American Journal of Obstetrics and Gynecology (2004) 190, 1541e50

www.elsevier.com/locate/ajog

Evidence supporting a role for blockade of the vascular

endothelial growth factor system in the pathophysiology
of preeclampsia
Young Investigator Award
Tinnakorn Chaiworapongsa,a,b Roberto Romero,a,* Jimmy Espinoza,a
Emmanuel Bujold,b Yeon Mee Kim,a Luis F. Goncxalves,a,b
Ricardo Gomez,c Samuel Edwina

Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Mda; Department of Obstetrics and Gynecology,
Wayne State University/Hutzel Hospital, Detroit, Michb; CEDIP, Department of Obstetrics and Gynecology, Sotero
del Rio Hospital, Puente Alto, Chilec

––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
KEY WORDS Objective: Soluble vascular endothelial growth factor receptor 1 (sVEGFR-1), which antagonizes
Preeclampsia VEGF functions, has been implicated in the pathophysiology of preeclampsia. The purpose of this
Soluble vascular study was to determine whether preeclampsia is associated with a change in the plasma concentra-
endothelial growth tion of sVEGFR-1, and, if so, whether such a change is correlated with the severity of the disease.
factor receptor 1 Methods: A cross-sectional study was conducted to determine the concentrations of sVEGFR-1 in
Early-onset preeclampsia plasma obtained from normal pregnant women (n = 61) and patients with preeclampsia (n = 61).
Vascular endothelial Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay.
growth factor Results: Preeclampsia had a higher median plasma concentration of sVEGFR-1 than normal
pregnancy (P ! .001). The median plasma concentration of sVEGFR-1 was higher in early-onset
(%34 weeks) than late-onset (>34 weeks) preeclampsia (P = .005), and higher in severe than in
mild preeclampsia (P = .002). In normal pregnancy, there was a correlation between plasma con-
centration of sVEGFR-1 and gestational age (r = 0.5; P ! .001). In contrast, there was a negative
correlation between plasma concentration of sVEGFR-1 and gestational age at the onset of pre-
eclampsia (r = e0.5; P ! .001).
Conclusion: Preeclampsia is associated with an increased plasma sVEGFR-1 concentration. The ele-
vation of sVEGFR-1 concentration is correlated with the severity of the disease. These observations
suggest the participation of VEGF and its soluble receptor in the pathophysiology of preeclampsia.
Ó 2004 Elsevier Inc. All rights reserved.
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Presented at the 70th Annual Meeting of the Central Association of Preeclampsia, a syndrome diagnosed by the presence
Obstetricians and Gynecologists, October 1-4, 2003, LaJolla, Calif. of hypertension and proteinuria, is thought to be due to
Young Investigator’s Award endothelial cell dysfunction.1,2 The mechanisms respon-
* Reprint requests: Roberto Romero, MD, Perinatology Research
Branch, NICHD, NIH, DHHS Wayne State University/Hutzel Hos-
sible for the development of endothelial dysfunction in
pital, Department OB/GYN, 4707 St Antoine Blvd, Detroit, MI 48201. this disorder remain unclear. Some investigators have
E-mail: warfiela@mail.nih.gov proposed that placental factors, such as cytokines,3

0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajog.2004.03.043
1542
growth factors,4 and placental debris,5 released into the
maternal circulation result in intravascular inflamma-
tion,6 leukocyte activation,7 and endothelial cell dys-
function.2 However, the precise nature of these ‘‘toxic
factors’’ is still not defined.
Vascular endothelial growth factor (VEGF) is a di-
meric glycoprotein with potent angiogenic properties.
The function of VEGF is to promote endothelial cell
proliferation, migration,8 and survival.9 VEGF exerts
its biologic effect through 2 high-affinity receptor tyro-
sine kinases: VEGFR-1 (VEGF receptor-1 or flt-1)
and VEGFR-2 (or KDR/Flk-1). VEGFR-1 has 2 iso-
forms: (1) a transmembranous isoform and (2) a soluble
isoform. The latter is generated by a splice variant of the
VEGFR-1 gene and contains the extracellular ligand-
binding domain, although lacking the signaling tyrosine
kinase domain. Thus, this isoform binds VEGF and
inhibits its biologic activities.8 Another ligand for
VEGFR-1 is placental growth factor (PlGF), whose
function is to potentiate the angiogenic response
of VEGF. It is generally agreed that VEGFR-2 is the
major mediator of the mitogenic, angiogenic, permeabil-
ity-enhancing,8 and endothelial survival9 effects of
VEGF, whereas the precise function of VEGFR-1 is still
the subject of debate.8 Most investigators believe that
VEGFR-1 may not primarily be a receptor transmitting
a mitogenic signal, but rather a ‘‘decoy’’ receptor able to
inhibit the activity of VEGF on vascular endothelium by
preventing binding of VEGF to VEGFR-2.8
Accumulating evidence suggests that the balance be-
tween VEGF, PlGF, and their receptors is important
for effective vasculogenesis, angiogenesis, and placental
development during pregnancy. Indeed, a role for block-
ade of VEGF action in the pathophysiology of pre-
eclampsia has been suggested recently by several
studies in both animals and humans. Administration
of anti-VEGF compounds can induce hypertension
and proteinuria in nonpregnant animals10,11 and hu-
mans enrolled in antiangiogenic trials.12 Moreover,
administration of sVEGFR-1 to pregnant animals has
been shown to induce the clinical features of preeclamp-
sia, including hypertension, proteinuria, and glomerular
endotheliosis.13
The purpose of this study was to determine whether
preeclampsia was associated with a change in the plasma
concentration of sVEGF-R1, and whether this change is
correlated with the severity of the disease.
Patients and methods
Study design
A cross-sectional study was conducted by searching our
clinical database and bank of biologic samples. This
study included patients with preeclampsia (n = 61) and
Chaiworapongsa et al
normal pregnancies (n = 61). Preeclampsia was defined
as hypertension (systolic blood pressure R 140 mm
Hg or diastolic blood pressure R 90 mm Hg on at least
2 occasions, 4 hours to 1 week apart) and proteinuria
(R300 mg in a 24-hour urine collection or 1 dipstick
measurement R2C).14 Patients with preeclampsia were
subclassified as either early-onset (%34 weeks of gesta-
tion) or late-onset (>34 weeks) disease, according to
gestational age when preeclampsia developed. Severe
preeclampsia was defined as either severe hypertension
(diastolic blood pressure R110 mm Hg) and protein-
uria, or mild hypertension and severe proteinuria (a
24-hour urine sample containing 3.5 g protein or urine
specimen R3C protein by dipstick measurement).14 Pa-
tients with normal pregnancies were matched for gesta-
tional age (within 2 weeks) with preeclamptic patients if
they met the following criteria: (1) no medical, obstetric,
or surgical complications and (2) delivery of a normal
term (R37 weeks) infant whose birth weight was more
than 2500 g. All women provided written informed con-
sent before the collection of plasma samples. All samples
were collected between May 1999 and January 2003.
The collection and use of the samples was approved
by the Human Investigation Committee of the Sotero
del Rio Hospital, Santiago, Chile (an affiliate of the
Catholic University of Santiago), and approved for re-
search purposes by the Institutional Review Board of
the National Institute of Child Health and Human De-
velopment.
Sample collection and human sVEGFR-1
immunoassay
Venipuncture was performed and blood collected into
tubes containing EDTA. The samples were centrifuged
and stored at
70(C. The concentrations of sVEGFR-
1 were measured with the use of enzyme-linked immuno-
assay (ELISA; R&D Systems, Minneapolis, Minn). This
assay uses the quantitative sandwich immunoassay tech-
nique. Briefly, recombinant human VEGFR-1 standards
and maternal plasma specimens were incubated in dupli-
cate wells of the microtiter plates precoated with mono-
clonal antibodies specific for VEGFR-1. During this
incubation, the immobilized antibodies in the microtiter
plate bound VEGFR-1 that was present in the standards
and samples. After washing unbound substances, poly-
clonal antibodies to human VEGFR-1 conjugated to
an enzyme (horseradish peroxidase) were added to the
assay wells. After an incubation period, the assay plates
were washed to remove unbound antibody-enzyme re-
agent. With the addition of a substrate solution (tetra-
methylbenzidine), color developed in the assay plates
proportionally to the amount of VEGFR-1 bound in
the initial step. The microtiter plates were read with
a programmable spectrophotometer (Ceres 900 Micro-
plate Workstation, Bio-Tek Instruments, Winooski,
Chaiworapongsa et al 1543

Table I Clinical characteristics of the study population

Normal pregnancy (n = 61) Preeclampsia (n = 61) P
Age (y) 29 (18-43) 24 (16-44) .06
Nulliparity 17 (28%) 37 (61%) .001*
Smoking 12 (20%) 3 (5%) .03*
Weight (kg) y 59 (42-83) 59 (42-110) .5
Body mass index (Kg/m2) z 23.9 (17.8-32.8) 24.1 (18.2-38.9) .6
GA at blood sampling (wks) 36 (26-41) 37 (26-41) .9
GA at delivery (wks) 39 (37-41) 37 (27-41) !.001*
Birth weight (g) 3,400 (2,650-4,580) 2,570 (880-4,280) .001*
Adjusted birth weight for GA (MOM) 0.02 (-0.2 -0.3)
0.1 (
0.4 -0.5) .001*
Female fetus 31 (51%) 28 (46%) .6
Interval from blood sampling to delivery (d) 23 (0-105) 0 (0-9) .001*
Value expressed as median (range) or number (percent).
GA, Gestational age; MOM, multiple of the median.
* Statistically significant, P ! .05.
y
Normal pregnancy n = 59; preeclampsia n = 60.
z
Normal pregnancy n = 59; preeclampsia n = 59.

Vt). The inter- and intra-assay coefficients of variation

Table II Clinical characteristics of patients with preeclamp-
(CVs) were 4.8% and 6.9%, respectively. The sensitivity sia
was 17.8 pg/mL.
Blood pressure (mm Hg)
Statistical analysis Systolic 150 (140-210)
Diastolic 100 (90-130)
Kolmogorov-Smirnov tests were used to test for normal Mean arterial pressure 117 (106-156)
distribution of the data. Mann-Whitney U tests were Urine protein (C dipstick) 3 (2-4)
used to determine the differences of the median between Aspartate aminotransferase* (SGOT) (U/L) 22 (10-172)
groups. The c2 and Fisher exact tests were used for com- Platelet county (!103) (m/L) 208 (78-309)
parisons of proportions. Spearman rank correlation was Birth weight !10th percentile 13 (21%)
used to assess the correlations between 2 continuous Severe preeclampsia 46 (75%)
variables. Significance was assumed for a P value of Chronic hypertension or renal disease 5 (8%)
!.05. Power analysis indicated that a sample of 61 con- History of preeclampsia 3 (5%)
trols and 61 cases would have a power over 95% with an Value expressed as median (range) or number (percent).
alpha .05 (2-tails) for the detection of a mean difference * n = 32;
y
n = 51.
of 7406 pg/mL in the plasma concentrations of
sVEGFR-1 between the 2 groups. The effect size was es-
timated from previous observations.15
patients were categorized as having either early- or late-
onset preeclampsia (less than or more than 34 weeks),
Results and either preterm or term preeclampsia (less than or
more than 37 weeks of gestation), the results were similar
There were no significant differences in maternal age, (Table III). The median plasma concentration of
maternal weight, body mass index, and gestational age sVEGFR-1 was significantly higher in early-onset (%34
at blood sampling between the 2 groups (Table I). Clin- weeks) than late-onset (>34 weeks) (P = .005), and sig-
ical characteristics of patients with preeclampsia are dis- nificantly higher in preterm (!37 weeks) than term (R37
played in Table II. Among preeclamptic patients, 46 weeks) preeclampsia (P ! .001; Figure 1). Patients with
(75%) were categorized as having severe preeclampsia. severe preeclampsia had a significantly higher median
Four patients had a history of chronic hypertension, 1 plasma concentration of sVEGFR-1 than those with
had renal disease, and none had diabetes before preg- mild preeclampsia (P = .002; Figure 2, B and C). Among
nancy. patients with preeclampsia, there was a positive correla-
Patients with preeclampsia had a median plasma con- tion between the plasma concentration of sVEGFR-1
centration of sVEGFR-1 higher than women with nor- and the degree of proteinuria (r = 0.4; P = .002), and
mal pregnancy (preeclampsia: median 5,063 pg/mL, a negative correlation between plasma concentration of
range 816-28,500 pg/mL vs normal pregnancy: median sVEGFR-1 and the platelet count (r = e0.3; P = .04),
1,375 pg/mL, range 372-6,908 pg/mL; P ! .001). When neonatal birth weight (r = e0.6; P ! .001), adjusted
1544 Chaiworapongsa et al

Figure 1 Plasma sVEGFR-1 concentrations in patients with preeclampsia. The median plasma concentration of sVEGFR-1 was
significantly higher in early-onset (%34 weeks) than late-onset (>34 weeks) (P = .005), and significantly higher in preterm (!37
weeks) than term (R37 weeks) preeclampsia (P ! .001). For median (range) values, see Table II.

Table III Plasma sVEGFR-1 in patients with preeclampsia and normal pregnant women categorized as either less than or more than 34
weeks, and either less than or more than 37 weeks of gestation
sVEGFR-1 (pg/mL)
Gestational age Normal pregnancy Preeclampsia P
!34 wks 763 (372-1,776) 7,732 (816-28,500) .001
n = 15 n = 15
O34 wks 1,539 (561-6,909) 4,147 (1,157-11,750) !.001
n = 46 n = 46
!37 wks 1,063 (372-2,252) 7,103 (816-28,500) !.001
n = 35 n = 29
O37 wks 1,763 (639-6,909) 3,605 (1,157-11,750) !.001
n = 26 n = 32

neonatal birth weight for gestational age (r = e0.4;
P ! .001), as well as gestational age at
delivery (r = e0.5; P ! .001). There were no significant
differences in the median plasma concentration of
sVEGFR-1 between nulliparous and parous women
(P = .5) or between patients with and without underly-
ing chronic hypertension (P = .4). Patients with a prior
history of preeclampsia had a median plasma
sVEGFR-1 concentration significantly higher than those
without such a history (P = .01). Among normal preg-
nant women, there was a positive correlation between
plasma concentrations of sVEGFR-1 and advancing ges-
tational age (r = 0.5; P ! .001; Figure 2, A). In contrast,
there was a negative correlation between plasma concen-
trations of sVEGFR-1 and gestational age at the onset of
preeclampsia (r = e0.5; P ! .001; Figure 2, B).
With the use of the analysis of covariance and adjust-
ing for antihypertensive drugs, steroids, magnesium sul-
fate, labor status, epidural analgesia, parity status,
storage time, and gestational age at blood sampling,
the results were similar and remained significant
(P = .008). Plasma sVEGF-R1 concentration in pre-
eclampsia was significantly higher than in normal preg-
nant women, even after exclusion of 5 patients who had
chronic hypertension or renal disease (P ! .001). There
was no difference in median plasma sVEGFR-1 concen-
tration between nulliparous and parous women in either
the control group or in patients with preeclampsia
(P = .5 for each comparison).
Comment
Our results indicate that women with preeclampsia have
a higher plasma concentration of sVEGFR-1 than nor-
mal pregnant women. Moreover, the magnitude of the
increase was much higher in early-onset or preterm than
in late-onset or term preeclampsia. The increased
plasma concentration of sVEGFR-1 in preeclampsia
was associated with the severity of the disease.
Our findings are consistent with previous studies of
Maynard et al13 and Koga et al,15 who found elevated
Chaiworapongsa et al 1545

Figure 2 A, Plasma sVEGFR-1 concentrations in relation to gestational age in patients with preeclampsia and normal pregnancy.
Among normal pregnant women, there was a positive correlation between plasma concentration of sVEGFR-1 and advancing
gestational age from 26 to 41 weeks of gestation (r = 0.5; P ! .001). B, In contrast, there was a negative correlation between plasma
concentration of sVEGFR-1 and gestational age at the onset of preeclampsia (r = e0.5; P ! .001). Please note the difference of the
scales on the y-axis between A and B. C, Patients with severe preeclampsia had a significantly higher median plasma concentration
of sVEGFR-1 than patients with mild preeclampsia (severe: median 6,060 pg/mL, range 1,157-28,500 pg/mL vs mild: median 3,353
pg/mL, range 816-8,076 pg/mL; P = .002). Severe preeclampsia: circles, mild preeclampsia: squares, and normal pregnancy:
triangles.

plasma concentrations of sVEGFR-1 in patients with
preeclampsia at the time of diagnosis. However, our
study extends their observations by examining the rela-
tionship of plasma sVEGFR-1 concentrations and the
severity of preeclampsia. This is demonstrated by the
significant correlation between the concentrations of
this soluble receptor and the degree of proteinuria, ma-
ternal platelet count, unadjusted and adjusted neonatal
birth weight for gestational age, gestational age at de-
livery, the clinical criteria for the classification of the
disease, and gestational age at which the disease was
diagnosed.
What is the significance of this finding? sVEGFR-1
has a higher affinity for VEGF than VEGFR-2, and
thus the increased plasma concentration of sVEGFR-1
in preeclampsia could lead to reduced availability of free
VEGF to bind VEGFR-2. This hypothesis is in agree-
ment with the observations that plasma concentration
of free VEGF in preeclampsia is lower than normal
pregnancy.16 Consequently, reduced concentrations of
free VEGF could interfere with endothelial cell function
and survival.9,17
Experimental evidence13 suggests that the serum of
normal pregnant women is capable of inducing endothe-
lial cells to form tube-like structures (an established in vi-
tro assay of angiogenesis), a biologic effect inhibited by
adding sVEGFR-1. Moreover, serum from preeclamptic
patients inhibited endothelial tube formation, and this ef-
fect could be restored by adding VEGF and PlGF. The
inhibiting effect of serum from women with preeclampsia
disappeared after delivery, suggesting that the factor may
be released by the placenta.13 These observations support
1546
the concept that the antiangiogenic properties of serum
from preeclamptic patients may result from the blockade
of VEGF and PlGF by sVEGFR-1.
Our observation that plasma concentrations of
sVEGFR-1 were higher with advancing gestational age
is consistent with the reported increased VEGF concen-
trations (bound and unbound) in normal pregnancy in
a previous study.18 The sVEGFR-1 may thus act as
a natural inhibitor of VEGF during pregnancy to pre-
vent excessive stimulation to endothelial cells.17
A likely source of plasma sVEGFR-1 during preg-
nancy is the placenta. Indeed, plasma concentration of
sVEGFR-1 is higher in normal pregnancy than in
nonpregnant women19 and decreases dramatically after
delivery.15 Moreover, previous studies localized
VEGFR-1 protein and messenger RNA (mRNA) to ex-
travillous trophoblast, syncytiotrophoblast, and villous
cytotrophoblast in normal pregnancy.20,21 Clark et al22
demonstrated that both VEGFR-1 isoforms were de-
tectable in the placenta, and that sVEGFR-1 protein
could be found in supernatant of explants of the placen-
tal villi. These observations suggest that sVEGFR-1 was
produced by the human placenta and could be released
into the maternal circulation. Indeed, the sVEGFR-1
concentrations in cytotrophoblast-conditioned medium
were higher in patients with preeclampsia than in pa-
tients without this syndrome.23 Furthermore, the
mRNA expression of sVEGFR-1 in the placenta was
higher in preeclampsia than in normal pregnancy.13
An alternative or complementary source of sVEGFR-1
is endothelial cells, as they can release sVEGFR-1 in re-
sponse to specific agents.17 Therefore, the increased
plasma sVEGFR-1 in preeclampsia may be related to
the altered endothelial cell function observed in this con-
dition. However, it would be difficult to reconcile this
hypothesis with the dramatic decrease in plasma
sVEGFR-1 concentration observed in preeclampsia af-
ter delivery (mean 4360 vs 95 pg/mL).15
The mechanisms responsible for the elevation of
sVEGFR-1 in preeclampsia remain to be determined.
The promoter region of the VEGFR-1 gene contains
a hypoxic response element,24 and there is experimental
data suggesting that VEGFR-1 expression on human
umbilical endothelial cells can be upregulated in re-
sponse to hypoxia.24 Indeed, an increased sVEGFR-1
concentration has been observed in the supernatant of
the term villous explants incubated under low oxygen
tension.17 It is possible that an ischemic placenta could
induce expression and release of sVEGFR-1 from
villous trophoblasts, which is in direct contact with ma-
ternal blood in the intervillous space. However, mecha-
nisms other than hypoxia may be involved in this
process. The increased availability of sVEGFR-1 in pre-
eclampsia may counteract the nitric oxide-induced va-
sodilatation effect of VEGF8,25 and result in the
elevation of maternal blood pressure. The teleologic
Chaiworapongsa et al
benefit of the response would be to increase the mater-
nal vascular tone so that uterine perfusion can be sus-
tained. Further studies are required to determine
whether the increase in sVEGFR-1 is specific only to
preeclampsia, as opposed to other obstetric syndromes
as well.
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25. Shen BQ, Lee DY, Zioncheck TF. Vascular endothelial growth clinical findings of preeclampsia.
factor governs endothelial nitric-oxide synthase expression via Chaiworapongsa et al performed a cross-sectional
a KDR/Flk-1 receptor and a protein kinase C signaling pathway. study comparing the concentrations of the soluble forms
J Biol Chem 1999;274:33057-63. of VEGFR-1 in plasma obtained from normotensive
pregnant women (n = 61) and a gestational agee
matched preeclamptic women (n = 61). Similar to previ-
Discussion ous studies,2,3 they found that women with preeclampsia
had higher median plasma concentrations of sVEGFR-1
Dr Baha M. Sibai, Cincinnati, Ohio. The cause and than those with normotensive pregnancies. These values
pathogenesis of preeclampsia have eluded researchers were significantly higher in those with severe disease
for decades. During the past 50 years, a variety of mech- compared with mild disease and in those with early on-
anisms and theories by which certain substances or set 34 weeks or less compared with early-onset pre-
pathways may cause preeclampsia have been suggested eclampsia. On the basis of these results, they suggest
by various investigators, but most of them have not that blockade of the VEGF system may play a role in
withstood the test of time. A popular hypothesis that the pathophysiology of preeclampsia.
is still under consideration suggests that defective pla- This study may be clinically relevant to pregnancies
cental vascular remodeling early in pregnancy with re- that are complicated by preeclampsia, intrauterine fetal
sultant placental ischemia plays a central role in the growth restriction (IUGR) or both. Severe preeclampsia
pathogenesis of preeclampsia.1 and IUGR are diseases of inadequate placentation, and
The mechanism by which placental ischemia leads to both are associated with reduced uteroplacental perfu-
the clinical syndrome of preeclampsia is thought to be sion. It seems reasonable that the placenta in both of
related to the production of placental factors that enter these conditions would increase production of
the maternal circulation resulting in endothelial cell dys- sVEGFR-1 (sFLt-1) in an attempt to compensate for
function.2 Soluble fms-like tyrosine kinase I (sFLt-1) is the reduced perfusion or oxygenation. This increase in
a protein that is produced by the placenta. sFLt-1 acts sFLt-1 will lead to an increase in maternal blood pres-
by binding to the receptor-binding domains of VEGF sure as a fetal rescue mechanism to increase uteroplacen-
and it also binds to PlGF.2 Increased levels of this pro- tal perfusion. I would venture to speculate that
tein in the maternal circulation will result in reduced lev- increased sVEGFR-1 is one of the compensatory