royal

College of Surgeons in Ireland,b and the Department of Obstetrics and
Gynaecology, University of Southampton.c
Supported by The Health Research Board of Ireland.
Received for publication November 22, 1999; revised March 16, 2000;
accepted April 28, 2000.
Reprint requests: Timothy Wheeler, DM, Department of Obstetrics and
Gynaecology, University of Southampton, Princess Anne Hospital, Coxford Rd, Southampton, United Kingdom SO16 5YA.
Copyright 2001 by Mosby, Inc.
0002-9378/2001 $35.00 + 0 6/1/108342
doi:10.1067/mob.2001.108342

146

der. This view is based on morphologic evidence of

glomerular endotheliosis and biochemical evidence of
endothelial activation or damage, including elevated levels of von Willebrand factor, fibronectin, and thrombomodulin.1 In addition, altered endothelial production of
such vasoactive substances as prostacyclin, nitric oxide,
and endothelin has been implicated in the abnormal hemodynamics associated with the disorder.2 The cause of
the endothelial damage is unknown. A number of mechanisms have been proposed; these include placental debris, immunologic maladaptation, oxidative stress, and
shear stress.3
Vascular endothelial growth factor (VEGF) is a powerful cytokine, with receptors almost exclusively on the endothelium, where it promotes cell replication, permeability, and nitric oxide production.4 It is likely to play an

Volume 184, Number 2

Am J Obstet Gynecol

important role in the development, control, and repair of

the vascular system.5 Several studies have shown that
VEGF concentrations are increased in the plasma or
serum of women with preeclampsia.6, 7 The origin of the
VEGF and the reasons for its increase in preeclampsia are
not known.
We recently described how the maternal cardiovascular
system changes during preeclampsia and postulated that
shear stress may promote the vasoconstricted state characteristic of the clinical condition.8 In this article we present longitudinal data that show for the first time how maternal plasma VEGF concentrations change in normal
pregnancies and in pregnancies complicated by hypertension and preeclampsia and how these concentrations
correlate with the changes in peripheral resistance associated with preeclampsia.
Material and methods
The Rotunda Hospital, Dublin, Ireland, is a tertiary referral maternity hospital with approximately 6500 deliveries per year. The 70 subjects in this study were selected
from a group of 400 healthy normotensive primigravid
women recruited from the antenatal clinic at 10 to 14
weeks gestation and followed up during the course of
pregnancy as part of a larger study that investigated the
hemodynamics of preeclampsia.8 Of the original cohort
of 400 women, 20 subsequently had preeclampsia and 24
had gestational hypertension. These women, together
with a matched control group of 26 normotensive women
with normal obstetric outcomes, form the basis of this article. The frequency of body mass index in the control
group was matched with those in the hypertensive groups
to allow for the influence of body mass on maternal
serum VEGF concentration.9 Hypertension was considered to be a single diastolic blood pressure reading of
110 mm Hg or a minimum of two consecutive (>4 hours
apart) diastolic blood pressure readings of 90 mm Hg.
Significant proteinuria was defined as a 24-hour total urinary protein excretion of 300 mg. The presence of both
hypertension and significant proteinuria was required for
a diagnosis of preeclampsia, whereas patients with hypertension alone in the absence of significant proteinuria at
any time were considered to have gestational hypertension.10
All 70 women had hemodynamic monitoring and
blood samples taken at 10 to 14 weeks gestation, 20 to 24
weeks gestation, 28 to 32 weeks gestation, 34 to 36
weeks gestation, and 37 weeks gestation, unless earlier
delivery had taken place, and at 6 to 8 weeks post partum.
The investigator (Paul M. Bosio) was unaware of previous
hemodynamic measurements and the presence or absence of proteinuria at each monitoring session. Hemodynamic measurements were made with the patient in a
semirecumbent left lateral position after the blood pressure and heart rate were stable. Blood pressure was mea-

Bosio et al 147

sured with a mercury sphygmomanometer according to

recommended practice,11 and heart rate was recorded
from a simultaneous 3-lead electrocardiogram. Echocardiography was performed with an ATL HDI3000 ultrasonographic system (ATL Ultrasound, Bothell, Wash)
with a dedicated cardiology computation package and independent continuous-wave Doppler transducer. Total
peripheral resistance was calculated from the cardiac output and mean arterial pressure measurements.8 Both hemodynamic monitoring and blood sample collection
were performed before any therapeutic intervention in
the case of patients with hypertension.
Venous blood samples were collected with a 3.13%
sodium citrate 10% [vol/vol] Monovette (Sarstedt Ltd,
Wexford, Ireland) system. Each sample was centrifuged
at 2000g for 20 minutes at 4C within 30 minutes of collection. Aliquots of plasma were snap frozen and stored
at 70C. The plasma samples were transferred by air on
dry ice (at 40C) to the University of Southampton,
where the measurements of plasma VEGF concentration
were made. The investigators in Southampton (Timothy
Wheeler and Frederick Anthony) were blinded to the
clinical outcomes. Levels of VEGF in the plasma samples
were measured with a direct competitive radioimmunoassay, developed by Anthony et al,12 that is capable
of detecting both bound and free (total immunoreactive) VEGF. Briefly, recombinant human VEGF165 was labeled with iodine 125 to act as tracer, and known quantities of unlabeled VEGF were used to construct a standard
curve. Standard preparations, control preparations, and
unknown plasma samples were incubated overnight with
tracer and rabbit polyclonal antiserum to VEGF. After a
30-minute incubation with donkey antirabbit antibody
coated cellulose suspension, the mixture was suspended
in 1 mL distilled water and centrifuged. After decantation the radioactivity of the pellets was measured by a
gamma counter and analyzed by computer. The interassay coefficient of variation for the VEGF assay for the period during which the samples were measured was 5.3%
for a pregnancy plasma sample of mean concentration of
3.26 g/L. The sensitivity of the assay was 0.1 g/L.
Descriptive data are presented as means and 95% confidence intervals, except for gestational age at delivery,
which was not normally distributed and for which the median and an interpolated binomial 95% confidence interval are reported. One-way analysis of variance followed by
a Scheff post hoc test was used to compare each hypertensive group with the control group. Mean values of
VEGF at each period of gestation were calculated, and
the differences in means for the preeclampsia and gestational hypertension groups versus the control group were
calculated with the Tukey wholly significant difference
method.13 Total peripheral resistance was analyzed by
means of multinomial logistic regression, as described in
our original article.8 All regression analyses were cross-

148 Bosio et al

January 2001
Am J Obstet Gynecol

Table I. Patient characteristics according to study group

Control (n = 26)

Age (y)
Weight* (kg)
Height* (m)
Body mass index* (kg/m2)
Hemoglobin level* (g/dL)
Hematocrit*
Hematocrit at 37 wk
Median gestational age at delivery (wk)
Birth weight (kg)

Gestational hypertension (n = 24)

Preeclampsia (n = 20)

Mean

95%
Confidence interval

Mean

95%
Confidence interval

Mean

95%
Confidence interval

23.7
68.2
1.62
26
12.3
36%
35%
40
3.65

21.9-25.5
62.8-73.7
1.59-1.64
24.3-27.6
11.9-12.6
34%-37%
32%-36%
39.5-40.6
3.49-3.80

27.9
72.5
1.61
27.9
12.6
37%
35%
39.6
3.55

25.8-29.9
67.5-77.4
1.60-1.62
26.0-29.8
12.2-13.0
35%-38%
33%-37%
39.3-40.1
3.30-3.78

24.4
70.4
1.63
26.6
12.5
36%
36%
36.4
2.69

22.6-26.2
63.5-77.2
1.61-1.68
24.2-28.9
12.1-13.0
34%-38%
33%-38%
35.1-37.8
2.48-3.26

* Measurements at 10 to 14 weeks gestation.

checked with Statas robust regression procedure (Stata

Corporation, College Station, Tex) to verify that substantive conclusions were not altered by outlying values.14
Results
Clinical characteristics of the 3 groups are shown in
Table I. There were no significant differences between
the groups in hemoglobin concentration at first examination (P = .41), hematocrit at first examination (P = .50),
or hematocrit at 37 weeks gestation (P = .47). Women
with gestational hypertension were older than women in
the control (P = .01) and preeclampsia (P = .07) groups.
The mean birth weights and gestational ages of the babies
born to the subjects in the gestational hypertension and
control groups were not significantly different from each
other; as expected, women in the preeclampsia group
were delivered sooner, and their babies were lighter. The
mean diastolic blood pressures at diagnosis were 114 mm
Hg (95% confidence interval, 110-119 mm Hg) in the
preeclampsia group and 103 mm Hg (95% confidence interval, 99-108 mm Hg) in the gestational hypertension
group. The preeclampsia group had a mean urinary protein excretion of 1.6 g/24 h (95% confidence interval,
1.1-2.1 g/24 h).
Mean levels of VEGF throughout pregnancy were
higher than postpartum levels for all subjects (P < .0001;
Fig 1; Table II). The trends in the mean VEGF concentrations were similar between the control and gestational hypertension groups, with stable levels until 34 to 36 weeks
gestation, when the levels were significantly increased
(P < .01; Fig 1; Table II). By 28 to 32 weeks gestation and
thereafter the mean VEGF concentrations in the women
who had preeclampsia were significantly higher than the
levels in the control and gestational hypertension groups
(Fig 1; Table II). Adjustment for hematocrit, which was
possible at 10 to 14 weeks gestation and 37 weeks gestation, had no effect on these associations. At 28 to 32
weeks gestation mean VEGF concentrations were 10.2
g/L for the 4 patients with clinical evidence of preeclampsia, 5.9 g/L for the 16 patients who subsequently

had preeclampsia, and 3.8 g/L for the control and gestational hypertension groups. At 34 to 36 weeks gestation
the mean VEGF concentrations were 11.8 g/L for the 11
women with clinically confirmed preeclampsia, 8.5 g/L
for the 7 women who subsequently had preeclampsia,
and 5.1 g/L for the control and gestational hypertension groups. Both at 28 to 32 weeks gestation and at 34 to
36 weeks gestation, Scheff post hoc tests showed that
the women with preclinical preeclampsia had VEGF values that were significantly higher than those in the control and gestational hypertension groups and significantly lower than those in the clinical preeclampsia
group (all P < .05). At 6 to 8 weeks post partum the mean
VEGF level in all groups had fallen to between 0.83 and
0.91 g/L, with no significant differences between
groups.
The total peripheral resistance measurements in the
three groups of subjects are shown in Fig 1. Total peripheral resistance was elevated in the preeclampsia cohort as
a whole from 34 weeks gestation onward relative to the
total peripheral resistances in both the control and gestational hypertension cohorts (P < .001). Further analysis of
the preeclampsia group at 28 to 32 weeks gestation and
34 to 36 weeks gestation showed that mean total peripheral resistance was elevated only in those subjects who
had already had preeclampsia (P < .001). In contrast,
women with gestational hypertension had normal total
peripheral resistances recorded during much of the pregnancy except close to term, when lower total peripheral
resistances were noted (P < .001). There were no significant differences in total peripheral resistance between
the groups at 6 to 8 weeks post partum.
No relationship was found between plasma VEGF concentration and total peripheral resistance in either the
control group or the gestational hypertension group.
There was no correlation between VEGF concentration
and total peripheral resistance before the clinical diagnosis of preeclampsia. Although all subjects with clinically
diagnosed preeclampsia had elevated VEGF concentrations, only some were found to have raised total periph-

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Am J Obstet Gynecol

Fig 1. Mean total peripheral resistances (A) and levels of VEGF (B) throughout pregnancy and 6 to 8 weeks post partum in normotensive control group (Norm; open squares), gestational hypertension group (GH; filled squares), and preeclampsia group (PET; filled diamonds).

Table II. Levels of VEGF for normotensive (control) group and differences for preeclampsia and gestational
hypertension groups according to gestational age
Preeclampsia,
difference from normotensive (g/L)
Gestational age (wk)

Normotensive mean (g/L)

Mean

10-14
20-24
28-32
34-36
37
Post partum

3.9
4.2
3.9
5.1
5.8
0.83

0.2
0.5
2.8
5.5
4.3
0.04

eral resistance at the time of blood sampling (Fig 2).

At 37 weeks gestation, however, when all subjects in the
preeclampsia group had clinically diagnosed preeclampsia and significantly elevated total peripheral resistance
(Fig 3), there was a positive and significant correlation
between VEGF concentration and total peripheral resistance (0.15 g/L increase in VEGF for a 100 dyne sec
cm5 increase in total peripheral resistance; P = .001). Maternal cardiac output and plasma VEGF concentration
were not correlated at any time point in any of the 3
groups of subjects.
Comment
This article reports the first longitudinal study of maternal plasma VEGF concentrations during pregnancy.
VEGF concentrations were significantly greater than nonpregnant levels, as has previously been reported.12 Our
earlier study9 showed that maternal serum VEGF concentration increases during the first 10 weeks of pregnancy;
this study shows that thereafter VEGF concentration remains elevated until the last trimester, when a further significant increase occurs in both normal and hypertensive
pregnancies. During the third trimester the increase in

95% Confidence interval

1.5 to 1.1
0.9 to 2.0
1.5 to 4.2
3.6 to 7.5
2.9 to 5.6
0.13 to 0.21

Gestational hypertension,
difference from normotensive (g/L)
Mean

95% Confidence interval

0.1
0.2
0.2
0.004
0.6
0.08

1.4 to 1.2
1.7 to 1.3
1.7 to 1.3
1.9 to 1.9
0.6 to 1.9
0.15 to 0.3

plasma VEGF concentration was significantly greater in

the women with preeclampsia. The elevated VEGF levels
in women with preeclampsia are unlikely to be explained
by hemoconcentration, because there were no significant
differences between the hematocrits of the 3 groups at
37 weeks gestation (Table I). Our data also show that
women who have preeclampsia show a significant increase in VEGF concentration at some point during the
preceding 4 weeks. The blood sampling frequency in our
study did not allow more precise timing. In addition, the
increase in VEGF concentration predated the hemodynamic crossover seen in women with preeclampsia, and
in the presence of this circulatory crossover there was a
positive association between plasma VEGF concentration
and total peripheral resistance.
The increase in maternal plasma VEGF during early
pregnancy may be related to a number of the functions of
this substance. First, VEGF is an angiogenic growth factor; raised levels may therefore reflect the development
of new blood vessels in the endometrium and trophoblast
in response to the increased metabolic requirements.15
Second, the production of VEGF by vascular smooth muscle cells in the systemic circulation may be increased in

150 Bosio et al

January 2001
Am J Obstet Gynecol

Fig 2. Data from 28 weeks gestation onward for all 20 subjects with preeclampsia (18 subjects appear more than once).
Filled circles, After diagnosis of preeclampsia; open circles, before diagnosis of preeclampsia.

Fig 3. Regression slopes (solid lines) showing relationships at 37 weeks gestation between VEGF and total peripheral
resistance in subjects with preeclampsia (crosses; all clinically diagnosed cases of preeclampsia with elevated total peripheral resistance) and subjects without preeclampsia (open circles). Lengths of regression lines correspond to range of
data.

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Am J Obstet Gynecol

response to estrogen.16 In this way VEGF, perhaps acting

through nitric oxide,5 may be involved in the initiation of
the systemic vasodilatation that characterizes early pregnancy.
VEGF concentrations in the women who had preeclampsia were not different from the levels found in
other women during the first half of pregnancy. This finding suggests that VEGF does not play a role in the early
pathogenesis of the disorder. The source of the raised
VEGF concentrations found in later pregnancy remains
uncertain. One possibility is that the VEGF originates
from the placenta and that its production there is upregulated in response to local ischemia; hypoxia is known
to up-regulate VEGF production,17 and areas of infarction are a feature of the placenta in preeclampsia. However, Cooper et al18 did not find evidence of an increase
in messenger ribonucleic acid for VEGF in the placentas
of women with preeclampsia. Alternatively, the raised
VEGF concentrations found in preeclampsia may be related to the endothelial damage associated with the condition. Damaged vascular endothelium has recently been
shown to have increased VEGF production, possibly as a
mechanism of endothelial repair.5 In addition, increased
circulating VEGF may contribute to the extravasation of
plasma proteins and proteinuria4 characteristic of the
clinical condition.
The possibility that VEGF may play a cytoprotective
role through nitric oxide production19 makes its association with total peripheral resistance in preeclampsia intriguing. Our data suggest that the development of preeclampsia is characterized by a phase in which VEGF
production increases above levels seen in normotensive
women or women with gestational hypertension. Because
VEGF has a vasodilatory effect on isolated resistance vessels,20 it appears paradoxic that VEGF concentration
should be increased in preeclampsia when endotheliumdependent dilatation is reduced.21 We recently proposed
that the hyperdynamic circulation that characterizes the
preclinical phase of preeclampsia exacerbates a preexisting endothelial defect and that this ultimately triggers the
circulatory crossover from a circulation characterized by
high cardiac output and low resistance to the damaging
vasoconstricted state.8 The possibility of such a vascular
defect has been highlighted by a recent study in which
flow-mediated dilatation (a local vascular response operating through the endothelium) was found to be reduced
in women who previously had preeclampsia.22 Thus the
raised VEGF concentration found in preeclampsia may
reflect an unsuccessful vasodilatory rescue mechanism
triggered by increased circulatory shear stress.
Finally, VEGF induces matrix metalloproteinase production in endothelial cells,23 and recent work suggests
that matrix metalloproteinases induce endothelin cleavage to yield a potent vasoconstrictor.24 The reduction in
endothelium-dependent relaxation known to occur in

women with preeclampsia has recently been shown to be

significantly altered by incubation with antibody to
VEGF.25 Therefore it may be that under certain conditions VEGF could play a vasoconstrictive role by acting
through matrix metalloproteinases and endothelin. This
would imply that the raised VEGF production in preeclampsia not only is unsuccessful as a rescue mechanism
but actually may contribute to the damaging vasoconstricted state associated with the clinical syndrome.
In conclusion, we have shown that raised plasma VEGF
levels precede the clinical onset of preeclampsia and subsequently show a positive association with the elevated peripheral resistance observed during the clinical course of
that disorder. VEGF may therefore play an important role
in the pathogenesis of the disorder. This speculation is reinforced by the normal VEGF levels recorded in association with gestational hypertension, because patients with
gestational hypertension do not exhibit the vasoconstricted state seen in preeclampsia and almost invariably
have good obstetric outcomes.
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