Preeclampsia (PE) is a multisystem disorder, that affects approximately 5 % of
pregnancies worldwide. PE is one of the leading causes of maternal, fetal and neonatal
morbidity or mortality. The onset of PE occurs about 20. gestational week (exceptionally
before 20 weeks; Tanaka et al., 2015) and it is characterized by many heterogenous
symptoms. The most detectable symptoms are hypertension and proteinuria, which also
serves as the main diagnostic markers. In addition, several other symptoms could be linked to
PE such as abnormalities of placenta, kidney, and liver, neurological and hematological
complications which could lead to fetal damage. In general, the treatment of PE is to manage
the symptoms however the disorder persists. Since PE is a disorder of the placenta, the only
direct treatment is the delivery. More than half of women are forced to undergo the delivery
in the form of a section (Roberts and Lain, 2002; Zhang et al, 2003; Wagner, 2004; Liu et al.,
The major criteria for diagnosing the disease are de novo hypertension, which appears
after 20 weeks gestation, in combination with proteinuria. Preeclamptic hypertension is
defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg,
measured twice, at intervals of 4 – 6 hours. Proteinuria (elevated levels of proteins in urine) is
determined by the protein content in urine ≥ 300 mg/day (Mol et al., 2016; Townsend et al.,
There is a group of abnormalities, known together as the hypertensive disorders of
pregnancy, which includes preeclampsia and gestational hypertension. It is possible, that
hypertension is elevated for the first time after 20 weeks gestation, suggesting a potential
onset of PE, but the patient does not suffer from proteinuria. This condition is classified as
having gestational hypertension. One of four women, suffering from gestational
hypertension, subsequently develop proteinuria, leading to the onset of PE (Saudan et al.,
1998; Report of the National High Blood Pressure Education Program Working Group on
High Blood Pressure in Pregnancy, 2000; Wagner, 2004). The similarity of symptoms
detected in the hypertensive disorders of are the reason of the unclear and inaccurate
diagnostics of PE.
Dong et al. monitored PE in women of varying severity of proteinuria. Based on the
obtained data, authors suggest that the level of proteins in urine may be associated with the
development of severity of PE. In addition, they refer, that the amount of proteinuria is
positively correlated with time of onset in PE, but time between the onset of PE and delivery
is not associated with the severity of proteinuria (Dong et al., 2017). Despite the mentioned
diagnostic features, up to 10 % of patients with PE have no proteinuria at the time of clinical
presentation (Sibai, 1990; Thornton et al., 2010; Dong et al., 2017). These knowledges
complicate the detection of disorder onset causing difficulties in diagnostics of PE.
Trophoblast and placenta
The structure and functionality of the placenta is related to the health of mother and
developing fetus (Guttmacher et al., 2014). The process of placentation is the key point in PE,
because the placenta formation provides the functional connection between mother and fetus.
The result of placentation is the implantation of blastocyst in uterus. Invasion of the
trophoblast into the maternal endometrium is necessary for placentation. The blastocyst
contains a layer of cytotrophoblast cells on its surface, the cells that fuse and form a
multinucleated syncytiotrophoblast (fig. 1). Only the multinucleated unit can invade into the
maternal endometrium, what is indispensable for the proper placentation process (Popek,
1999; Ji et al., 2013).
Syncytin-1 in placentation
Syncytin-1 protein is encoded by ERVW-1 gene belonging to the human endogenous
retroviral family – HERV-W. The highest level of ERVW-1 expression was detected in
placenta. The product of this gene mediates the cytotrophoblast cell fusion, from which
differentiates multinucleated syncytiotrophoblast (fig. 2). Without the fusogenic activity of
syncytin-1, normal placentation could not occur (Blond et al., 1999; Blond et al., 2000; Mi et
al., 2000; Voisset et al, 2000; Huang et al., 2014).
Molecular structure of ERVW-1 gene
ERVW-1 gene is located on q21.2 of chromosome 7 in the genome. It consists of
three, originally retroviral, parts of which gag and pol regions are found in the human
genome as pseudogenes, while the env (coding envelope protein) region has been
functionally preserved. Only the env region has retained complete retroviral ORF (Open
Reading Frame), whose product is fusogenic protein syncytin-1, required for the cell fusion
in syncytiotrophoblast forming (fig. 3). Env sequence is flanked by two LTR (Long Terminal
Repeat) regions. Downstream from 5ʼLTR is laying an intron with the size of 2 kb (Blond et
al, 1999; Blond et al., 2000; Voisset et al., 2000).
The structure of the syncytin-1 protein
The functional syncytin-1 consist of surface-associated unit (SU) and transmembrane
unit (TM), which are linked to each other by disulfide bonds. SU plays a role in interaction
with receptors. The role of the TM is to cross the membrane and anchor the peptide in the cell
membrane. Moreover, TM contains the potential immunosuppressive domain, which has a
competence to supress the immune response of mother towards fetus. Fully functional
syncytin-1 is organised as a homotrimeric structure. Without this spatial arrangement, it loses
the fusogenic activity (Fass and Kim, 1995; Cheynet et al., 2005).
Syncytin-1 and preeclampsia
According to Holder et al., the level of syncytin-1 is elevated in placenta of PE
women, compared to physiological placentas (Holder et al., 2012). This founding contrasts
with other studies, they refer decreased expression of syncytin-1 at the mRNA but also
protein level (Lee et al., 2001; Knerr et al., 2002; Vargas et al., 2011). In addition, many
studies included inadequate number of samples considering the frequency of incidence of PE.
Despite the knowledge obtained regarding the association between syncytin-1 and PE, the
overall conclusions are still unclear. Consequently, there is a need for a closer study of the
pathophysiology of PE in terms of correlation of ERVW-1 gene expression with the disease,
and the results need to be demonstrated in a sufficiently large sample of patients.
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Project supported by the Ministry of Health of the Slovak Republic (MZSR 2018/40-LFUK-14)
Supported priority areas chosen from the approved list for a year 2018: Innovative diagnostic and
therapeutic procedures and products personalized / precision medicine - 1. Early, fast and valid
diagnosis - Products for the identification of novel biomarkers of disease