Pathology - Research and Practice 214 (2018) 7–14

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Pathology - Research and Practice

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

Review

Angiogenic and antiangiogenic factors in preeclampsia T

a b c
Fernanda Rodrigues Helmo , Angela Maria Moed Lopes , Anna Cecília Dias Maciel Carneiro ,
Carolina Guissoni Camposb, Polyana Barbosa Silvab, Maria Luíza Gonçalves dos Reis Monteiroa,
Laura Penna Rochaa, Marlene Antônia dos Reisa, Renata Margarida Etchebehered,
⁎
Juliana Reis Machadoa,e, Rosana Rosa Miranda Corrêaa,
a
Discipline of General Pathology, Institute of Biological and Natural Sciences, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
b
Oncology Research Institute, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
c
Discipline of Histology, Institute of Biological and Natural Sciences, Federal University of Triângulo Mineiro. Uberaba, Minas Gerais, Brazil
d
Surgical Pathology Service, Clinical Hospital, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
e
Department of General Pathology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Pre-eclampsia is a multifactorial hypertensive disorder that is triggered by placental insufficiency
Preeclampsia and that accounts for up to 15% of maternal deaths. In normal pregnancies, this process depends on the balance
Endothelial dysfunction between the expression of angiogenic factors and antiangiogenic factors, which are responsible for remodeling
Soluble fms-like-tyrosine-kinase receptor the spiral arteries, as well as for neoangiogenesis and fetal development.
Soluble endoglin
Purpose: The aim of this review is to discuss the main scientific findings regarding the role of angiogenic and
Angiogenisis
antiangiogenic factors in the etiopathogenesis of preeclampsia.
Methods: An extensive research was conducted in the Pubmed database in search of scientific manuscripts
discussing potential associations between angiogenic and antiangiogenic factors and preeclampsia. Ninety-one
papers were included in this review.
Results: There is an increased expression of soluble fms-like tyrosine kinase receptor and soluble endoglin in pre-
eclampsia, as well as reduced placental expression of vascular endothelial growth factor and placental growth
factor. Systemic hypertension, proteinuria and kidney injury – such as enlargement and glomerular fibrin de-
posit, capillary occlusion due to edema, and hypertrophy of endocapillary cells – are some of these changes. The
complex etiopathogenesis of preeclampsia instigates research of different biomarkers that allow for the early
diagnosis of this entity, such as vascular endothelial growth factor, placental growth factor, soluble fms-like
tyrosine kinase receptor, soluble endoglin, placental glycoprotein pregnancy-associated plasma protein-A and
protein 13.
Conclusion: Even though it is possible to establish an efficient and effective diagnostic tool, three key principles
must be observed in the management of preeclampsia: prevention, early screening and treatment.

1. Introduction and/or diastolic blood pressure ≥ 90 mm Hg in hypertensive women,

Preeclampsia (PE) is a complex hypertensive pregnancy syndrome
that affects between 2 and 7% of pregnant women after the 20th week,
and which may appear superimposed on chronic hypertension (CH), for
instance. It is characterized by systolic blood pressure ≥ 140 mm Hg
followed by proteinuria ≥ 300 mg/L in urine/24 h [1–3]. Moreover,
the presence of thrombocytopenia (platelets < 100,000/mμl), renal
failure (creatinine ≥ 1.1 mg/dl) or impairment of liver function (dou-
bled normal concentration of oxaloacetic transaminase and pyruvate
transaminase), pulmonary edema, as well as cerebral and visual

Abbreviations: AT1-AA, angiotensin II type 1 receptor agonistic autoantibodies; ATF, activating transcription factor; CH, chronic hypertension; dNK, decidual NK cell; ECM, extracellular
matrix; eIF2a, eukaryotic initiation factor 2 subunit a; ER, endoplasmatic reticulum Flk-1 kinase insert domain receptor; Flt-1, fms-like tyrosine kinase receptor; GRP78, glucose-regulated
protein 78; ICAM, intercellular adhesion molecule; IL, interleukin; NOTCH, notch transmembrane receptors; PAPP-A, placental glycoprotein pregnancy-associated plasma protein-A; PE,
preeclampsia; PERK, PKR-like endoplasmic reticulum kinase; PlGF, placental growth factor; PP13, protein 13; sEng, soluble endoglina; sFlt-1, soluble form of Flt-1; sTNF-R, soluble tumor
necrosis factor receptors; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor
⁎
Corresponding author at: Instituto de Ciências Biológicas e Naturais/Disciplina de Patologia Geral/Universidade Federal do Triângulo Mineiro, Rua Frei Paulino n° 30, Bairro Nossa
Senhora da Abadia, CEP: 38025-180, Uberaba, Minas Gerais, Brazil.
E-mail address: rosana.correa@uftm.edu.br (R.R.M. Corrêa).

https://doi.org/10.1016/j.prp.2017.10.021
Received 13 March 2017; Received in revised form 23 October 2017; Accepted 25 October 2017
0344-0338/ © 2017 Elsevier GmbH. All rights reserved.
F.R. Helmo et al.
disturbances, accompanied by hypertension [4] in the absence of pro-
teinuria, are other criteria for the diagnosis of PE [3,5].
Eclampsia, from the Greek eklampsis (lightning), refers to the sudden
onset of persistent headache, photophobia, scotomas, epigastric pain or
pain in the right upper quadrant, as well as seizures [3,6]. It is note-
worthy that the impairment of hepatic and renal function may lead to
hemolysis, which is characterized by increased plasma level of lactate
dehydrogenase, persistent increase in the level of liver enzymes and in
thrombocytopenia, which is called HELLP (hemolysis, elevated liver
enzymes and low platelets) [7]; and which may lead to intense in-
flammatory response, endothelial injury, generalized vascular re-
sistance [8], disseminated intravascular coagulation, hepatic infarction,
cerebral vascular disease, premature placental abruption and oliguria
[2,3], for instance.
Different risk factors for PE have been discussed in the literature,
and predisposing factors may include the following: African descent,
obesity, short stature, nutritional deficiencies, previous CH (prevalent
in up to 35% of the cases) or gestational hypertension [9] in previous
pregnancies, heredity, urinary tract infections, diabetes mellitus, auto-
immune diseases, hydatidiform mole, multiple pregnancy, and fetal
macrosomia [10–13]. According to Chaiworapongsa et al. [15], other
factors include primiparity in young women, which is associated with
intolerance of the maternal immune system to paternal alloantigens
present in the seminal fluid and in the sperm; heredity, represented by
the presence of genetic variations in collagen α1-chain (I), interleukin-
1α (IL-1α), urokinase-type plasminogen activator receptor; maternal-
fetal incompatibility of lymphotoxin-α, von Willebrand factor, and α2
chain of collagen [14]; mutations in factor V Leiden, in human leuko-
cyte antigen, in endothelial nitric oxide synthases, and in angiotensin
converting enzyme [15].
Although little is known about the etiopathogenesis of pre-
eclampsia, this syndrome has a major impact on maternal and fetal
health worldwide, since it is responsible for 10–15% of maternal deaths
[16,17], preterm births, intrauterine growth restriction (IUGR), and
fetal deaths [2]. In developing countries, there are high rates of ma-
ternal morbidity and mortality from PE, mainly due to poor prenatal
care [16]. In Brazil, according to data by the National Health System
(SUS, in Portuguese) [18], approximately 76,000 maternal deaths and
500,000 perinatal deaths are estimated to be associated with PE every
year, with an average of three maternal deaths/day due to complica-
tions arising from the disease [19].
Therefore, the identification of risk factors and the establishment of
criteria for the diagnosis of PE are essential for the effective treatment
and prevention of complications during pregnancy. Platelet count,
measurement of hepatic enzymes, evaluation of proteinuria and blood
pressure levels, weight gain monitoring, analysis of kidney and lung
function, and assessment of previous pregnancy history (e.g. premature
birth, children born small for gestational age, etc.) must be recorded
during prenatal care. However, it is interesting to note that this entity
may have atypical manifestations as those observed in the HELLP
syndrome, yet in the absence of proteinuria and hypertension; thereby,
careful research and analysis of signs and symptoms of pregnant women
are required [2,3].
According to the literature, several mechanisms are associated with
the development of this multifactorial syndrome, including changes
during placentation [20], oxidative stress [21,22], exacerbated in-
flammatory response [23–25], thrombosis, activation of the renin-an-
giotensin-aldosterone system [25,26], and endothelial dysfunction
caused by changes in the angiogenic profile [27]; the latter is associated
with the pathophysiological changes described in PE.
2. Etiopathogenesis of preeclampsia
The pathophysiology of PE remains largely unknown. Nonetheless,
this hypertensive disorder is thought to be triggered by placental dys-
function, which favors the synthesis of specific factors in the maternal
8
Pathology - Research and Practice 214 (2018) 7–14
circulation that are responsible for causing clinical changes in PE
[2,28].
In normal pregnancies, cytotrophoblasts (cells outside the blastocyst
layer) invade the uterine wall between the 6th and 8th week, destroy
the muscular middle layer, acquire endothelial cell phenotype, and
transform spiral arteries into large vessels of low vascular resistance in
order to increase blood flow to the intervillous space and thence to the
fetus during embryonic development [2,14,28,29]. However, there are
failures in this process in PE, and the absence of arterial remodeling
promotes lipid deposition in the vessel wall, as well as blood flow
turbulence, platelet aggregation, fibrinoid necrosis, and intense acti-
vation of the inflammatory response [2,14,17].
Even though the mechanisms of this disorder are not fully known
[2,14], it is believed that poor cytotrophoblast invasion concomitant
with uteroplacental hypoperfusion may contribute to PE, since multiple
areas of infarction, sclerotic arterioles, increasing vascular resistance,
and reduced placental perfusion are observed in the placenta
[28,30,31], thus oxidative stress and IUGR are favored [30,32]. Fur-
thermore, there is a reduction in the area and volume of the intervillous
space, in the intermediate and terminal villi, both in cases with PE
alone and in cases with PE accompanied by IUGR. Remodeling of blood
vessels in both villi is also significantly reduced [32].
Therefore, placental hypoxia is considered as a triggering factor for
the increase in the synthesis of vasoconstrictors such as endothelin and
superoxide, as well as the increase in von Willebrand factor antigen,
cellular fibronectin, soluble tissue factor, soluble E-selectin, platelet-
derived growth factor, susceptibility to the effects of angiotensin II and
norepinephrine; placental hypoxia is also a triggering factor for the
reduction in nitric oxide synthesis by the maternal vascular en-
dothelium. This endothelial dysfunction has systemic effects, since
these factors affect the blood vessels in the liver, brain and kidneys, for
example; in the latter, there is a reduction in the glomerular filtration
rate as well as impairment of blood pressure regulation [17,28,29].
Abnormalities in placentation in patients with PE appear to be as-
sociated with changes in different components of the signaling pathway
that mediates cytotrophoblast migration/invasion. Studies have showed
that the activation of the Notch signaling pathway is associated with the
differentiation and modulation of functions of trophoblast cells through
the interaction of the Notch transmembrane receptors (NOTCH1-4) and
their respective ligands, DLL1,3,4 and JAG1,2 [29,33]. An experimental
study showed a correlation between the non-expression of the NOTCH-
2 receptor and the reduction in the diameter of maternal uterine vessels
during placentation, with significant impairment of perfusion [33].
Mutations in the gene encoding STOX1 transcription factor may also be
associated with the pathogenesis of PE, since the overexpression of this
factor in choriocarcinoma cells mimics the same transcriptional profile
observed in PE [29,34].
Endoplasmatic reticulum (ER) stress, characterized by the accu-
mulation of unfolded proteins and misfolded proteins within the orga-
nelle, interfering with functions of synthesis, post-translational folding
and assembly of all secreted and membrane-bound proteins, including
hormones, growth factors, and receptors [35–37]. Loss of homeostasis
activates unfolded proteins response, consisting of three main signaling
routes: PKR-like endoplasmic reticulum kinase (PERK), activating
transcription factor 6 (ATF6) and inositol-requiring 1 (Ire1). Under
normal conditions, these transmembrane proteins become inactive by
binding glucose-regulated protein 78 (GRP78 or BiP) to its N terminal.
However, consumption of GRP78 (Ca2+–dependent chaperone protein)
triggered by accumulation of misfolded proteins promotes dimeriza-
tion, autophosphorylation and activation of PERK and Ire1. Conse-
quently, activation of PERK favors the phosphorylation of eukaryotic
initiation factor 2 subunit a (eIF2a) and translation of activating tran-
scription factor-4 (ATF4), which results in blocking protein translation
and reducing accumulation in ER. In Golgi complex, ATF6 is cleaved by
the transcription factor responsible for the expression of ER chaperone
genes. Splices Xbp1 mRNA (originated from activation of Ire
F.R. Helmo et al.
endoribonuclease domain) is responsible for the transcription of genes
that regulate degradation of misfolded proteins and ER biogenesis. In
intense ER stress, PERK and ATF6 favor CHOP and caspase-4 (proa-
poptotic proteins) synthesis and apoptosis of the affected cell [35,38].
Dilatation of ER cistaernae in syncytotrophoblast, greater phos-
phorylation of eIF2a, reduction of protein synthesis, greater apoptosis
and impairment of placentation are some changes triggered by ER stress
in PE [35]. A research indicates that the expression of GRP78, PERK,
eIF2a, ATF4, CHOP, and caspase-12 mRNA, as well as their respective
proteins, were significantly higher in human placentas with early and
late-onset PE, compared with normal placentas [38].
In addition to the metabolic pathway disorders in this disease, re-
search has reported that there may be maternal immune tolerance to
fetal antigens during intrauterine development. It is assumed that the
recognition of fetal antigens by CD4+ T cells and by uterine natural
killer [33] cells is fundamental to placental growth. Failures in this
process cause miscarriages, impaired placentation, changes in placental
perfusion and in the activation of the immune system throughout
pregnancy [29].
Particular differences are identified in decidual NK cell (dNK)
phenotype in PE. Effective trophoblast invasion is regulated by acti-
vation and inhibition of receptors (KIR, CD94/NKG2, ILT families) in
dNK cells, which favor interaction with trophoblast HLA Class I mole-
cules (HLA-C/G/E). Evidence shows that the frequency of genotype KIR
AA associated with the allele HLA-C with C2 epitope, is higher in
pregnancies with impairment of spiral artery remodeling [39,40]. In
addition, dNK cells from women with high resistance index (uterine
artery Doppler ultrasound) have lower expression of KIR2DL/S1,3,5
and LILRB1 (ILT-2); in turn, the reduction of LILRB1 stimulates the
greater expression of tumor necrosis factor-α (TNF-α) and the lower
expression of CXCL10. There is also greater secretion of endostatin,
angiogenin and the soluble IL-2 receptor. These changes interfere in the
ability of dNK cells to regulate trophoblast invasion and migration
[40,41].
An in vitro assay in which endothelial cells form 3D tube-like
structures was used to investigate effects of dNK on vessel stability. The
results indicate that dNK cells from women with high spiral artery re-
sistance index had reduced ability to activate endothelial cells, since
endothelial cells presented lower expression of ICAM-1 and TNF-α,
compared with endothelial cells activated by dNK from women with
normal spiral artery resistance index. Consequently, there will also be
impairment in remodeling of uterine arteries [42].
The higher levels of syncytiotrophoblast micro-particles in the ma-
ternal circulation also seems to contribute to a systemic inflammatory
response, leading to increased production of inflammatory mediators
[9,29,43,44]. It is important to note that hypoxia associated with pla-
cental insufficiency causes oxidative stress, which is when there is an
increased synthesis of reactive oxygen species (e.g. peroxynitrite, hy-
drogen peroxide, hydroxyl radical) and reduction of antioxidant
synthesis (e.g. superoxide dismutase, glutathione, vitamin C) [21,30].
These reactive oxygen species lead to lipid peroxidation and, hence,
the synthesis of toxic byproducts (lipid peroxide, malondialdehyde, and
lipid hydroperoxide), and severe damage and dysfunction of the vas-
cular endothelium, which is associated with increased synthesis of in-
flammatory mediators and with change in the serum levels of angio-
genic and antiangiogenic factors [21,45–47], such as soluble receptor
tyrosine kinase, soluble endoglin, vascular endothelial growth factor
(VEGF), and placental growth factor (PlGF) [1,13,21,47,48].
3. Angiogenic and antiangiogenics factors
The placenta is an organ that is highly vascularized by maternal and
fetal blood vessels, and its development, maturation and functions de-
pend on efficient vasculogenesis (de novo formation of new blood ves-
sels), on angiogenesis (the formation of new blood vessels from other
pre-existing vessels), and on cytotrophoblast invasion for spiral artery
9
Pathology - Research and Practice 214 (2018) 7–14
remodeling, which is called pseudo-vasculogenesis [49–51].
In normal pregnancies, the expression of different molecules, such
as integrins, cadherins and metalloproteinases, allows the cytotropho-
blast to switch from an epithelial to an endothelial cell phenotype,
thereby stimulating the formation of pseudoendothelium in the spiral
arteries between the 12th and 20th weeks of embryonic development
[49]. Several factors are believed to interfere with this process, such as
oxygen tension, and the activation of decidual NK cells and macro-
phages, for instance. Nonetheless, shifting the balance in the expression
of angiogenic and antiangiogenic factors seems to be the key factor in
the endothelial dysfunction observed in PE [22,49,50].
According to the literature, VEGF, PlGF, endoglin, basic fibroblast
growth factor, angiopoietins, and transforming growth factor-β (TGF-β)
are some angiogenic factors associated with the development of the
extensive vascular network [17,49]; and the first three factors are
particularly relevant to the etiopathogenesis of PE.
VEGF is a cytokine synthesized by macrophages, T cells, tumor cells,
and cytotrophoblasts [51] and, thus, it is involved in various physio-
logical and pathological conditions [5]. VEGF isoforms include VEGF-A,
VEGF-B, VEGF-C, VEGF-D and PlGF. Moreover, cells can express three
main types of cellular receptors known as Flt-1 (fms-like tyrosine kinase
receptor or VEGFR1), Flk-1 (kinase insert domain receptor or VEGFR2)
and Flt-4 (VEGFR3), and they all have an extracellular domain, a
transmembrane domain and an intracellular tyrosine kinase domain; as
well as the soluble form of Flt-1 (sFlt-1), in which transmembrane and
cytoplasmic domains are absent. In syncytiotrophoblast, sFlt-1 is syn-
thesized through a splicing of mRNA of VEGRF-1 (or Flt-1) gene, which
encodes proteins without the ability to bind to the VEGF or PlGF within
cells, but capable of interacting with free growth factors in maternal
circulation [13,52–54]. VEGF-A, -B and PlGF bind to Flt-1; VEGF-A and
-C bind to Flk-1; whereas VEGF-C and -D bind to Flt-4. Furthermore,
VEGF-A, VEGF-B and PlGF may also bind to sFlt-1 [5,49,54–56].
Therefore, VEGF and its receptors are expressed in different organs,
including the kidneys, the liver and the brain [55]. In the human pla-
centa, VEGF is mainly synthesized by cytotrophoblast and Hofbauer
cells early in the first trimester, whereas Flk-1 and Flt-1 receptors are
expressed throughout the placenta, mainly in cytotrophoblasts. Studies
indicate that the activation of Flk-1 and Flt-1 receptors would trigger
signaling pathways associated with endothelial migration and pro-
liferation, as well as vascular permeability, formation, tubular ramifi-
cation and maintenance of blood vessels; whereas Flt-4 would be re-
lated to the development of lymphatic vessels. Because sFlt-1 has
antiangiogenic properties, when it binds to VEGF and PlGF, it prevents
their interactions with Flt-1 and Flk-1 receptors [5,49].
PlGF, in turn, has been described to be expressed in four isoforms
(PlGF-1, PlGF-2, PlGF-3 and PlGF-4), which play a key role in vascu-
logenesis throughout the embryonic development. In the placenta, this
factor is first detected in the syncytiotrophoblast, and serum levels in-
crease from the 30th week with subsequent decrease in normotensive
pregnancies [13].
Endoglin, also known as CD105, is a membrane-bound protein that
acts as a coreceptor for TGF-β1 and TGF-β3. It consists of an extra-
cellular domain, a single transmembrane domain, and a short cyto-
plasmic domain and, similarly to Flt-1, it also has a soluble isoform
(sEng) that has antiangiogenic properties [5,57,58]. Endoglin has a
little expression in quiescent endothelial cells, but a significant ex-
pression in stromal cells, hematopoietic stem cells, proliferative en-
dothelial cells, and in the syncytiotrophoblast [5]; it inhibits apoptosis
and activates the synthesis of endothelial nitric oxide [13]. Therefore, it
is capable of inducing cell migration and proliferation [5,59].
It is believed that in breast and colo-rectal neoplasias sEng is formed
through the action of metalloproteinase-14 in the transmembrane do-
main of endoglin; however maintains its extracellular domain and thus
the ability to bind to TGF-β and BMP-9. Metalloproteinase-14 is also
expressed in syncytiotrophoblast and in PE acts on endoglin of placental
cells. Research has shown that the greater expression of inhibitors of
F.R. Helmo et al.
this metalloproteinase attenuates the synthesis of sEng by placenta
[5,59,60].
In circulation, both sFlt-1 and sEng interact with their respective
binders (VEGF, PlGF and TNF-β), impairing the binding of these pro-
angiogenic molecules to their native endothelial cell-surface receptors.
Thus, elevated serum levels of sFlt-1 and sEng, and reduced serum le-
vels of PlGF are observed in the PE [53,54,59,61,62]. According to a
research, plasma concentrations of sFlt-1(41.5 ± 15.8 vs
6.11 ± 3.3 ng/ml) and sEng (86.8 ± 38.3 vs 13.4 ± 6.1 ng/ml) in
women with PE were significantly higher in relation to those normo-
tensive; in contrast, PlGF (96.1 ± 46.4 vs 508.2 ± 332.3 pg/ml)
presented a significant reduction in relation to normotensive pregnant
women [62].
Thus, it is clear that placentation is dependent on the balance be-
tween the expression of angiogenic and antiangiogenic factors
throughout pregnancy. The expression of VEGF-A, PlGF, endoglin, and
their receptors, Flt-1, Flk-1, sFlt-1 and sEng, appears to be essential for
the establishment of uteroplacental circulation and for fetal develop-
ment [63,64]. Studies have showed that VEGF-A, VEGF-B and PlGF are
responsible for modulating cytotrophoblast proliferation, differentia-
tion and invasion via Flt-1 and Flk-1 receptors; since when promoting
placental angiogenesis, they also promote the expression of coreceptor
neuropilin-1, contributing to the enhancement of VEGF-A activity
through interaction with Flk-1. As for endoglin, not only does it con-
tribute to the formation of new blood vessels, but also to the regulation
of muscle tone [51].
There is a higher expression of sFlt-1 in the placenta of PE patients,
so increased maternal serum concentration of this substance is notice-
able. On the other hand, a lower expression of VEGF-A and PlGF is
observed, since sFlt-1 binds to both factors in the circulation and pre-
vents interaction with endogenous receptors [53,54,65–68]. In addition
to these changes, the serum concentration and the mRNA expression of
sEng are increased; and because sEng competes with the endogenous
receptor when binding to TGF-β, both the vasculogenesis and placental
angiogenesis of pregnant women with PE are impaired [51,69–72]. Due
to intense endothelial dysfunction, both antiangiogenic factors (Flt-1
and sEng) can be detected in the maternal circulation early in the first
trimester of pregnancy, prior to the first clinical signs of disease
[51–53,61,73–75].
Maynard et al. [54] demonstrated that serum levels of sFlt-1 were
five times higher in pregnant women with PE than in normotensive
women; as a consequence, VEGF and PlGF levels were found to be
proportionally reduced in these women [54]. The literature confirms
that there is a sharp increase in sFlt-1 levels between 11 and 5 weeks
before the first signs of PE [52,53], as well as a substantial reduction in
PlGF and VEGF levels [53], whereas sEng levels increased significantly
between 11 and 9 weeks before clinical signs [52,61].
Experimental tests have showed that the increased synthesis of sFlt-
1 inhibits angiogenic activity due to the blockade of endogenous
functions of VEGF and PlGF, as well as physiological vasodilation.
Furthermore, pregnant and non-pregnant rats were given a dose of
recombinant adenovirus (responsible for the gene encoding of sFlt-1
mRNA) developed systemic hypertension, proteinuria and kidney in-
jury, such as glomerular enlargement and glomerular fibrin deposits,
capillary occlusion due to edema, hypertrophy of endocapillary cells,
podocytes with protein absorption droplets, and effacement of podocyte
foot processes, hence characterizing glomerular endotheliosis [54].
These findings are in agreement with other studies since in PE alone
or in the concomitant presence of HELLP syndrome, the levels of Flt-1
mRNA increased 27.7 times, and Eng mRNA increased 6.9 times [76];
and there was a reduction of 85.4% in the expression of VEGF mRNA
[77]. Moreover, Strevens et al. [78] found similar changes in renal
biopsies from women with PE [78].
Laboratory tests have confirmed that PlGF serum levels are lower in
pregnancies with severe PE (104 pg/ml) or eclampsia (84.3 pg/ml) in
comparison with pregnancies without abnormalities (335.6 pg/ml); as
10
Pathology - Research and Practice 214 (2018) 7–14
for sFlt-1 levels, a significant average increase was observed in severe
EP (19,070.6 pg/ml) or eclampsia (28,527.9 pg/ml) when compared to
normal pregnancies (6483.3 pg/ml). A result similar to that of sFlt-1
was found regarding sEng in severe PE (37.2 pg/ml) or eclampsia
(46.7 pg/ml) in comparison with pregnancies without changes
(12.7 pg/ml) [57,79]. It should be noted that in early-onset PE (< 34
weeks), the levels of PlGF appear to be significantly lower, with a dif-
ference of 500% in relation to late-onset PE (> 34 weeks); as for sFlt-1,
it has a higher level of early-onset PE, and it may reach a concentration
difference of 600% in comparison with late-onset PE [52,80].
In premature births, whose diagnosis of PE was confirmed, there
was a reduction in PlGF levels in the first and second trimesters of
pregnancy; whereas sFlt-1 and sEng levels, although lower in the first
quarter, were substantially higher in the following quarter. Thus, it was
possible to infer that pregnant women whose variation of PlGF was
minimal or absent between the first and second trimester, and whose
sFlt-1 and sEng levels increased continuously in the second trimester,
were at high risk for PE [52,53,57,61,73–75,81].
Studies have already showed that the synthesis of anti-angiogenic
factors can be triggered by several stimuli. For example, the expression
of endothelin-1, TNF-α and angiotensin II type 1 receptor agonistic
autoantibodies (AT1-AA) is increased in PE and it promotes the
synthesis of sFlt-1 and sEng, as well as proteinuria and systemic hy-
pertension [82,83]. Hypoxia, in turn, promotes the expression of hy-
poxia-inducible factor 1α (HIF-1α); and HIF-1α promotes the expres-
sion of TGF-β3, which acts as an antagonist of cytotrophoblast
proliferation [72,82,84,85].
Other factors have a significant influence on endothelial dysfunc-
tion, concomitantly to antiangiogenic factors. mRNA expression of the
angiotensin II type 1 receptor and of angiotensin II is increased in
chorionic villi, and it is responsible for the reduction of uteroplacental
perfusion and vasoconstriction stimulation. Hence, the persistence of
hypoxia, syncytiotrophoblast micro-particles in the circulation, and the
increased expression of TNF-α [82] promote an exacerbated synthesis
of IL-6, IL-16 and TNF-α, which also contributes to worsening the en-
dothelial dysfunction present in this disease [25,82]. Endostatin (frag-
ment of collagen XVII), in turn, affects the interaction of VEGF with
Filk-1 and, thus, interferes with the intracellular signaling pathways
responsible for cell motility [50,51]. Finally, the increased levels of
matrix metalloproteinase-9 in the placenta seems to be associated with
impaired extracellular matrix (ECM) degradation during angiogenesis,
as well as with cytotrophoblast invasion in PE [51].
Finally, impaired endothelial integrity culminates in an increased
plasma protein concentration in the interstitial space, and thus accu-
mulation of fluid in the ECM, favoring the swelling of the face and limbs
[2] mainly. Concurrently with this systemic change, there is intense
activation of coagulation, reduced tissue perfusion, and increased
synthesis of vasoconstrictor agents [69,86].
4. Biomarkers and management of preeclampsia
The complex etiopathogenesis of PE instigates worldwide research
on the definition of clinical and laboratory parameters that allow for
the early diagnosis of this entity. Because systemic hypertension and
proteinuria are not specific symptoms [5], different biomarkers have
been investigated as promising diagnostic tools [69,87,88].
In the first and second trimesters of pregnancy, the relationship
between sFlt-1/PlGF is regarded as a promising index of the imbalance
between angiogenic and antiangiogenic factors [53,75,89,90]. Serum
levels of both factors are already altered in early pregnancy; for in-
stance, sFlt-1 can be detected from the fifth week. When it is associated
with changes in plasma concentration of sEng and with Doppler ultra-
sound of the uterine artery between 20th and 24th week, the predictive
value of these factors reaches up to 89.5% sensitivity and 95% speci-
ficity [68,90]; whereas in the presence of abnormal uterine perfusion
there may be 100% sensitivity with 93.3% specificity [66]. It is also
F.R. Helmo et al.
suggested that nulliparous pregnant women who have serum levels of
PlGF < 107 pg/ml or < 20 pg/ml on the 26th week are at risk of de-
veloping moderate and severe PE [91], respectively.
In the third quarter, the change in PlGF levels, combined with
maternal characteristics, has a sensitivity of 86% for the diagnosis of PE
between the 34th and 37th weeks of pregnancy, and 53% from the 37th
week; with 10% false positive results [68]. Other studies point out that
the combined assessment of sFlt-1 and PlGF has a sensitivity of
74.1–78%, with a specificity of 67.2–84% [2,92,93].
Moreover, measurement of sFlt-1 and PlGF can contribute to the
identification and interpretation of abnormal uterine artery Doppler
ultrasound parameters in GA < 34 weeks [90,94]. Pregnant women
with increased rates of sFlt-1:PlGF are increasingly at risk of severe
hypertensive disorders, placental rupture, inotropic support, and en-
dotracheal intubation [94,95], whereas women with high levels of sEng
only present a serious risk of hematoma or hepatic rupture [94].
A prospective observational study conducted in 14 countries, en-
titled PROGNOSIS (Prediction of Short-Term Outcome in Pregnant
Women with Suspected Preeclampsia Study), investigated the value of
using the sFlt-1:PlGF ratio for prediction of preeclampsia in short term.
The median sFlt-1:PlGF ratio was higher among pregnant women with
PE or HELLP syndrome (146.4) within the first week or four weeks of
evaluation (104.8), when compared to those who did not develop any
disorder within the first week (6.3) or within four weeks (5.5). For the
single-cutoff model (independent of gestational age; sFlt-1:PIGF
ratio = 38), the gestational phase model [a model with two cutoff
points, one for the earlier gestational phase (24 to < 34 weeks) and one
for the later gestational phase (≥34 weeks)], and the gestational-week
model (a model with a cutoff point for each gestational week), the area
under the curve were 89.2%, 90.9%, and 90.5% for 1-week rule out and
86.4%, 86.2%, and 86.2% for 4-week rule in, respectively. Moreover,
the median cutoff points were 38.2 (1-week rule out) and 37.5 (4-week
rule in); indicating that the single cutoff point of 38 was suitable for
validation [96].
In validation phase, the median sFlt-1:PlGF ratio was 87.8 for
pregnant women diagnosed with PE or HELLP syndrome within the first
week of evaluation and 59.4 within four weeks, when compared to
those who did not develop any disorder within the first week (8.0) and
within four weeks (6.3). Negative predictive value (absence of diag-
nosis within 1 week) of 38 or lower for the sFlt-1:PlGF ratio was 99.3%,
and the positive predictive value (diagnosis of PE, eclampsia or HELLP
syndrome within 4 weeks) was 36.7%. Thus, the results suggest that the
use of sFlt-1:PlGF ratio to evaluate proteinuria and blood pressure
contributes to the diagnosis of PE [96].
It is noteworthy that in both cases there is a higher risk for pre-
maturity [44,61,97,98] and for deliveries of newborn small for GA
[89,95,97,98]. sFlt-1:PlGF has been showed to be inversely correlated
with GA at birth, since 86% of pregnant women who gave birth at < 34
weeks had rates higher than 85 [81].
Other biomarkers and experimental treatments have a promising
future according to the literature. The serum level of placental glyco-
protein pregnancy-associated plasma protein-A (PAPP-A) and of pla-
cental protein 13 (PP13), associated with Doppler ultrasound of the
uterine artery, have a predictive value of approximately 70% [87,99]
and 86% [22,87], with 5% and 10% false positive results, respectively;
the concentration of PAPP-A and PP13 is higher in PE. Similarly, serum
levels of fetal hemoglobin, of α1-microglobulin, of activin A, of inhibin
A, and of cellular metabolism products become altered in PE, and ap-
pear to significantly contribute to the progression of the disease
[87,100,101].
Laboratory tests indicate elevated levels of urinary prolactin in PE
accompanied by HELLP syndrome or eclampsia [95]; as well as high
plasma levels of malondialdehyde (10.72 ± 2.20 mmol/ml) than in
normotensive women (9.53 ± 2.45 mmol/ml), and positively asso-
ciated with maternal plasma sFlt-1 levels [47]. It is also observed an
increase in plasma levels of sTNF-R1 [29.34 (16.76–55.29) vs. 4.45
11
Pathology - Research and Practice 214 (2018) 7–14
(3.94–5.10) pg/ml] and sTNF-R2 (8698 ± 1602 vs. 6508 ± 1241 pg/
ml) when compared with non-pregnant women [58].
A recent study developed with 4380 offsprings from preeclamptic
pregnancies, highlighted the first genome-wide significant suscept-
ibility locus (rs4769613), located nearby Flt-1 gene encoding Fms-like
tyrosine kinase-1. Higher expression of rs4769613 showed strong re-
lation with offspring from pregnancies with late PE or which birth
weights exceeded the tenth centile. Thus, this finding reinforces the
hereditary risk associated with PE, since a placental isoform of sFlt-1 is
implicated in its etiopathogenesis [102].
Experimental treatments are another promising research area.
According to a multicentric study, 10 mg of pravastatin (a hydrophilic
statin) helps diminishing PE and premature delivery in pregnant
women at high risk for PE. In this study, placebo group (10 subjects)
had four women who developed PE and five had preterm deliveries
before 37 weeks compared with none PE cases and one preterm delivery
in pravastatin group (10 subjects). In addition, a higher concentration
of PlGF and a reduction of sFlt-1 and sEng concentration was observed
in the group receiving pravastatin. It is also noted that five newborns
from women in placebo group were admitted to an intermediate nur-
sery or to neonatal intensive care unit, while in the other group, only
two newborns required such attention [103].
Another research that evaluated the removal of sFlt-1 by whole-
blood apheresis using charged dextran sulfate column, pointed out that
pregnant women who received apheresis treatment presented a re-
duction in serum levels of sFlt-1. Comparing the mean pre-apheresis
and post-apheresis sFlt-1 concentration, there was a reduction from
17,394 (range 7916–35,301) pg/ml to 14,265 (6446–26,259) pg/ml,
respectively; an average reduction in sFlt-1 concentration of 18%
(7%–28%) per treatment. It is still outstanding a decrease in protein/
creatinine (P/C) ratios following apheresis in almost all pregnant
women. When compared the mean starting P/C ratio and post-treat-
ment values there was a reduction from 6.5 g/g (0.4–16.9 g/g) to 3.2
(0.2–8.6) g/g, respectively; an average reduction in P/C ratio of 44%
[104].
Although in the future it will be possible to establish an efficient and
effective diagnostic tool, the management of PE needs to follow three
key principles: prevention, early screening, and treatment. Therefore,
the identification of and risk calculation for PE is important, since
dietary changes, smoking cessation, comorbidity monitoring, blood
pressure (BP), and weight gain, for example, can contribute to the
prevention of this condition [105].
The evaluation of serum electrolytes (e.g.: sodium, potassium, urea,
creatinine, and uric acid), liver transaminases, blood counts (e.g.
identification of thrombocytopenia, and bilirubin), 24-h urine (in order
to monitor proteinuria), and heart rate and lung function of the mother
should be performed continuously, and so should analysis of cardioto-
cography, fetal growth, amniotic fluid volume, and umbilical artery
perfusion through Doppler ultrasound [3,105]. Therefore, the im-
portance of high quality prenatal care for pregnancy risk stratification
into low- and high-risk groups.
The introduction of oral anti-hypertensives (e.g.: methyldopa, hy-
dralazine, β-blockers, and nifedipine) [105,106] and low-dose acet-
ylsalicylic acid (in high-risk pregnancies after the first trimester) [96]
should be taken into account for the control of BP (BP < 160 × 105
mm Hg, mean BP < 125 mm Hg), for the reduction of heart attack risk
in hypertensive emergencies (≥160 × 105 mm Hg), as well as for the
increase in placental blood flow [22,105]. In the imminence or signs of
seizure, it is recommended to administer magnesium sulfate (MgSO4)
[dose of 4 g MgSO4, followed by infusion for 1 g/h up to 24 h after
delivery] [17,105,107] and plasma expanders [105,106]. Nonetheless,
delivery is indicated in the presence of fetal distress, when BP is diffi-
cult to control and clinical parameters and eclampsia deteriorate, since
PE resolves after the delivery of the fetus and the delivery of the pla-
centa [105].
Furthermore, postpartum follow-up is essential for monitoring
F.R. Helmo et al.
maternal blood pressure, and for the subsequent confirmation of the
resolution of gestational hypertension or diagnosis of systemic hy-
pertension in postpartum mothers, as well as for monitoring the risk of
renal and cardiovascular diseases [2,28,105].
The literature highlights the increased risk for cardiovascular dis-
eases (ex.: coronary death, myocardial infarction, fatal or non-fatal
stroke, coronary insufficiency, angina pectoris, transient ischemic at-
tack, intermittent claudication or congestive heart failure) among
women with previous PE [108–110]. In these women, significant
changes in blood pressure, fasting glucose, fasting insulin, high-sensi-
tive C-reactive protein, triglycerides and cholesterol were observed
about three months postpartum [108].
A research has shown that women diagnosed with isolated PE
showed a doubled risk for major coronary events, compared with
women without PE; and the risk may triple if PE is accompanied by
newborns small for gestational age and/or preterm delivery, or become
even larger than 4,7 times for women with recurrent PE, and with a risk
of dying even 23% higher in relation to women without PE [110].
It should be noted that a meta-analysis indicates a relative risk of
3.70 for the diagnosis of hypertension after PE, compared to women
who did not develop PE. As well as a risk of 2.60 for fatal ischemic heart
disease, which can be almost eight times higher if PE develops before
37 weeks. It also stands out the relative increased risk for fatal and non-
fatal stroke and venous thromboembolism in women who developed PE
[111].
5. Conclusion
Preeclampsia has a major impact on maternal and fetal health, since
it is responsible for up to 15% of maternal deaths. Even though there
are different predisposing factors, such as African descent, obesity and
previous CH, this hypertensive disorder is believed to be triggered by a
change in the expression of angiogenic and anti-angiogenic factors,
which appears to be the key factor in the endothelial dysfunction ob-
served in this entity.
The expression of VEGF-A, PlGF, endoglin, and their respective re-
ceptors Flt-1, Flk-1, sFlt-1 and sEng, is fundamental to the establish-
ment of uteroplacental circulation. Nevertheless, in PE there is an in-
creased expression of sFlt-1 and sEng by the placenta, a decreased
expression of VEGF-A and PlGF, and, thus, impaired angiogenesis and
vasculogenesis. The imbalance between angiogenic and anti-angiogenic
factors seems to be triggered by the increased expression of endothelin-
1, TNF-α and AT1-AAs, for instance.
Studies have identified promising biomarkers that can promote the
early diagnosis of this entity in the future, such as VEGF, PlGF, sFlt-1,
sEng, PAPP-A and PP13. However, screening and early treatment may
contribute to the prevention of PE.
Compliance with ethical standards
Funding
This study was funded by Conselho Nacional de Desenvolvimento
Cientifico e Tecnológico (CNPq) (grant number 470029/20110),
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
(grant number PNPD-02604/094), Fundação de Amparo a Pesquisa do
Estado de Minas Gerais (FAPEMIG) (grant number CDS-APQ-02135-
14), and Fundação de Ensino e Pesquisa de Uberaba (FUNEPU) (grant
number CDS-922/2009). All them from Brazil.
Ethical approval
This article does not contain any studies with human participants or
animals performed by any of the authors.
12
Pathology - Research and Practice 214 (2018) 7–14
Author contributions
Fernanda Rodrigues Helmo: ‘I declare that I participated in the
project development, data collection, manuscript writing/editing and
that I have seen and approved the final version. I have no conflicts of
interest’. Angela Maria Moed Lopes: ‘I declare that I participated in
the project development, data collection, manuscript writing and that I
have seen and approved the final version. I have no conflicts of in-
terest’. Anna Cecília Dias Maciel Carneiro: ‘I declare that I partici-
pated in the project development, data collection, manuscript writing
and that I have seen and approved the final version. I have no conflicts
of interest’. Carolina Guissoni Campos: ‘I declare that I participated in
the project development, data collection, manuscript writing and that I
have seen and approved the final version. I have no conflicts of in-
terest’. Polyana Barbosa Silva: ‘I declare that I participated in the
project development, data collection, manuscript writing and that I
have seen and approved the final version. I have no conflicts of in-
terest’. Maria Luíza Gonçalves dos Reis Monteiro: ‘I declare that I
participated in the manuscript writing and that I have seen and ap-
proved the final version. I have no conflicts of interest’. Laura Penna
Rocha: ‘I declare that I participated in the data collection and that I
have seen and approved the final version. I have no conflicts of in-
terest’. Marlene Antônia dos Reis: ‘I declare that I participated in the
management and that I have seen and approved the final version. I have
no conflicts of interest’. Renata Margarida Etchebehere: ‘I declare
that I participated in the management and that I have seen and ap-
proved the final version. I have no conflicts of interest’. Juliana Reis
Machado: ‘I declare that I participated in the management and that I
have seen and approved the final version. I have no conflicts of in-
terest’. Rosana Rosa Miranda Corrêa: ‘I declare that I participated in
the project development, management and that I have seen and ap-
proved the final version. I have no conflicts of interest’.
Acknowledgements
We thank Conselho Nacional de Desenvolvimento Cientifico e
Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior (CAPES), Fundação de Amparo a Pesquisa do Estado de
Minas Gerais (FAPEMIG), and Fundação de Ensino e Pesquisa de
Uberaba (FUNEPU) for financial support.
References
[1] E. Eiland, C. Nzerue, M. Faulkner, Preeclampsia 2012, J. Pregnancy 2012 (2012)
586578.
[2] T. Chaiworapongsa, P. Chaemsaithong, L. Yeo, R. Romero, Pre-eclampsia part 1:
current understanding of its pathophysiology, Nat. Rev. Nephrol. 10 (2014)
466–480.
[3] ACOG, Hypertension in Pregnancy, American College of Obstetricians and
Gynecologists (ACOG), Washington, 2013.
[4] A.B. Lerner, J.D. Case, Y. Takahashi, Isolation of melatonin and 5-methoxyindole-
3-acetic acid from bovine pineal glands, J. Biol. Chem. 235 (1960) 1992–1997.
[5] Z. Liu, G.B. Afink, P.T. Dijke, Soluble fms-like tyrosine kinase 1 and soluble en-
doglin are elevated circulating anti-angiogenic factors in pre-eclampsia,
Pregnancy Hypertens. 2 (2012) 358–367.
[6] M.D. Lindheimer, W. Benson, P. Harer, The history of preeclampsia and eclampsia
as seen by a nephrologist, Clin. Rev. 31 (2013) 8–12.
[7] M. Silasi, B. Cohen, S.A. Karumanchi, S. Rana, Abnormal placentation angiogenic
factors, and the pathogenesis of preeclampsia, Obstet. Gynecol. Clin. North Am. 37
(2010) 239–253.
[8] A.M. Borzychowski, I.L. Sargent, C.W. Redman, Inflammation and pre-eclampsia,
Semin. Fetal Neonatal Med. 11 (2006) 309–316.
[9] M. Schmidt, B. Hoffmann, D. Beelen, A. Gellhaus, E. Winterhager, R. Kimmig,
S. Kasimir-Bauer, Detection of circulating trophoblast particles in peripheral ma-
ternal blood in preeclampsia complicated pregnancies, Hypertens. Pregnancy 27
(2008) 131–142.
[10] R. Hong, M. Ruiz-Beltran, Impact of prenatal care on infant survival in Bangladesh,
Matern. Child Health J. 11 (2007) 199–206.
[11] L.O. Walker, L.W. Chesnut, Identifying health disparities and social inequities
affecting childbearing women and infants, J. Obstet. Gynecol. Neonatal Nurs. 39
(2010) 328–338.
[12] R.W. Powers, A. Jeyabalan, R.G. Clifton, P. Van Dorsten, J.C. Hauth,
F.R. Helmo et al.
M.A. Klebanoff, M.D. Lindheimer, B. Sibai, M. Landon, M. Miodovnik, Soluble fms-
Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in
preeclampsia among high risk pregnancies, PLoS One 5 (2010) e13263.
[13] L.L. Jardim, D.R. Rios, L.O. Perucci, L.P. de Sousa, K.B. Gomes, L.M. Dusse, Is the
imbalance between pro-angiogenic and anti-angiogenic factors associated with
preeclampsia, Clin. Chim. Acta 447 (2015) 34–38.
[14] G.E. Lash, H.A. Otun, B.A. Innes, M. Kirkley, L. De Oliveira, R.F. Searle,
S.C. Robson, J.N. Bulmer, Interferon-gamma inhibits extravillous trophoblast cell
invasion by a mechanism that involves both changes in apoptosis and protease
levels, FASEB J. 20 (2006) 2512–2518.
[15] T. Chaiworapongsa, R. Romero, S.J. Korzeniewski, J.P. Kusanovic, E. Soto, J. Lam,
Z. Dong, N.G. Than, L. Yeo, E. Hernandez-Andrade, A. Conde-Agudelo,
S.S. Hassan, Maternal plasma concentrations of angiogenic/antiangiogenic factors
in the third trimester of pregnancy to identify the patient at risk for stillbirth at or
near term and severe late preeclampsia, Am. J. Obstet. Gynecol. 208 (2013) 287
e281–287. e215.
[16] L. Duley, The global impact of pre-eclampsia and eclampsia, Semin. Perinatol. 33
(2009) 130–137.
[17] S.E. Maynard, S.A. Karumanchi, Angiogenic factors and preeclampsia, Semin.
Nephrol. 31 (2011) 33–46.
[18] T.C. Nogueira, C. Lellis-Santos, D.S. Jesus, M. Taneda, S.C. Rodrigues, F.G. Amaral,
A.M. Lopes, J. Cipolla-Neto, S. Bordin, G.F. Anhê, Absence of melatonin induces
night-time hepatic insulin resistance and increased gluconeogenesis due to sti-
mulation of nocturnal unfolded protein response, Endocrinology 152 (2011)
1253–1263.
[19] Brasil, DATASUS (Ed.), Mortalidade e nascidos vivos: óbitos maternos, Ministério
da Saúde, Brasília, 2015.
[20] R. Pijnenborg, J.M. Bland, W.B. Robertson, I. Brosens, Uteroplacental arterial
changes related to interstitial trophoblast migration in early human pregnancy,
Placenta 4 (1983) 397–413.
[21] S. Gupta, A. Agarwal, R.K. Sharma, The role of placental oxidative stress and lipid
peroxidation in preeclampsia, Obstet. Gynecol. Surv. 60 (2005) 807–816.
[22] A.F. Tanbe, R.A. Khalil, Circulating and vascular bioactive factors during hy-
pertension in pregnancy, Curr. Bioact. Compd. 6 (2010) 60–75.
[23] A. Kharfi, Y. Giguere, V. Sapin, J. Masse, B. Dastugue, J.C. Forest, Trophoblastic
remodeling in normal and preeclamptic pregnancies: implication of cytokines,
Clin. Biochem. 36 (2003) 323–331.
[24] B. Sibai, G. Dekker, M. Kupferminc, Pre-eclampsia, Lancet 365 (2005) 785–799.
[25] W. Ramma, I.A. Buhimschi, G. Zhao, A.T. Dulay, U.A. Nayeri, C.S. Buhimschi,
A. Ahmed, The elevation in circulating anti-angiogenic factors is independent of
markers of neutrophil activation in preeclampsia, Angiogenesis 15 (2012)
333–340.
[26] A. Elsheikh, G. Creatsas, G. Mastorakos, S. Milingos, D. Loutradis, S. Michalas, The
renin-aldosterone system during normal and hypertensive pregnancy, Arch.
Gynecol. Obstet. 264 (2001) 182–185.
[27] F. Khan, J.J. Belch, M. MacLeod, G. Mires, Changes in endothelial function pre-
cede the clinical disease in women in whom preeclampsia develops, Hypertension
46 (2005) 1123–1128.
[28] M. Sircar, R. Thadhani, S.A. Karumanchi, Pathogenesis of preeclampsia, Curr.
Opin. Nephrol. Hypertens. 24 (2015) 131–138.
[29] A.C. Palei, F.T. Spradley, J.P. Warrington, E.M. George, J.P. Granger,
Pathophysiology of hypertension in pre-eclampsia: a lesson in integrative phy-
siology, Acta Physiol. (Oxf.) 208 (2013) 224–233.
[30] C.W. Redman, I.L. Sargent, Latest advances in understanding preeclampsia,
Science 308 (2005) 1592–1594.
[31] E. Soto, R. Romero, J.P. Kusanovic, G. Ogge, Y. Hussein, L. Yeo, S.S. Hassan,
C.J. Kim, T. Chaiworapongsa, Late-onset preeclampsia is associated with an im-
balance of angiogenic and anti-angiogenic factors in patients with and without
placental lesions consistent with maternal underperfusion, J. Matern. Fetal
Neonatal Med. 25 (2012) 498–507.
[32] M. Egbor, T. Ansari, N. Morris, C.J. Green, P.D. Sibbons, Morphometric placental
villous and vascular abnormalities in early- and late-onset pre-eclampsia with and
without fetal growth restriction, BJOG 113 (2006) 580–589.
[33] N.M. Hunkapiller, M. Gasperowicz, M. Kapidzic, V. Plaks, E. Maltepe,
J. Kitajewski, J.C. Cross, S.J. Fisher, A role for Notch signaling in trophoblast
endovascular invasion and in the pathogenesis of pre-eclampsia, Development 138
(2011) 2987–2998.
[34] V. Rigourd, C. Chauvet, S.T. Chelbi, R. Rebourcet, F. Mondon, F. Letourneur,
T.M. Mignot, S. Barbaux, D. Vaiman, STOX1 overexpression in choriocarcinoma
cells mimics transcriptional alterations observed in preeclamptic placentas, PLoS
One 3 (2008) e3905.
[35] G.J. Burton, H.W. Yung, Endoplasmic reticulum stress in the pathogenesis of early-
onset pre-eclampsia, Pregnancy Hypertens. 1 (2011) 72–78.
[36] D.S. Charnock-Jones, Placental hypoxia, endoplasmic reticulum stress and ma-
ternal endothelial sensitisation by sFLT1 in pre-eclampsia, J. Reprod. Immunol.
114 (2016) 81–85.
[37] L. Du, F. He, L. Kuang, W. Tang, Y. Li, D. Chen, eNOS/iNOS and endoplasmic
reticulum stress-induced apoptosis in the placentas of patients with preeclampsia,
J. Hum. Hypertens. 31 (2017) 49–55.
[38] J. Fu, L. Zhao, L. Wang, X. Zhu, Expression of markers of endoplasmic reticulum
stress-induced apoptosis in the placenta of women with early and late onset severe
pre-eclampsia, Taiwan J. Obstet. Gynecol. 54 (2015) 19–23.
[39] A. Moffett, S. Hiby, Influence of activating and inhibitory killer immunoglobulin-
like receptors on predisposition to recurrent miscarriages, Hum. Reprod. 24
(2009) 2048–2049.
[40] J.E. Cartwright, L. James-Allan, R.J. Buckley, A.E. Wallace, The role of decidual
13
Pathology - Research and Practice 214 (2018) 7–14
NK cells in pregnancies with impaired vascular remodelling, J. Reprod. Immunol.
119 (2017) 81–84.
[41] A.E. Wallace, G.S. Whitley, B. Thilaganathan, J.E. Cartwright, Decidual natural
killer cell receptor expression is altered in pregnancies with impaired vascular
remodeling and a higher risk of pre-eclampsia, J. Leukoc. Biol. 97 (2015) 79–86.
[42] R. Fraser, G.S. Whitley, B. Thilaganathan, J.E. Cartwright, Decidual natural killer
cells regulate vessel stability: implications for impaired spiral artery remodelling,
J. Reprod. Immunol. 110 (2015) 54–60.
[43] A. Moffett, S.E. Hiby, How Does the maternal immune system contribute to the
development of pre-eclampsia? Placenta 28 (Suppl. A) (2007) S51–S56.
[44] T. Chaiworapongsa, R. Romero, J. Espinoza, E. Bujold, Y. Mee Kim, L.F. Goncalves,
R. Gomez, S. Edwin, Evidence supporting a role for blockade of the vascular en-
dothelial growth factor system in the pathophysiology of preeclampsia. Young
Investigator Award, Am. J. Obstet. Gynecol. 190 (2004) 1541–1547 discussion
1547–1550.
[45] S.W. Walsh, Maternal-placental interactions of oxidative stress and antioxidants in
preeclampsia, Semin. Reprod. Endocrinol. 16 (1998) 93–104.
[46] T.H. Hung, G.J. Burton, Hypoxia and reoxygenation: a possible mechanism for
placental oxidative stress in preeclampsia, Taiwan J. Obstet. Gynecol. 45 (2006)
189–200.
[47] A.V. Kulkarni, S.S. Mehendale, H.R. Yadav, A.S. Kilari, V.S. Taralekar, S.R. Joshi,
Circulating angiogenic factors and their association with birth outcomes in pre-
eclampsia, Hypertens. Res. 33 (2010) 561–567.
[48] A. Ahmed, New insights into the etiology of preeclampsia: identification of key
elusive factors for the vascular complications, Thromb. Res. 127 (Suppl. 3) (2011)
S72–S75.
[49] A.S. Cerdeira, S.A. Karumanchi, Angiogenic factors in preeclampsia and related
disorders, Cold Spring Harb. Perspect. Med. 2 (2012).
[50] A.E. Wallace, R. Fraser, S. Gurung, S.S. Goulwara, G.S. Whitley, A.P. Johnstone,
J.E. Cartwright, Increased angiogenic factor secretion by decidual natural killer
cells from pregnancies with high uterine artery resistance alters trophoblast
function, Hum. Reprod. 29 (2014) 652–660.
[51] A. Pratt, F. Da Silva Costa, A.J. Borg, B. Kalionis, R. Keogh, P. Murthi, Placenta-
derived angiogenic proteins and their contribution to the pathogenesis of pre-
eclampsia, Angiogenesis 18 (2015) 115–123.
[52] R. Romero, J.K. Nien, J. Espinoza, D. Todem, W. Fu, H. Chung, J.P. Kusanovic,
F. Gotsch, O. Erez, S. Mazaki-Tovi, R. Gomez, S. Edwin, T. Chaiworapongsa,
R.J. Levine, S.A. Karumanchi, A longitudinal study of angiogenic (placental
growth factor) and anti-angiogenic (soluble endoglin and soluble vascular en-
dothelial growth factor receptor-1) factors in normal pregnancy and patients
destined to develop preeclampsia and deliver a small for gestational age neonate,
J. Matern. Fetal Neonatal Med. 21 (2008) 9–23.
[53] R.J. Levine, S.E. Maynard, C. Qian, K.H. Lim, L.J. England, K.F. Yu,
E.F. Schisterman, R. Thadhani, B.P. Sachs, F.H. Epstein, B.M. Sibai, V.P. Sukhatme,
S.A. Karumanchi, Circulating angiogenic factors and the risk of preeclampsia, N.
Engl. J. Med. 350 (2004) 672–683.
[54] S.E. Maynard, J.Y. Min, J. Merchan, K.H. Lim, J. Li, S. Mondal, T.A. Libermann,
J.P. Morgan, F.W. Sellke, I.E. Stillman, F.H. Epstein, V.P. Sukhatme,
S.A. Karumanchi, Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may
contribute to endothelial dysfunction hypertension, and proteinuria in pre-
eclampsia, J. Clin. Invest. 111 (2003) 649–658.
[55] M. Shibuya, L. Claesson-Welsh, Signal transduction by VEGF receptors in regula-
tion of angiogenesis and lymphangiogenesis, Exp. Cell Res. 312 (2006) 549–560.
[56] A.S. Maharaj, P.A. D’Amore, Roles for VEGF in the adult, Microvasc. Res. 74
(2007) 100–113.
[57] C.L. Haggerty, M.E. Seifert, G. Tang, J. Olsen, D.C. Bass, S.A. Karumanchi,
R.B. Ness, Second trimester anti-angiogenic proteins and preeclampsia, Pregnancy
Hypertens. 2 (2012) 158–163.
[58] L.O. Perucci, K.B. Gomes, L.G. Freitas, L.C. Godoi, P.N. Alpoim, M.B. Pinheiro,
A.S. Miranda, A.L. Teixeira, L.M. Dusse, L.P. Sousa, Soluble endoglin, transforming
growth factor-Beta 1 and soluble tumor necrosis factor alpha receptors in different
clinical manifestations of preeclampsia, PLoS One 9 (2014) e97632.
[59] S. Venkatesha, M. Toporsian, C. Lam, J. Hanai, T. Mammoto, Y.M. Kim, Y. Bdolah,
K.H. Lim, H.T. Yuan, T.A. Libermann, I.E. Stillman, D. Roberts, P.A. D'Amore,
F.H. Epstein, F.W. Sellke, R. Romero, V.P. Sukhatme, M. Letarte, S.A. Karumanchi,
Soluble endoglin contributes to the pathogenesis of preeclampsia, Nat. Med. 12
(2006) 642–649.
[60] T.J. Kaitu’u-Lino, K.R. Palmer, C.L. Whitehead, E. Williams, M. Lappas, S. Tong,
MMP-14 is expressed in preeclamptic placentas and mediates release of soluble
endoglin, Am. J. Pathol. 180 (2012) 888–894.
[61] R.J. Levine, C. Lam, C. Qian, K.F. Yu, S.E. Maynard, B.P. Sachs, B.M. Sibai,
F.H. Epstein, R. Romero, R. Thadhani, S.A. Karumanchi, Soluble endoglin and
other circulating antiangiogenic factors in preeclampsia, N. Engl. J. Med. 355
(2006) 992–1005.
[62] P.K. Aggarwal, N. Chandel, V. Jain, V. Jha, The relationship between circulating
endothelin-1: soluble fms-like tyrosine kinase-1 and soluble endoglin in pre-
eclampsia, Am. J. Pathol. 180 (2012) 888–894.
[63] N. Ferrara, H.P. Gerber, J. LeCouter, The biology of VEGF and its receptors, Nat.
Med. 9 (2003) 669–676.
[64] M.G. Cardenas-Mondragon, G. Vallejo-Flores, J. Delgado-Dominguez, J.F. Romero-
Arauz, A. Gomez-Delgado, G. Aguilar-Madrid, J.J. Sanchez-Barriga, J. Marquez-
Acosta, Preeclampsia is associated with lower production of vascular endothelial
growth factor by peripheral blood mononuclear cells, Arch. Med. Res. 45 (2014)
561–569.
[65] A. Wang, S. Rana, S.A. Karumanchi, Preeclampsia: the role of angiogenic factors in
its pathogenesis, Physiology (Bethesda) 24 (2009) 147–158.
F.R. Helmo et al.
[66] H. Stepan, A. Geipel, F. Schwarz, T. Kramer, N. Wessel, R. Faber, Circulatory so-
luble endoglin and its predictive value for preeclampsia in second-trimester
pregnancies with abnormal uterine perfusion, Am. J. Obstet. Gynecol. 198 (2008)
175 e171–176.
[67] L. Govender, I. Mackraj, P. Gathiram, J. Moodley, The role of angiogenic: anti-
angiogenic and vasoactive factors in pre-eclamptic African women: early- versus
late-onset pre-eclampsia, Cardiovasc. J. Afr. 23 (2012) 153–159.
[68] E. Llurba, F. Crispi, S. Verlohren, Update on the pathophysiological implications
and clinical role of angiogenic factors in pregnancy, Fetal Diagn. Ther. 37 (2015)
81–92.
[69] C. Lam, K.H. Lim, S.A. Karumanchi, Circulating angiogenic factors in the patho-
genesis and prediction of preeclampsia, Hypertension 46 (2005) 1077–1085.
[70] A.C. Valbuena-Diez, F.J. Blanco, B. Oujo, C. Langa, M. Gonzalez-Nunez, E. Llano,
A.M. Pendas, M. Diaz, A. Castrillo, J.M. Lopez-Novoa, C. Bernabeu, Oxysterol-
induced soluble endoglin release and its involvement in hypertension, Circulation
126 (2012) 2612–2624.
[71] A. Goel, S. Rana, Angiogenic factors in preeclampsia: potential for diagnosis and
treatment, Curr. Opin. Nephrol. Hypertens. 22 (2013) 643–650.
[72] S.E. Maynard, S. Venkatesha, R. Thadhani, S.A. Karumanchi, Soluble Fms-like
tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia,
Pediatr. Res. 57 (2005) 1R–7R.
[73] S. Rana, S.A. Karumanchi, R.J. Levine, S. Venkatesha, J.A. Rauh-Hain, H. Tamez,
R. Thadhani, Sequential changes in antiangiogenic factors in early pregnancy and
risk of developing preeclampsia, Hypertension 50 (2007) 137–142.
[74] L.J. Vatten, A. Eskild, T.I. Nilsen, S. Jeansson, P.A. Jenum, A.C. Staff, Changes in
circulating level of angiogenic factors from the first to second trimester as pre-
dictors of preeclampsia, Am. J. Obstet. Gynecol. 196 (2007) 239 e231–236.
[75] A.R. Saxena, E.W. Seely, J.W. Rich-Edwards, L.E. Wilkins-Haug, S.A. Karumanchi,
T.F. McElrath, First trimester PAPP-A levels correlate with sFlt-1 levels long-
itudinally in pregnant women with and without preeclampsia, BMC Pregnancy
Childbirth 13 (2013) 1–9.
[76] Y. Purwosunu, A. Sekizawa, A. Farina, N. Wibowo, K. Koide, S. Okazaki,
M. Nakamura, T. Okai, Evaluation of physiological alterations of the placenta
through analysis of cell-free messenger ribonucleic acid concentrations of angio-
genic factors, Am. J. Obstet. Gynecol. 198 (2008) 124 e121–127.
[77] S.C. Kim, M.J. Park, B.S. Joo, J.K. Joo, D.S. Suh, K.S. Lee, Decreased expressions of
vascular endothelial growth factor and visfatin in the placental bed of pregnancies
complicated by preeclampsia, J. Obstet. Gynaecol. Res. 38 (2012) 665–673.
[78] H. Strevens, D. Wide-Swensson, A. Hansen, T. Horn, I. Ingemarsson, S. Larsen,
J. Willner, S. Olsen, Glomerular endotheliosis in normal pregnancy and pre-
eclampsia, BJOG 110 (2003) 831–836.
[79] E. Vaisbuch, J.E. Whitty, S.S. Hassan, R. Romero, J.P. Kusanovic, D.B. Cotton,
Y. Sorokin, S.A. Karumanchi, Circulating angiogenic and antiangiogenic factors in
women with eclampsia, Am. J. Obstet. Gynecol. 204 (2011) 152 e151–159.
[80] F. Crispi, C. Dominguez, E. Llurba, P. Martin-Gallan, L. Cabero, E. Gratacos,
Placental angiogenic growth factors and uterine artery Doppler findings for
characterization of different subsets in preeclampsia and in isolated intrauterine
growth restriction, Am. J. Obstet. Gynecol. 195 (2006) 201–207.
[81] S. Rana, C.E. Powe, S. Salahuddin, S. Verlohren, F.H. Perschel, R.J. Levine,
K.H. Lim, J.B. Wenger, R. Thadhani, S.A. Karumanchi, Angiogenic factors and the
risk of adverse outcomes in women with suspected preeclampsia, Circulation 125
(2012) 911–919.
[82] E. Laresgoiti-Servitje, N. Gomez-Lopez, The pathophysiology of preeclampsia in-
volves altered levels of angiogenic factors promoted by hypoxia and autoantibody-
mediated mechanisms, Biol. Reprod. 87 (2012) 36.
[83] M.R. Parrish, S.R. Murphy, S. Rutland, K. Wallace, K. Wenzel, G. Wallukat,
S. Keiser, L.F. Ray, R. Dechend, J.N. Martin, J.P. Granger, B. LaMarca, The effect of
immune factors tumor necrosis factor-alpha, and agonistic autoantibodies to the
angiotensin II type I receptor on soluble fms-like tyrosine-1 and soluble endoglin
production in response to hypertension during pregnancy, Am. J. Hypertens. 23
(2010) 911–916.
[84] D.S. Torry, H.S. Wang, T.H. Wang, M.R. Caudle, R.J. Torry, Preeclampsia is as-
sociated with reduced serum levels of placenta growth factor, Am. J. Obstet.
Gynecol. 179 (1998) 1539–1544.
[85] D. Fujita, A. Tanabe, T. Sekijima, H. Soen, K. Narahara, Y. Yamashita, Y. Terai,
H. Kamegai, M. Ohmichi, Role of extracellular signal-regulated kinase and AKT
cascades in regulating hypoxia-induced angiogenic factors produced by a tro-
phoblast-derived cell line, J. Endocrinol. 206 (2010) 131–140.
[86] T. Cindrova-Davies, D.A. Sanders, G.J. Burton, D.S. Charnock-Jones, Soluble FLT1
sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF re-
ceptor-mediated signalling, Cardiovasc. Res. 89 (2011) 671–679.
[87] U.D. Anderson, M.G. Olsson, K.H. Kristensen, B. Akerstrom, S.R. Hansson, Review:
biochemical markers to predict preeclampsia, Placenta 33 (Suppl) (2012)
S42–S47.
[88] W. Schaarschmidt, S. Rana, H. Stepan, The course of angiogenic factors in early- vs
late-onset preeclampsia and HELLP syndrome, J. Perinat. Med. 41 (2013)
511–516.
[89] E.R. Unal, C.J. Robinson, D.D. Johnson, E.Y. Chang, Second-trimester angiogenic
factors as biomarkers for future-onset preeclampsia, Am. J. Obstet. Gynecol. 197
(2007) 211 e211–214.
[90] J.P. Kusanovic, R. Romero, T. Chaiworapongsa, O. Erez, P. Mittal, E. Vaisbuch,
S. Mazaki-Tovi, F. Gotsch, S.S. Edwin, R. Gomez, L. Yeo, A. Conde-Agudelo,
S.S. Hassan, A prospective cohort study of the value of maternal plasma con-
centrations of angiogenic and anti-angiogenic factors in early pregnancy and
midtrimester in the identification of patients destined to develop preeclampsia, J.
Matern. Fetal Neonatal Med. 22 (2009) 1021–1038.
14
Pathology - Research and Practice 214 (2018) 7–14
[91] S.K. Ghosh, S. Raheja, A. Tuli, C. Raghunandan, S. Agarwal, Serum PLGF as a
potential biomarker for predicting the onset of preeclampsia, Arch. Gynecol.
Obstet. 285 (2012) 417–422.
[92] H. Stepan, A. Unversucht, N. Wessel, R. Faber, Predictive value of maternal an-
giogenic factors in second trimester pregnancies with abnormal uterine perfusion,
Hypertension 49 (2007) 818–824.
[93] A. Molvarec, A. Szarka, S. Walentin, E. Szucs, B. Nagy, J. Rigo Jr., Circulating
angiogenic factors determined by electrochemiluminescence immunoassay in re-
lation to the clinical features and laboratory parameters in women with pre-
eclampsia, Hypertens. Res. 33 (2010) 892–898.
[94] J. Stubert, S. Ullmann, M. Bolz, T. Külz, M. Dieterich, D.U. Richter, T. Reimer,
Prediction of preeclampsia and induced delivery at < 34 weeks gestation by sFLT-
1 and PlGF in patients with abnormal midtrimester uterine Doppler velocimetry: a
prospective cohort analysis, BMC Pregnancy Childbirth 14 (2014) 1–11.
[95] A. Leaños-Miranda, I. Campos-Galicia, K.L. Ramírez-Valenzuela, Z.L. Chinolla-
Arellano, I. Isordia-Salas, Circulating angiogenic factors and urinary prolactin as
predictors of adverse outcomes in women with preeclampsia, Hypertension 61
(2013) 1118–1125.
[96] H. Zeisler, E. Llurba, F. Chantraine, M. Vatish, A.C. Staff, M. Sennstrom,
M. Olovsson, S.P. Brennecke, H. Stepan, D. Allegranza, P. Dilba, M. Schoedl,
M. Hund, S. Verlohren, Predictive value of the sFlt-1:PlGF ratio in women with
suspected preeclampsia, N. Engl. J. Med. 374 (2016) 13–22.
[97] O. Erez, R. Romero, J. Espinoza, W. Fu, D. Todem, J.P. Kusanovic, F. Gotsch,
S. Edwin, J.K. Nien, T. Chaiworapongsa, P. Mittal, S. Mazaki-Tovi, N.G. Than,
R. Gomez, S.S. Hassan, The change in concentrations of angiogenic and anti-an-
giogenic factors in maternal plasma between the first and second trimesters in risk
assessment for the subsequent development of preeclampsia and small-for-gesta-
tional age, J. Matern. Fetal Neonatal Med. 21 (2008) 279–287.
[98] L.J. Vatten, B.O. Åsvold, A. Eskild, Angiogenic factors in maternal circulation and
preeclampsia with or without fetal growth restriction, Acta Obstet. Gynecol.
Scand. 91 (2012) 1388–1394.
[99] A.O. Odibo, Y. Zhong, K.R. Goetzinger, L. Odibo, J.L. Bick, C.R. Bower,
D.M. Nelson, First-trimester placental protein 13 PAPP-A, uterine artery Doppler
and maternal characteristics in the prediction of pre-eclampsia, Placenta 32
(2011) 598–602.
[100] A. Reddy, S. Suri, I.L. Sargent, C.W. Redman, S. Muttukrishna, Maternal circu-
lating levels of activin A, inhibin A, sFlt-1 and endoglin at parturition in normal
pregnancy and pre-eclampsia, PLoS One 4 (2009) e4453.
[101] A.Y. Pramatirta, J. Mose, J.S. Effendi, S.R. Krisnadi, A.D. Anwar, P.N. Fauziah,
J.I. Gurnadi, D.D. Rihibiha, Correlation between cell-free mRNA expressions and
PLGF protein level in severe preeclampsia, BMC Res. Notes 8 (2015) 1–6.
[102] R. McGinnis, V. Steinthorsdottir, N.O. Williams, G. Thorleifsson, S. Shooter,
S. Hjartardottir, S. Bumpstead, L. Stefansdottir, L. Hildyard, J.K. Sigurdsson,
J.P. Kemp, G.B. Silva, L.C.V. Thomsen, T. Jaaskelainen, E. Kajantie, S. Chappell,
N. Kalsheker, A. Moffett, S. Hiby, W.K. Lee, S. Padmanabhan, N.A.B. Simpson,
V.A. Dolby, E. Staines-Urias, S.M. Engel, A. Haugan, L. Trogstad, G. Svyatova,
N. Zakhidova, D. Najmutdinova, A.F. Dominiczak, H.K. Gjessing, J.P. Casas,
F. Dudbridge, J.J. Walker, F.B. Pipkin, U. Thorsteinsdottir, R.T. Geirsson,
D.A. Lawlor, A.C. Iversen, P. Magnus, H. Laivuori, K. Stefansson, L. Morgan,
Variants in the fetal genome near FLT1 are associated with risk of preeclampsia,
Nat. Genet. 49 (2017) 1255–1260.
[103] M.M. Costantine, K. Cleary, M.F. Hebert, M.S. Ahmed, L.M. Brown, Z. Ren,
T.R. Easterling, D.M. Haas, L.S. Haneline, S.N. Caritis, R. Venkataramanan,
H. West, M. D’Alton, G. Hankins, E.K.S.N.I.o.C.H.a.H.D.O.-F.P.R.U. Network,
Safety and pharmacokinetics of pravastatin used for the prevention of pre-
eclampsia in high-risk pregnant women: a pilot randomized controlled trial, Am. J.
Obstet. Gynecol. 214 (2016) 20 e21–720. e717.
[104] R. Thadhani, H. Hagmann, W. Schaarschmidt, B. Roth, T. Cingoez,
S.A. Karumanchi, J. Wenger, K.J. Lucchesi, H. Tamez, T. Lindner, A. Fridman,
U. Thome, A. Kribs, M. Danner, S. Hamacher, P. Mallmann, H. Stepan, T. Benzing,
Removal of soluble Fms-like tyrosine kinase-1 by dextran sulfate apheresis in
preeclampsia, J. Am. Soc. Nephrol.: JASN 27 (2016) 903–913.
[105] F.A. English, L.C. Kenny, F.P. McCarthy, Risk factors and effective management of
preeclampsia, Integr. Blood Press Control 8 (2015) 7–12.
[106] L. Duley, J. Williams, D.J. Henderson-Smart, Plasma volume expansion for treat-
ment of women with pre-eclampsia, Cochrane Database Syst. Rev. (2000)
CD001805.
[107] D. Altman, G. Carroli, L. Duley, B. Farrell, J. Moodley, J. Neilson, D. Smith,
M.T.C. Group, Do women with pre-eclampsia and their babies, benefit from
magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial,
Lancet 359 (2002) 1877–1890.
[108] J.H. Veerbeek, W. Hermes, A.Y. Breimer, B.B. van Rijn, S.V. Koenen, B.W. Mol,
A. Franx, C.J. de Groot, M.P. Koster, Cardiovascular disease risk factors after early-
onset preeclampsia late-onset preeclampsia, and pregnancy-induced hypertension,
Hypertension 65 (2015) 600–606.
[109] N.M. Breetveld, C. Ghossein-Doha, S. van Kuijk, A.P. van Dijk, M.J. van der Vlugt,
W.M. Heidema, R.R. Scholten, M.E. Spaanderman, Cardiovascular disease risk is
only elevated in hypertensive formerly preeclamptic women, BJOG 122 (2015)
1092–1100.
[110] H.K. Riise, G. Sulo, G.S. Tell, J. Igland, O. Nygard, S.E. Vollset, A.C. Iversen,
R. Austgulen, A.K. Daltveit, Incident coronary heart disease after preeclampsia:
role of reduced fetal growth, preterm delivery, and parity, J. Am. Heart Assoc. 6
(2017).
[111] L. Bellamy, J.P. Casas, A.D. Hingorani, D.J. Williams, Pre-eclampsia and risk of
cardiovascular disease and cancer in later life: systematic review and meta-ana-
lysis, BMJ 335 (2007) 974.