BBA - Molecular Basis of Disease 1866 (2020) 165349

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BBA - Molecular Basis of Disease

journal homepage: www.elsevier.com/locate/bbadis

Biology of preeclampsia: Combined actions of angiogenic factors, their T

receptors and placental proteins☆
Berthold Huppertz
⁎

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria

ARTICLE INFO ABSTRACT

Keywords: Although massive efforts have been undertaken to elucidate the etiology of the pregnancy syndrome pre-
Preeclampsia eclampsia, its developmental origin remains a mystery. Most efforts of the last decade have focused on bio-
PP13 markers to predict and/or diagnose preeclampsia, including the anti-angiogenic factor sFlt-1 (soluble fms-like
PGF tyrosin kinase-1), the angiogenic factor PGF (placental growth factor) and PP13 (placental protein 13). The
sFlt-1
origins of these marker proteins are still under debate, and so far their actions have only been describe separate
Sepsis
Vasodilation
from each other. This study will focus on the origins and actions of all three markers during pregnancy and
outside pregnancy and will describe a scenario where all three markers act synergistically to rescue the mother
from the deleterious effects of the debris that is released from the placenta during preeclampsia. This more
holistic approach may open new avenues to think about maternal-fetal interactions and putative therapies.

1. Introduction
Preeclampsia, the syndrome of hypotheses, remains one of the
major pathologies of pregnancy that results in mortality and morbidity
of mothers, fetuses and neonates. Recent data from the USA show that
the rate of preeclampsia in inpatient deliveries increased by 21% from
2005 to 2014 [1]. In 2014 a total of 4.7% of all inpatient deliveries in
the USA were associated with preeclampsia, i.e. 176,925 women. Also,
looking at the numbers from 2014, 37% of all women suffering from
preeclampsia showed clinical features of the severe form of the syn-
drome, which is an increase of 50% from 2005 to 2014. At the same
time, the percentage of cases developing eclampsia slightly dropped
from 0.9% to 0.7%. Interestingly, the numbers from the USA show that
black women have a rate of preeclampsia of 7.0%, while only 4.3% of
white women developed the syndrome [1]. The above numbers clearly
show the impact of preeclampsia on pregnant women and their children
even today and even in industrialized countries.
Based on this impact, the last decades have seen massive efforts to
elucidate the etiology of preeclampsia, to identify predictive bio-
markers and to start preventive therapeutic approaches. Today, new
approaches to identify putative predicting biomarkers include disease
map analysis and circulating RNA markers.
So far, none of these efforts has resulted in unravelling the etiology
of preeclampsia nor in the clinical use of a single biomarker for
monitoring the progress of the syndrome. The task force for hyperten-
sion in pregnancy of the American College of Obstetricians and
Gynecologists (ACOG) clearly defined in 2013 [2]: “Screening to predict
preeclampsia beyond obtaining an appropriate medical history to evaluate
for risk factors is not recommended.”. Only regarding options of ther-
apeutic approaches, a first break through has been made. Based on data
of the ASPRE study, low dose aspirin given daily from 11–14 weeks of
pregnancy to 36 weeks lowers the rate of preterm preeclampsia sig-
nificantly [3].
This overview will focus on specific biomarkers that have been
targets of extensive studies and will discuss their involvement in recent
developments in explaining the etiology of preeclampsia. Interestingly,
as described above, the quest to identify predictive biomarkers for
preeclampsia already lasts two decades. At the same time, the WHO has
defined requirements for biomarkers in general [4], while none of the
predictive biomarkers for preeclampsia identified so far meets these
requirements. According to the WHO, the biomarker (1) should be
specific for a well-defined disease with a known prevalence, (2) should
be used with a disease where the respective information of the bio-
marker can improve outcome and decrease severity, and (3) should be
cost effective.

☆
This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.
⁎
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/II, 8010 Graz, Austria.
E-mail address: berthold.huppertz@medunigraz.at.

https://doi.org/10.1016/j.bbadis.2018.11.024
Received 21 September 2018; Received in revised form 7 November 2018; Accepted 22 November 2018
Available online 13 December 2018
0925-4439/ © 2018 Elsevier B.V. All rights reserved.
B. Huppertz
2. Definition of preeclampsia
2.1. Diagnosis
The diagnosis of preeclampsia is based on changes in blood pressure
and kidney function in a so far normotensive pregnant woman after
20 weeks of pregnancy [5]. Values of ≥140 mm Hg for systolic blood
pressure and/or ≥90 mm Hg for diastolic blood pressure indicate the
development of hypertension, while values of ≥300 mg/day protein in
the urine or a protein to creatinine ratio of ≥3 indicate the develop-
ment of proteinuria. Recently, the fact that preeclampsia is a syndrome
rather than a defined disease led to the widening of the diagnosis and
the inclusion of other criteria that indicate dysfunctions of other organs
such as liver, kidney, lungs and brain [5].
2.2. Subtypes
80% to 90% of all preeclampsia cases are pure maternal syndromes
with normally grown babies. As an example, of the 26,893 deliveries in
a single hospital within a two year period, 7.3% were diagnosed with
preeclampsia, of which 92.1% delivered after 34 weeks of pregnancy. In
the group with preeclampsia 24.4% of all cases were delivered with a
small for gestational age fetus, while in the non-preeclampsia group
10.8% of all fetuses were born small for gestational age [6]. In the
majority of these cases delivery takes place at term or slightly preterm,
while a small percentage of cases is additionally associated with growth
restriction of the baby (intra uterine growth restriction, IUGR). Most of
these combined cases belong to the type of early-onset preeclampsia
with the need for delivery prior to 34 weeks of gestation. In addition,
such combined cases affect both, mother and child, and hence are those
of the highest clinical relevance.
The above differences have led to a sub-classification of pre-
eclampsia into different subtypes [7]:
- Early-onset preeclampsia with delivery prior to 34 weeks of gesta-
tion
- Late-onset preeclampsia with delivery after 34 weeks of gestation
In another recent study [8], 35,948 singleton pregnancies were in-
cluded, of which 1058 (2.9%) developed preeclampsia. These authors
used a different cut-off and defined term preeclampsia (delivery at >
37 weeks of gestation) compared to preterm preeclampsia (delivery
at < 37 weeks of gestation). The weeks of delivery for the preeclampsia
cases were as follows: 6.2% at < 32 weeks, 21.4% at 32 + 0 to
36 + 6 weeks, 48.6% at 37 + 0 to 39 + 6 weeks and 23.8% at > 40
weeks. Hence, 72.4% of all preeclampsia cases delivered after 37 weeks
of gestation [8].
Interestingly, since pregnancy is terminated at 40 + 6 weeks in most
industrialized countries today, those cases that would have developed
term preeclampsia at 41 or 42 weeks of gestation are no longer included
in the percentage values above. Hence, the proportion of late-onset
preeclampsia cases may even be higher than reported here. Also, taking
into account the above regimen of termination of pregnancy at
40 + 6 weeks, the performance of predictive markers such as mean
arterial pressure (MAP), which showed the best performance as a single
predictive marker in this study [8], may be underestimated as a certain
number of cases of preeclampsia (> 41 weeks) are no longer reaching
disease state.
There is a variety of other definitions such as preterm, intermediate
and early and late preterm, all subclassifying preeclampsia based on
gestational age at delivery. There are also definitions based on the se-
verity of symptoms leading to subtypes such as mild and severe pre-
eclampsia.
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BBA - Molecular Basis of Disease 1866 (2020) 165349
2.3. Evolving hypotheses on the etiology of preeclampsia
Preeclampsia is a pregnancy specific syndrome. The current hy-
potheses describe this syndrome to be centered on the presence of a
placenta. The release of so far unknown factors from the placenta over
the course of pregnancy finally leads to the occurrence of the clinical
symptoms of preeclampsia of the mother [9]. Of course, the suscept-
ibility of the mother is a major player in the development of this syn-
drome [9,10]. Hence, it is believed to be the interaction between the
quality and quantity of placental factors and how the mother can
handle these factors that decides whether a woman develops pre-
eclampsia or remains healthy. The combination of placental factors and
the maternal susceptibility seems to define the time of onset and the
severity of symptoms as well as the progression of the syndrome and the
association with fetal growth [9,10]. Of course, it is still a matter of
discussion whether early and late onset types of preeclampsia share the
same etiology or derive from mechanistically different defects [9].
Very recently, a new hypothesis has been developed centering on
the pregnant woman alone [11]. This new hypothesis is based on the
cardiovascular predisposition of the woman to preeclampsia. If the
woman's cardiovascular system fails to adapt to the changes occurring
in pregnancy, this may well lead to the symptoms of preeclampsia. As
has been described before [9,10], preeclampsia may develop with a
very normal placenta but a highly susceptible mother. The recent hy-
pothesis [11] focuses on the susceptibility of the maternal cardiovas-
cular system and its adaptation to pregnancy. In this new concept,
factors released from the placenta are not decisive for the development
of preeclampsia, but rather the ability of the maternal cardiovascular
system to adapt to the changes occurring during pregnancy. Further
knowledge is needed to unravel whether placental factors are needed
for the development of preeclampsia or whether it is a pure mala-
daptation of the woman to vascular changes during pregnancy [10,11].
3. Placental growth factor (PGF) and its soluble receptor sFlt-1
3.1. Expression pattern in the placenta
Placental growth factor (PGF) and its soluble receptor (soluble fms-
like tyrosin kinase-1, sFlt-1) are well known predictive markers for
adverse pregnancy outcome including but not limited to preeclampsia
[12]. Both have been detected to be expressed in the placenta 20 years
ago [13,14]. Expression in the placenta was mainly found in the villous
syncytiotrophoblast, the cover of the placental villi in direct contact
with maternal blood. Release of PGF and sFlt-1 from this tissue directly
flushes the angiogenic factor PGF and its soluble scavenging receptor
sFlt-1 into the maternal circulation with actions on cells of the maternal
vascular system.
Early reports showed that placental expression of PGF mRNA was
slightly decreased at the end of the first trimester [15] and unchanged
at the time of symptoms [16], while sFlt-1/Flt-1 mRNA expression was
upregulated at both time points [15,16]. In maternal blood, total (free
and bound) VEGF, the natural growth factor for the membrane bound
Flt-1 receptor, was increased, while free PGF was decreased and sFlt-1,
the soluble component of the VEGF receptor family, was increased in
cases with preeclampsia [16].
In contrast to such findings, the premature conclusion was drawn
that (1) the placenta is the sole source of these factors [17,18], and (2)
the placenta-derived factors are nearly exclusively decisive for their
concentrations in maternal blood [19–21].
Recently, this topic has been revisited combining maternal serum
and placental tissues from the same pregnancies [22,23]. These authors
showed that reduced maternal PGF serum concentrations in pre-
eclampsia cases were associated with unchanged levels of PGF mRNA
and protein in the placenta as a whole. Interestingly, looking more
specifically, the PGF protein expression in the syncytiotrophoblast was
significantly increased in late onset preeclampsia cases [22], while it
B. Huppertz
remained unchanged in cases with early onset preeclampsia [23]
compared to age-matched controls. These data shows that a simple link
between changes of placental expression and respective changes in
maternal serum cannot easily be made. Thus, the serum levels of this
factor and its soluble receptor need to be explained taking into account
maternal sources [24,25].
If other sources are important in adding to the serum concentrations
of PGF and sFlt-1, the surface of the placental villous tree in comparison
to the surface of the maternal vascular system becomes a decisive ele-
ment. The surface of the villous tree is much smaller than the surface of
the vascular system of the mother. The maximal surface of the placental
villous tree at term is about 12 to 15 m2 [26], while the surface of an
adult vascular system has an area of > 3000 m2 [27]. Considering the
release of a factor with a similar range from the placenta and the ma-
ternal endothelium, the placenta-derived factor would contribute to the
total serum concentration with only 0.4% to 0.5%. Thus, even major
changes of the placental release will change the total serum con-
centration only marginally. These data shows that maternal sources of
factors and receptors need to be considered [25].
Importantly, the false presumption that angiogenic and anti-angio-
genic factors are altered in maternal serum of preeclamptic women due
to placental hypoxia has already been disproved [28]. These authors
compared levels of PGF and sFlt-1 in preeclamptic and healthy pregnant
women at altitudes of 400 m and 3600 m and did not find any differ-
ences between low and high altitude (i.e. normoxia and hypoxia, re-
spectively). This study reveals that oxygenation of maternal blood and
hence the placenta does not have any effect on the levels of PGF and
sFlt-1 in maternal blood [28].
3.2. Expression pattern outside the placenta
Of course, the placenta is not the only source of PGF and sFlt-1
[24,25]. While the expression of PGF in quiescent endothelial cells is
low, activated and/or stressed endothelial cells upregulate the expres-
sion and secretion of PGF [29]. Similarly, Flt-1 is expressed in en-
dothelial cells throughout the whole vascular system. Both, PGF and
Flt-1 are further expressed in non-endothelial cells such as fibroblasts
[30,31], osteoblasts [32], monocytes [33] and smooth muscle cells
[34]. The soluble Flt-1 receptor has been shown to be involved in
vascular changes of the cycling endometrium [35]. A recent review
highlights the importance of VEGF/PGF and their receptors and de-
scribes their body-wide expression pattern [36]. These authors describe
the presence of sFlt-1, but also of other soluble forms of the VEGF re-
ceptor-1, namely sFlt1-14 (or sFlt1-e5a) and an additional soluble form
of Flt1 generated by cleavage of the transmembrane part of the protein.
All soluble Fllt-1 receptors act as antagonists to the transmembrane Flt-
1 receptor. The authors also point to the fact that sFlt-1 levels in blood
are directly linked to cell function of endothelial cells in the kidney
leading to increased blood levels of sFlt-1 in patients with chronic
kidney disease [36].
3.3. Use of PGF and sFlt-1 in pregnancy
First trimester (11 to 13 weeks): Early in pregnancy, the serum level
of sFlt-1 does not show any significant changes in preeclampsia com-
pared to healthy pregnancies [37–39]. In addition, a very recent direct
comparison of first trimester angiogenic factor levels revealed no
changes of VEGF, PGF, sFlt-1 and sEng in late onset preeclampsia versus
controls [40].
However, early-onset preeclampsia as well as IUGR can be equally
well predicted using a set of first trimester biomarkers including serum
PGF, the uterine artery pulsatility index and maternal risk factors with
areas under the curve (AUC) of 0.92 for early-onset preeclampsia and
0.91 for IUGR [41]. The prediction of late-onset preeclampsia is best
done without serum PGF, but rather taking into account mean arterial
blood pressure and maternal risk factors [41].
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BBA - Molecular Basis of Disease 1866 (2020) 165349
Second trimester (19 to 24 weeks): IUGR is best predicted using a
marker panel including serum PGF, serum alpha-fetoprotein, fetal
biometry and maternal risk factors with [42] or without uterine artery
pulsatility index [43]. The AUC value to predict early-onset IUGR was
0.999 in both publications. The comparison of PGF with other serum
markers revealed that only PGF showed significantly different levels
between controls and IUGR cases, while other factors including sFlt-1
did not show any differences between cases and controls [43].
Third trimester: The sFlt-1/PGF ratio has been shown to be very
helpful in predicting adverse outcome of pregnancy, hence not speci-
fically focusing on preeclampsia [44]. Looking at early-onset pre-
eclampsia, the sFlt-1/PGF ratio has a clear advantage in patients who
have already been diagnosed with preeclampsia in predicting time to
delivery within a two or even four week period [12,44].
3.4. Use of PGF and sFlt-1 outside pregnancy
PGF and Flt-1 are angiogenic factors that are systemically expressed
in the vascular system to control angiogenesis [36]. With this expres-
sion pattern, they have been good candidates for the prediction of
diseases. In fact, PGF is used as a marker for colorectal and ovarian
cancer [45–47], while the PGF/sFlt-1 ratio is used for the stratification
of e.g. breast cancer patients [48].
Also, sFlt-1 alone has been used as a marker for subarachnoid he-
morrhage hypoxia [49], and studies have been published evaluating the
use of sFlt-1 for cancer treatment [50]. This anti-angiogenic soluble
receptor is known to be increased in sepsis and has been described as a
marker to identify severity stages of sepsis [36,51]. Similar data has
been published for cases with acute pancreatitis where sFlt-1 is used to
predict the severity of symptoms [52].
A direct comparison of changes and serum concentrations of PGF
and sFlt-1 in preeclampsia [53] and plasma cell myeloma [54] revealed
that in both cases not only the changes are going into the same direction
but also the serum concentrations are very similar [25]. This compar-
ison is important as it shows that the serum levels of PGF and sFlt-1 as
found in preeclampsia are also measured in diseases of non-pregnant
humans.
Applying this knowledge to preeclampsia and the placenta, one
could argue that non-angiogenic placental factors activate the maternal
endothelium, which in turn alters its secretion pattern of angiogenic
factors such as PGF and sFlt-1.
Different to what has been speculated at the time the angiogenic
factors were detected as markers for preeclampsia, it has become clear
today that:
(1) (Anti-) angiogenic factors are not specifically expressed in the pla-
centa but rather systemically in the mother/adult.
(2) These factors are not specific markers to predict preeclampsia but
rather can be used to predict adverse outcome in a variety of syn-
dromes and diseases during pregnancy and outside pregnancy.
(3) These factors are valuable markers to predict time to delivery once
an adverse outcome during pregnancy has been diagnosed.
3.5. Actions of PGF and sFlt-1 in general
As an angiogenic factor, PGF is not only involved in growth and
maturation of new vessels from already existing vessels [55], but also
shows direct action on existing vessels [56]. PGF directly interacts with
endothelial cells and enhances their survival/viability as well as pro-
liferation and migration [55,57]. Moreover, PGF induces dilation of
resistance arteries in the uterus, the mesentery and the skin [58].
Interestingly, PGF seems to be more active in disease states rather
than in health and development: PGF deficient mice are healthy, viable,
and fertile and display a normal development [57]. At the same time,
PGF has been reported to be up or downregulated in a large variety of
diseases outside pregnancy as well as preeclampsia [56]. It has been
B. Huppertz
hypothesized that alterations of PGF in disease states may be used to
counteract disease-related changes while this does not interfere with
normal physiology [56].
In addition, sFlt-1 has been described to be increased in cases of
sepsis [36,51]. Shapiro et al. [51] speculated on the function of sFlt-1 to
sequester the high levels of VEGF is these cases, thereby reducing the
negative effects of VEGF in sepsis such as vessel leakage. VEGF has been
shown to promote internalization of VE-cadherin leading to dis-
assembly of intercellular junctions of endothelial cells and thus vessel
leakage [59]. In a computational model, the interaction between VEGF
and sFlt-1 has been calculated [60]. These authors could show that
augmented local concentrations of sFlt-1 lead to local sequestration of
VEGF and reduced signaling through the transmembrane receptors Flt-1
and Flk-1 [60].
4. Placental protein 13
4.1. Expression pattern in the placenta
Placental protein 13 (PP13) RNA is expressed in the amnion of the
fetal membranes as well as in the placental syncytiotrophoblast [61].
The expression of PP13 is nearly exclusive to the fetal tissues of the
placenta, while other fetal and adult tissues show very little to no ex-
pression of this protein [61]. Recently, it has been shown that micro-
vesicles and exosomes, released from the syncytiotrophoblast into the
maternal circulation, contain high amounts of PP13 [62].
In cases with preeclampsia, the level of PP13 mRNA expression in
the placenta is significantly reduced. At term, there is a 3.5-fold de-
crease in PP13 mRNA in preeclampsia cases compared to controls
[63,64]. Interestingly, this decrease in PP13 expression is already pre-
sent in the first trimester in cases subsequently developing preeclampsia
[65]. Reduced expression of PP13 mRNA in the first trimester of
pregnancy can be regarded as one of the earliest signs for the devel-
opment of preeclampsia.
Surprisingly, levels of PP13 mRNA can also be detected in maternal
peripheral blood and seem to correlate with its expression in the pla-
centa. Again, reduced levels of PP13 mRNA in maternal blood were
detected in cases with clinical symptoms of preeclampsia [66] as well as
in asymptomatic women in the first trimester who developed pre-
eclampsia later in gestation [67].
Within the placenta proper, the PP13 protein is mostly located
within the syncytiotrophoblast and is specifically localized at the apical
membrane of the syncytiotrophoblast [63,68–70]. Im-
munohistochemical staining of PP13 reveals highest intensities around
weeks six to seven with a decreased intensity at the onset of maternal
blood flow into the placenta, i.e. weeks 12 to 14 [70]. Villous as well as
extravillous cytotrophoblasts do not show any staining for PP13 in
immunohistochemistry [69,70].
Interestingly, first trimester villous explants from healthy pregnan-
cies release twice as much PP13 as explants from term controls [71].
This feature explains why the release of PP13 from a small first tri-
mester placenta produces the same maternal serum PP13 level as a
much larger early third trimester placenta [69].
4.2. Use of PP13 in pregnancy
PP13 is one of the markers with the earliest changes related to
preeclampsia. This protein has been detected in maternal serum already
at five weeks of gestation with significant changes monitored at week
six in cases subsequently developing preeclampsia [69,72]. In normal
pregnancy, maternal serum levels of PP13 remain constant until the
beginning of the third trimester and increase until term to reach levels
4
BBA - Molecular Basis of Disease 1866 (2020) 165349
twice or three times as high as the level in the first trimester [69].
Interestingly, PP13 can still be detected in maternal serum two to five
weeks after delivery, in the absence of the placenta as the only source
[69].
In preeclampsia, the maternal serum levels show a biphasic beha-
vior. During the first and early second trimester, the levels are sig-
nificantly lower compared to healthy controls [69,73]. At the time of
clinical symptoms of preeclampsia, the PP13 levels in maternal serum
rise above normal levels up to twice the level compared to controls
[69]. In vitro, villous explants from placentas of preeclamptic women
release much higher amounts of PP13 compared to age-matched con-
trols [71].
Today, the use of PP13 as a predictive biomarker for preeclampsia
derived from maternal serum has been investigated in over 20 studies
(e.g. [69,72–76]). Unfortunately, various assays and platforms have
been used over time, which had a clearly negative effect on the per-
formance of the marker [77]. Nevertheless, testing of PP13 in different
cohorts and various risk populations revealed a detection rate for PP13
as single marker of 83% for early-onset preeclampsia (delivery prior to
34 weeks), 66% for preterm preeclampsia (delivery prior to 37 weeks)
and 47% for all preeclampsia cases at a false positive rate of 10% [77].
4.3. Actions of PP13 during and outside pregnancy
Identified in 1983 [78], the function and physiological properties of
PP13 were largely unknown until recently [77]. As one of the 56 pla-
cental proteins known today, its sequence revealed that it belongs to the
family of galectins, this is why it is also termed galectin 13. Galectins
bind to beta-galactoside-specific lectins by their evolutionarily con-
served carbohydrate-binding domains [79]. So far, PP13 has been de-
scribed to bind to beta-galactoside residues of a variety of proteins and
thus affecting molecular recognition and apoptosis of immune cells
without a known classical receptor entity [68,80].
Today, it has become clear that the effects of PP13 go far beyond
interactions with immune cells. In rat and rabbit models (pregnant and
non-pregnant), PP13 has been recognized as a strong factor inducing
expansion and dilation of the uterine vasculature [81,82]. During
pregnancy, administration of PP13 into rats induced systemic and re-
versible hypotension, dilation of uterine veins and arteries and resulted
in larger pups and placentas [82]. The vasodilatory effect of PP13 was
assessed using isolated uterine arteries from non-pregnant and pregnant
rats. Although no direct receptor could be identified, relaxation of ar-
teries was mediated by signaling pathways of nitric oxide and pros-
taglandin [83].
Interestingly, the dilating effect of PP13 on uterine vessels is dif-
ferent in veins and arteries. The larger the uterine vein (from radial via
arcuate to main uterine vein), the larger the dilating effect. In uterine
arteries, the effect is in the opposite direction. The smaller the uterine
artery (from main uterine via arcuate to radial artery), the larger is the
effect [82,84].
5. New thinking: concerted action of PP13 and (anti-) angiogenic
factors during preeclampsia
Although the detailed etiology of preeclampsia is still far from being
deciphered, the intensive work on predictive biomarkers for pre-
eclampsia has helped in putting some further pieces together to unravel
how this syndrome may develop (Fig. 1).
While the initial insult on the placenta is still unclear, the first effect
that is visible today is the reduced level of PP13 in maternal blood
already at six weeks in women developing preeclampsia later in preg-
nancy [69]. This may already prime the maternal vascular system and
B. Huppertz BBA - Molecular Basis of Disease 1866 (2020) 165349

Fig. 1. Interaction of (anti-) angiogenic factors and placental proteins in the course of the development of preeclampsia.
The left part of the scheme represents the normal release of factors during healthy pregnancy. The right part of the scheme represents the altered release of factors
during the development of preeclampsia. One of the earliest signs of developing preeclampsia is a reduced PP13 level in maternal blood (week 6), which may already
have a negative impact on the maternal vasculature and prime maternal vessels. This and the release of placental “factors” may in turn lead to endothelial activation
and thus increased levels of sFlt-1 leading to reduced levels of free PGF. This could lead to a further reduction of vessel dilation, which in the third trimester may be
counteracted by an increased release of PP13.

reduce vessel dilation necessary to adapt to the needs of pregnancy.
This reduced level of PP13 very early in gestation may result in in-
creased arterial stiffness already at weeks 11 to 13, which leads to
subclinical values of increased blood pressure [85] (Fig. 1).
The ongoing activation of the maternal vascular system by so far
unknown placental factors may result in an increased release of VEGF,
similar to what can be seen in sepsis [51] (Fig. 2). In sepsis, bacterial
factors induce a cascade of events including increased secretion of
VEGF, which in turn activates signaling cascades that increase leuko-
cyte adhesion and clot formation. Respective changes of the clotting
system as well as increased leukocyte adhesion have been described for
preeclampsia as well [86,87] (Fig. 2). Spiezia et al. [87] showed an
increase in clot firmness as well as a decrease in blood fibrinolysis in
women suffering from preeclampsia.
In addition, in sepsis activated VEGF signaling induces dilation of
vessels as well as vascular leakage and formation of edema [51]. The
dilatory and leakage effects of VEGF have recently been shown outside
of sepsis in an in vivo mouse model [88]. These authors showed a di-
latory effect of VEGF on venules (diameter increase by factor of 1.7)
and a much stronger dilatory effect on capillaries (diameter increase by
a factor of 3.0). Again, leakage and thus formation of edema are a ty-
pical feature of preeclampsia and have long been part of the diagnostic
triage with hypertension, proteinuria and edema.
Maybe as a counteracting event, increased expression and release of
the soluble VEGF receptor sFlt-1 can be observed in sepsis (Fig. 2),
which has been described as a marker for the severity of sepsis [36,51].
Increased levels of sFlt-1 in turn reduce the level of free VEGF and thus
may reduce the negative effects of this factor during sepsis.
Also in preeclampsia, increased levels of sFlt-1 [37,38], paralleled
by reduced levels of free VEGF [89] have been reported at the time of
diagnosis in patients with preeclampsia, while the total concentration
of VEGF does not change [40].
Sequestration of VEGF by sFlt-1 to hinder leakage, clot formation
and leukocyte adhesion is achieved with the price of less dilation of
vessels. This may in turn activate secretion of PP13 from the placenta in
cases with preeclampsia – this time different to sepsis. Since PP13 is
using different signaling pathways compared to the angiogenic system,
vessel dilation by PP13 may be achieved in the presence of high sFlt-1
levels (Figs. 1, 2). Depending on the maternal system, this may or may
not be sufficient to significantly reduce blood pressure. Hence, this
could explain why some women with high sFlt-1 levels do not develop
preeclampsia.
Although the above comparison reveals a number of similarities
between sepsis and preeclampsia, there are also major differences in-
cluding blood pressure (hypotension versus hypertension) and of course
bacterial infection [90] (Fig. 2).

5
B. Huppertz
Fig. 2. Similarities and differences between sepsis and preeclampsia.
Bacterial or placental factors may have a major impact on the vascular system
of an adult and thus lead to activation/dysregulation of endothelial cells. This
in turn may result in an increase of free VEGF with the respective effects of this
factor. The vascular system may counteract this increased VEGF by increasing
sFlt-1 to scavenge VEGF and reduce its negative effects. Besides the above si-
milarities between sepsis and preeclampsia, there are of course a number of
differences shown in the scheme as well. Finally, in preeclampsia PP13 may act
as a rescue response that is not present in sepsis.
6. Conclusions
Preeclampsia is still the syndrome of hypotheses; however, so far
the different aspects of marker actions have not been combined. For the
first time, the effects of various predictive biomarkers for preeclampsia
have been assembled into a logical order to identify causes and con-
sequences. This combination revealed that there may well be a direct
interaction between placental proteins and angiogenic factors and their
receptors. Recent insight into the effects of PP13 allowed a better un-
derstanding of the interactions between angiogenic factors/receptors
and placental proteins. This makes it tempting to speculate on a new
therapeutic option where replenishment of PP13 early in pregnancy
may help in preventing or reducing severity of preeclampsia.
Transparency document
The Transparency document associated with this article can be
found, in online version.
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