PRENATAL DIAGNOSIS

Prenat Diagn 2009; 29: 464–470.

Published online 25 February 2009 in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/pd.2203

The relationship of the level of circulating antiangiogenic

factors to the clinical manifestations of preeclampsia
Young Nam Kim1,2 , Dae Shim Lee2 , Dae Hoon Jeong1,2 , Moon Su Sung1 and Ki Tae Kim1,2 *
1
Department of Obstetrics and Gynecology, Pusan Paik Hospital, College of Medicine, Inje University, Busan, South Korea
2
Paik Institute for Clinical Research, Pusan Paik Hospital, College of Medicine, Inje University, Busan, South Korea

Objective This study investigated whether the antiangiogenic factors’ concentrations differ according to the
clinical manifestations of preeclampsia.

Methods This study included 62 preeclampsia and compared the soluble fms-like tyrosine kinase-1 (sFlt-
1), soluble endoglin (sEng), and placental growth factor (PlGF) concentrations among patients with different
clinical manifestations of preeclampsia. We also compared the patients with preeclampsia to 62 controls
matched by age, gestational age, and parity after 20 weeks of gestation.

Results The sEng concentrations were significantly elevated in early-onset than in late-onset preeclampsia
(105.4 ± 37.9 vs 66.3 ± 36.0 ng/mL, p = 0.0008). Moreover, the sEng levels were also higher in severe
preeclampsia compared to mild (42.5 ± 31.0 vs 79.2 ± 38.6 ng/mL, p = 0.0013) and in the small for
gestational age (SGA) group compared to the group without SGA (68.3 ± 39.3 vs 85.7 ± 38.2 ng/mL,
p = 0.0273). The sFlt-1 levels, however, did not reveal significant difference according to the onset-time,
severity, and presence of SGA. The antiangiogenic factors’ concentrations were not related with the degree of
hypertension or proteinuria.

Conclusion Altered antiangiogenic factors might be involved in the pathogenesis of preeclampsia with
synergistic, but different roles. Especially, sEng may be more related with early and severe preeclampsia.
Copyright  2009 John Wiley & Sons, Ltd.
KEY WORDS: preeclampsia; soluble fms-like tyrosine kinase-1 (sFlt-1); soluble endoglin (sEng)

INTRODUCTION release factors into the maternal circulation that cause

Preeclampsia is a pregnancy-specific disease character-
ized by new-onset hypertension, proteinuria, and other
systemic disturbances. Clinically, preeclampsia is a het-
erogenous disease, ranging from insidious clinical symp-
toms or mild hypertension to severe hypertension and an
often life-threatening condition. Preeclampsia is usually
associated with placental hypoperfusion, which can lead
to intrauterine growth restriction (IUGR) and oligohy-
dramnios. Moreover, the onset-time of the disease can
range from early to late and many differences exist
between early- and late-onset preeclampsia (Ness and
Roberts, 1996). Early-onset preeclampsia is considered
especially detrimental to the overall prognosis, because
the risks of maternal multiorgan dysfunction and mortal-
ity as well as fetal mortality are greater than with late-
onset disease (Hall et al., 2000; MacKay et al., 2001).
However, the pathophysiology of these heterogeneities
was unclear.
Preeclampsia has been considered as a two-stage dis-
ease in which abnormal placentation is followed by gen-
eralized endothelial cell dysfunction, most commonly
(Roberts and Hubel, 1999; Redman and Sargent, 2005).
In preeclampsia, the hypoxic placenta is believed to
*Correspondence to: Ki Tae Kim, Department of Obstetrics and
Gynecology, College of Medicine, Inje University, 633-165
Gaegum-dong, Busanjin-gu, Busan 614-735, South Korea.
E-mail: obgynkkt@inje.ac.kr
the clinical features of the disease. Studies have sought
to identify ‘preeclampsia factors,’ and several candi-
date factors have been proposed (Redman and Sargent,
2005). Recently, two antiangiogenic factors associated
with preeclampsia have been reported: soluble fms-like
tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng).
sFlt-1 is a secreted splice variant of Flt-1 that binds
to vascular endothelial growth factor (VEGF) and pla-
cental growth factor (PlGF) and inhibits the biological
activities of these angiogenic growth factors. sEng is
a coreceptor for transforming growth factor (TGF)-β
and an antiangiogenic protein thought to impair TGF-
β1 binding to cell surface receptors and to decrease
endothelial nitric oxide signaling. Recent studies have
found that sFlt-1 and sEng, which are of placental ori-
gin, were elevated in the sera of preeclamptic women,
not only during preeclampsia, but also before the onset
of clinical symptoms, with the levels falling after deliv-
ery (Tsatsaris et al., 2003; Levine et al., 2004, 2006),
whereas maternal serum PlGF levels were decreased
in preeclampsia (Livingston et al., 2000). Moreover, in
one animal model of the disorder, the administration of
sFlt-1 to pregnant rats induced hypertension, protein-
uria, and glomerular endotheliosis, the classic lesions of
preeclampsia, suggesting that excess circulating sFlt-1
has a causal role in the disease (Maynard et al., 2003).
Another study reported sEng overexpression in rodent
induced moderate hypertension without significant pro-
teinuria, whereas the overexpression of both sFlt-1 and

Copyright  2009 John Wiley & Sons, Ltd. Received: 11 September 2008
Revised: 25 November 2008
Accepted: 1 December 2008
Published online: 25 February 2009
 CLINICAL APPLICATIONS OF sFLT-1 AND sENG IN PREECLAMPSIA 465

sEng caused severe vascular damage, nephrotic-range
proteinuria, and severe hypertension (Venkatesha et al.,
2006). Based on these findings, we postulated that
antiangiogenic factors are involved in the pathogene-
sis of preeclampsia with synergistic, but different roles.
Here, we examined the levels of sFlt-1, sEng, and PlGF
in various clinical manifestations of preeclampsia, and
sought to explain the different pathophysiology of the
disease.
METHODS
This study included 124 pregnant women who visited
the Department of Obstetrics and Gynecology, Pusan
Paik Hospital, Inje University, Korea from January
2006 to December 2007. Of these 124 women, 62
were preeclamptic patients diagnosed after 20 weeks of
gestation (ranging from 23 to 40 weeks of gestation)
and 62 were normotensive pregnant women matched
for age, gestational age, and parity. Preeclampsia was
defined as gestational hypertension [systolic blood pres-
sure (SBP) ≥140 mmHg or diastolic blood pressure
(DBP) ≥90 mmHg, arising after 20 weeks of gestation,
on at least two occasions, 4 h to 1 week apart] and pro-
teinuria (≥300 mg in a 24-h urine collection or one
dipstick measurement ≥2+). The preeclamptic patients
(n = 62) were divided into subgroups according to the
clinical manifestations: the disease-onset time [early
(n = 13) vs late (n = 49)], severity [severe (n = 54)
vs mild (n = 8)], and presence of small for gestational
age (SGA) [present (n = 22) vs absent (n = 40)]. Early-
onset preeclampsia was defined as clinical manifesta-
tions occurring before 32 weeks of gestation. Severe
preeclampsia was defined by the presence of one or
more of the following criteria: blood pressure above
160/110 mmHg, proteinuria of at least 5 g/day, throm-
bocytopenia, elevated liver enzymes, pulmonary edema,
hemolytic anemia, elevated liver enzymes, and low
platelets (HELLP) syndrome, and fetal growth restric-
tion. Severe preeclampsia patients were more abundantly
included in this study than mild cases, because more
severe cases were referred to our tertiary hospital. SGA
was defined as an infant whose birth weight was below
the 10th percentile for gestational age. The degree of
hypertension and proteinuria were expressed as mean
blood pressure (MBP) and the amount of protein in 24-h
urine collection. We included only preeclampsia patients
diagnosed after 20 weeks of gestation and excluded
patients with multiple gestations, gestational hyperten-
sion, chronic hypertension, superimposed preeclamp-
sia, diabetes, nephrotic syndrome diagnosed postpartum,
other major metabolic disorders, or a history of illicit
drug use. There was no case of eclampsia during the
study period.
All women provided informed consent before sample
collection. The collection and use of the samples were
approved by the institutional review board of Pusan
Paik Hospital. Plasma samples were collected from
preeclampsia patients soon after disease onset. Healthy
pregnant women in their second or third trimester
were matched with the preeclampsia patients by age,
gestational age, and parity, and then blood samples
were obtained. Immediately after collecting 3 mL of
blood from each patient, the plasma was centrifuged
at 2500 rpm for 15 min at 4 ◦ C and stored at −80 ◦ C
until use. Plasma levels of sFlt-1, sEng, and PlGF
were determined using enzyme-linked immunosorbent
assays (ELISA; R&D Systems, Minneapolis, MN). All
samples were examined in duplicate, and the mean
values of individual samples were analyzed statistically.
The minimum detectable concentrations of sFlt-1, sEng,
and PlGF were 5.0 pg/mL, 0.1 ng/mL, and 7.0 pg/mL
respectively.
Statistical analysis
All values are expressed as the mean ± SD. The
Kruskal–Wallis test was used for intergroup compar-
isons of clinical parameters and plasma sFlt-1, sEng, and
PlGF levels. The correlations between parameters were
analyzed using Spearman’s rank correlation. P < 0.05
was considered statistically significant, and the statistical
analysis was carried out using the program MedCalc.
RESULTS
The clinical characteristics of the controls and pree-
clamptic patients are shown in Table 1. The gestational
ages of controls and preeclampsia were ranging from 23
to 40 weeks. No statistical differences were observed in
maternal age, parity, and gestational age at blood sam-
pling between normotensive and preeclamptic patients.
The plasma sFlt-1, sEng, and PlGF concentrations are
shown in Figure 1. The mean sFlt-1 and sEng con-
centrations were elevated in preeclampsia compared to
the normotensive women (both p < 0.0001), but the
mean PlGF concentration was decreased in preeclampsia
(p < 0.0001).
The 62 preeclampsia patients differed in the onset-
time and severity of disease. The clinical differences in
preeclampsia are summarized in Table 2. All early-onset
preeclampsia manifested severe preeclampsia, while
83.7% (n = 41) of late-onset preeclampsia manifested
severe disease. Within the preeclampsia group, the cor-
relations between the factors were shown in Figure 2.
Table 1—Clinical characteristics of studied populations
Control Preeclampsia
(n = 62) (n = 62) p-value
Maternal age (year) 30.4 ± 3.4 31.6 ± 3.7 0.1275
Gestational age at 33.8 ± 3.3 34.1 ± 3.6 0.9681
sampling (week)
Nulliparitiy (no.) 41 (66.1%) 44 (71.0%) 0.6989
Gestational age at 37.0 ± 3.3 34.6 ± 3.5 <0.0001
delivery (week)
Birth weight (kg) 3.1 ± 0.4 2.0 ± 0.9 <0.0001
SGAa (no.) 5 (8.1%) 22 (35.5%) 0.0005
a Small for gestational age.

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 464–470.
DOI: 10.1002/pd
466 Y. N. KIM ET AL.

p < 0.0001 p < 0.0001

p < 0.0001
8000 250 1000

200 800
6000

PlGF (pg/mL)
sEng (ng/mL)
sFlt-1 (pg/mL)

150 600
4000
100 400
2000 50 200

0 0 0
Controls Preeclampsia Controls Preeclampsia Controls Preeclampsia
(n = 62) (n = 62) (n = 62) (n = 62) (n = 62) (n = 62)

Figure 1—The plasma sFlt-1, sEng, PlGF concentrations in normotensive and preeclamptic pregnant women. The mean value of sFlt-1, sEng, and
PlGF were 553.9 ± 275.9 pg/mL, 17.2 ± 8.7 ng/mL, and 423.5 ± 219.6 pg/mL in normotensive pregnant women and 2755.2 ± 1163.1 pg/mL,
74.5 ± 30.6 ng/mL, and 159.6 ± 87.7 pg/mL in preeclamptic women

250 250 7000

r = -0.3402 r = -0.1308
r = 0.5099
6000
200 p = 0.0073 p = 0.3151
200 p < 0.0001
5000

sFlt-1 (pg/mL)
sEng (ng/mL)

sEng(ng/mL)

150 150 4000

3000
100 100
2000
50 50
1000

0 0 0
0 1000 2000 3000 4000 5000 6000 7000 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400
sFlt-1 (pg/mL) PlGF(pg/mL) PlGF(pg/mL)

Figure 2—The correlations of plasma sFlt-1, sEng, and PlGF concentrations in preeclamptic women. There was positive correlation between the
plasma sFlt-1 and sEng levels (p < 0.0001) and negative correlation between the plasma sEng and PlGF levels (p = 0.0073)

Table 2—Clinical variability of women with preeclampsia
(n = 62)
Clinical manifestations
Early-onset (<32 weeks)
Severe disease
Severe hypertension
Heavy proteinuria
Pulmonary edema
Impaired liver functiona
Thrombocytopeniab
HELLP syndromec
SGA
a AST >40 U/L and/or ALT >55 U/L or LDH >600 U/L.
b Plt <100 × 109 /L.
c HELLP (Hemolysis, elevated liver enzymes, and low platelet
count)
syndrome; total bilirubin ≥1.2 mg/dL, LDH >600 IU/L or AST
>70 U/L, and Plt <100 × 109 /L.
The plasma sEng and sFlt-1 concentrations were posi-
tively correlated with each other, but the plasma sEng
and PlGF concentrations were negatively correlated.
Firstly, we compared the levels of sFlt-1, sEng, and
PlGF according to the onset-time of preeclampsia. The
mean sEng concentration in early-onset preeclampsia
was significantly higher than in late-onset (105.4 ±
37.9 vs 66.3 ± 36.0 ng/mL, p = 0.0008), whereas the
mean PlGF concentration in early-onset was signifi-
cantly lower than in late-onset (93.7 ± 59.6 vs 177.5 ±
85.9 pg/mL, p = 0.0021). There was no significant dif-
ference in the mean sFlt-1 concentration according
to the onset-time (Figure 3A). Furthermore, the sEng
concentration in preeclampsia had a significant neg-
ative correlation with the onset-time of the disease
No. (%)
(p < 0.0001) and the PlGF concentration had a pos-
13 (21.0) itive correlation (p = 0.0073) (Figure 3B). Secondly,
54 (87.1) when we compared the levels of sFlt-1, sEng, and
32 (51.6) PlGF according to the severity of disease, the only
18 (29.0) plasma sEng concentrations were significantly elevated
23 (37.1)
29 (46.8) in severe preeclampsia compared to mild preeclamp-
7 (11.3) sia (42.5 ± 31.0 vs 79.2 ± 38.6 ng/mL, p = 0.0013)
3 (4.8) (Figure 4A). The sEng concentrations were also higher
22 (35.5) in the SGA group compared to the group without
SGA (68.3 ± 39.3 vs 85.7 ± 38.2 ng/mL, p = 0.0273)
(Figure 4B). In contrast, although the sFlt-1 concentra-
tions were increased and the PlGF concentrations were
decreased in severe preeclampsia and in the SGA group,
the differences were not significant. The clinical asso-
ciated finding that early-onset preeclampsia frequently
manifest severe preeclampsia and SGA can be explained
with our data showing elevated levels of sEng in early-
onset, severe preeclampsia, and SGA group. Hyperten-
sion and proteinuria are major diagnostic components
in preeclampsia, but the degrees of hypertension and
proteinuria differed within same preeclamptic group.
We evaluated the sFlt-1, sEng, and PlGF concentrations
according to the degree of hypertension and proteinuria
to reveal any pathophysiological difference, but no cor-
relation was observed between the mean concentrations
of sFlt-1, sEng, or PlGF and the degree of hypertension
or proteinuria (Figure 5A and B).

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 464–470.
DOI: 10.1002/pd
 CLINICAL APPLICATIONS OF sFLT-1 AND sENG IN PREECLAMPSIA 467

(A) p = 0.5979 p = 0.0008 p = 0.0021

8000 250 400

200
sFlt-1 (pg/mL)

PlGF (pg/mL)
300

sEng (ng/mL)
6000
150
4000 200
100
2000 100
50

0 0 0
Early Late Early Late Early Late
(n = 13) (n = 49) (n = 13) (n = 49) (n = 13) (n = 49)

(B) 7000 250 400

r = -0.1385 r = -0.4241 r = 0.3903
6000 350
p = 0.2831 200 p = 0.0006 p = 0.0019
300
sFlt-1 (pg/mL)

sEng (ng/mL)

PlGF (pg/mL)
5000
150 250
4000
200
3000 100 150
2000 100
50
1000 50
0 0 0
20 25 30 35 40 20 25 30 35 40 20 25 30 35 40
Onset time (weeks) Onset time (weeks) Onset time (weeks)

Figure 3—The mean values of plasma sFlt-1, sEng, PlGF according to the onset-time in preeclampsia. (a) Plasma sEng concentrations were higher
in early-onset compared with late-onset preeclampsia (105.4 ± 37.9 vs 66.3 ± 36.0 ng/mL, p = 0.0008), whereas plasma PlGF concentrations
were lower in early-onset preeclampsia (93.7 ± 59.6 vs 177.5 ± 85.9 pg/mL, p = 0.0021). (b) The onset-time of preeclampsia was negatively
correlated with plasma sEng levels (p = 0.0006) and positively correlated with plasma PlGF levels (p = 0.0019), but the plasma sFlt-1 levels
had no association with the onset-time of preeclampsia

(A) p = 0.5851 p = 0.0013 p = 0.1783

250 400
8000
200 300
PlGF(pg/mL)
sFlt-1 (pg/mL)

sEng (ng/mL)

6000
150
4000 200
100
2000 100
50

0 0 0
Mild Severe Mild Severe Mild Severe
(n = 8) (n = 54) (n = 8) (n = 54) (n = 8) (n = 54)

(B) p = 0.1260 p = 0.0273 p = 0.1913

8000 250 400
200
6000
sFlt-1 (pg/mL)

sEng (ng/mL)

300
PlGF(pg/mL)

150
4000 200
100
2000 100
50

0 0 0
SGA (-) SGA (+) SGA (-) SGA (+) SGA (-) SGA (+)
(n = 40) (n = 22) (n = 40) (n = 22) (n = 40) (n = 22)

Figure 4—(a) The mean values of plasma sFlt-1, sEng, and PlGF concentrations between mild and severe preeclamptic women. The plasma
sEng concentration in severe preeclampsia was elevated compared to mild preeclampsia (42.5 ± 31.0 vs 79.2 ± 38.6 ng/mL, p = 0.0013), but
sFlt-1 and PlGF levels did not differ between mild and severe preeclampsia. (b) The mean values of plasma sFlt-1, sEng, and PlGF according
to the presence of SGA. sEng levels were only significantly elevated in the presence of SGA compared to the absence of SGA (68.3 ± 39.3 vs
85.7 ± 38.2 ng/mL, p = 0.0273)

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 464–470.
DOI: 10.1002/pd
468 Y. N. KIM ET AL.

(A) 7000 250 400

r = 0.1290 r = 0.1787 r = -0.0901
6000 350
p = 0.3219 200 p = 0.1683 p = 0.4935
300
5000
sFlt-1 (pg/mL)

sEng (ng/mL)

PlGF(pg/mL)
150 250
4000
200
3000 100 150
2000
100
50
1000 50
0 0 0
80 85 90 95 100 105 110 115 120 80 85 90 95 100 105 110 115 120 80 85 90 95 100 105 110 115 120
Mean BP (mmHg) Mean BP (mmHg) Mean BP (mmHg)

(B) 7000 250 400

r = 0.1788 r = 0.1060 r = -0.0139
6000 350
p = 0.1643 200 p = 0.4124 p = 0.9156
5000 300
sFlt-1 (pg/mL)

sEng (ng/mL)

PlGF(pg/mL)
150 250
4000
200
3000 100 150
2000
100
50
1000 50
0 0 0
0 5000 10000 15000 20000 0 5000 10000 15000 20000 0 5000 10000 15000 20000
Proteinuria(mg/24hr) Proteinuria(mg/24hr) Proteinuria(mg/24hr)

Figure 5—The mean values of plasma sFlt-1, sEng, and PlGF concentrations according to the degree of hypertension (a) and proteinuria (b).
There were no correlations between the mean concentrations of sFlt-1, sEng, or PlGF and the degree of hypertension or proteinuria

DISCUSSION we hypothesize that sEng induces the early-onset dis-

ease. Most previous studies of angiogenic factors and
preeclampsia did not separate patients with early- and
This study supports the hypothesis that preeclampsia is
associated with altered plasma levels of the antiangio- late-onset preeclampsia. A few studies have reported that
genic proteins sFlt-1 and sEng, and angiogenic protein the serum PlGF levels were lower and those of sFlt-
PlGF. Our findings that the plasma levels of sFlt-1 1 were higher in women with early-onset preeclampsia
and sEng in preeclampsia were significantly higher than prior to the onset of the disease (Levine et al., 2004;
those in normal pregnancy were consistent with previ- Chaiworapongsa et al., 2005; Masuyama et al., 2006;
ous reports (Maynard et al., 2003; Levine et al., 2004, Ohkuchi et al., 2007), but we could find no reports that
2006; Masuyama et al., 2006). However, the power of simultaneously compared the factors with the onset-time
our study lies in its having evaluated the sFlt-1, sEng, of preeclampsia.
and PlGF concentrations according to the clinical mani- Current classification systems are based on the knowl-
festations of preeclampsia. The majority of recent studies edge of clinical picture of preeclampsia. These classi-
have focused on the relationship between preeclamp- fication systems should identify women and babies at
sia and antiangiogenic proteins, without considering the the greatest risk for adverse outcomes by assessing the
clinical variations in the disease (Levine et al., 2004, severity of disease; however, we do not know whether
2006). the published criteria for preeclampsia severity actu-
On investigating the pathophysiology of the condi- ally identify women at the greatest risk for adverse
tion, early- and late-onset preeclampsia seems to be outcomes (Menzies et al., 2007). In addition, the etiol-
two different entities, because the early-onset disease ogy and pathophysiology of severe preeclampsia remain
is more dangerous to the mother and the fetus. One unclear. We measured the plasma sFlt-1 and sEng levels
recent microarray analysis also revealed differentially according to the severity of preeclampsia and found a
expressed fetal genes between early- and late-onset significant elevation of sEng only in severe preeclamp-
severe preeclampsia (Nishizawa et al., 2007). Since no sia compared to mild preeclampsia, as in early-onset
criteria have been established that characterize early- preeclampsia, although the number of mild preeclampsia
onset preeclampsia, we defined early-onset preeclampsia cases examined was small. Venkatesha et al. (2006) also
as clinical manifestations occurring before 32 weeks of reported a novel soluble form of Eng of placental origin
gestation, and found that the plasma sEng levels were that is present in the sera of pregnant women, elevated
significantly elevated in early-onset preeclampsia com- in preeclamptic individuals, and correlated with disease
pared to late-onset preeclampsia. No similar elevation severity. Masuyama et al. (2006) reported that levels of
of the sFlt-1 levels was seen in early preeclampsia, the circulating angiogenic factors sFlt-1 and sEng were
although the sFlt-1 and sEng levels were positively cor- both correlated with preeclampsia severity, which differs
related. This result supports a report that the level of from our results.
sEng is elevated in maternal serum in preeclampsia Some forms of IUGR have been linked to preeclamp-
before the sFl-1 is elevated (Levine et al., 2006), and sia etiologically, based on similar placental disease

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 464–470.
DOI: 10.1002/pd
 CLINICAL APPLICATIONS OF sFLT-1 AND sENG IN PREECLAMPSIA
described as abnormal implantation and characterized by
the failure of trophoblasts to differentiate, invade, and
remodel the spiral arteries (Ness et al., 2006). These
similarities underlie the hypothesis that preeclampsia
and IUGR secondary to placental insufficiency share a
cause, but have different clinical manifestations. Shibata
et al. (2005) researched whether sFlt-1 also increases in
the villous and maternal serum of normotensive women
with SGA neonates, but found that the sFlt-1 levels were
not elevated in SGA pregnancies. We studied the mean
sFlt-1, sEng, and PlGF levels according to the pres-
ence of SGA in preeclampsia and found that the levels
of sEng only were higher in the SGA group than in
the group without SGA. We did not analyze the val-
ues between SGA groups with and without preeclampsia
separately.
Severe hypertension is one of the serious parameters
in preeclampsia. In one animal study of preeclampsia,
the overexpression of sEng and sFlt-1/sEng had dif-
ferent effects on hypertension, proteinuria, and vascu-
lar damage, suggesting cooperative, but different, con-
tributing roles in hypertension (Venkatesha et al., 2006).
Another report described significant differences in the
MBP between the high- and low-sEng groups, and in
proteinuria between the high- and low-sFlt-1 groups;
the study also found significant differences in placen-
tal sEng and sFlt-1 levels between patients with and
without severe hypertension or proteinuria (Masuyama
et al., 2006). Our study analyzed the levels of sFlt-1 and
sEng in preeclampsia according to the degree of hyper-
tension only; however, we found no correlation between
the degree of hypertension and the levels of sFlt-1, sEng,
or PlGF.
Proteinuria which was associated with endotheliosis
is one of the important characteristics of preeclamp-
sia. Opinions differ regarding the outcome of protein-
uric preeclampsia. Chan et al. (2005) reported a greatly
increased risk of adverse maternal and fetal outcomes
with increasing proteinuria and a high spot urine pro-
tein/creatinine ratio in preeclamptic women with pro-
teinuria greater than 900 mg/mmol, or greater than
500 mg/mmol in women over 35 years old. In con-
trast, several authors have reported that women with
preeclampsia and massive proteinuria did not have
increased maternal morbidity compared to women with
mild proteinuria (Schiff et al., 1996; Newman et al.,
2003). VEGF, which is synthesized constitutively in the
glomerulus by podocytes, is a critical factor in main-
taining endothelial health, including the induction of
fenestrae (Stillman et al., 2007). A great deal of sup-
portive evidence suggests that VEGF and PlGF antago-
nism by sFlt-1 produces the endothelial dysfunction in
preeclampsia. In pregnant rats, proteinuria was modest in
sEng-treated rats, but severe in the sFlt-1-treated group.
The sFlt-1 + sEng group had nephrotic-range proteinuria
(Venkatesha et al., 2006). Based on these findings, we
expected the levels of sFlt-1 to be higher according to
the degree of proteinuria; nevertheless, the mean sFlt-1
concentration in preeclampsia was not significantly cor-
related with the amount of proteinuria.
Copyright  2009 John Wiley & Sons, Ltd.
469
CONCLUSION
We hypothesized that antiangiogenic factors’ concen-
trations would differ according to the clinical manifes-
tations of preeclampsia, which could explain the dif-
ferent roles of angiogenic factors in the disease. Our
results suggest that the sFlt-1, sEng, and PlGF have
important pathophysiological roles in the development
of preeclampsia, and that sEng is more strongly associ-
ated with early-onset disease, severe disease, and fetal
growth restriction. We conclude that elevated sFlt-1 and
sEng are involved in the pathogenesis of preeclampsia
with cooperative, but different, roles.
ACKNOWLEDGEMENTS
This study was supported by a 2006 Inje University grant
for research.
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