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2. insufficiency, such as pregnancy-induced hyper
tension, preeclampsia, intrauterine growth restric
tion (IUGR), placental prolapse, and perinatal
mortality.3,4 Inadequate placental perfusion due to
dysfunction in uteroplacental arteries causes the
release of factors such as cytokines, leukotrienes,
and immunomodulatory hormones to circulation.5
Researchers have identified trophoblastic tumors,
invasive hydatidiform moles, and choriocarcino
mas in the noncomplicated placental area with
trophoblastic invasion.6
Apoptosis, known as programmed cell death,
plays an important role in pregnancy complica-
tions such as hydatidiform mole, preeclampsia,
and IUGR. The placental apoptosis can be induced
by a variety of stimuli, including hypoxia and oxi-
dative stress. Placental apoptosis occurs in pre
eclampsia, IUGR, and molar pregnancies, especial
ly hydatidiform moles (trophoblast hyperplasia).
Trophoblastic apoptosis induces signaling path
ways, resulting in caspase activation. Caspase
proteins are proteases involved in apoptosis and
inflammatory cascades. Caspase-12 is a member of
the inflammatory caspase subfamily. Yeretssian et
al7 suggested that estrogen-mediated inhibition of
Caspase-12 expression is a mechanism developed
to protect females from infection, preferring a
more robust inflammatory response to pathogens,
particularly at birth.7 The Caspase-12 gene in hu-
mans has been reported to function as the pre
dominant negative regulator of proinflammatory
signaling pathways rather than the cell death
pathway induced by endoplasmic reticulum (ER)
stress.
ADAMTS (A Disintegrin and Metalloproteinase
with Thrombospondin motifs) subtypes have been
reported to have the ability to activate the pro-
teolytic modification of extracellular matrix pro
teins such as ADAMTS-1, -4, and -5 cell surface
proteins, although their biological functions are
not fully understood.8,9 Zhu et al10 determined
that ADAMTS-5 was expressed in human decid-
ual stromal cells in vivo and in vitro. They sug
gested that interleukin-1β and transforming growth
factor beta 1, two key regulators of the proteo-
lytic mechanisms operative at the maternal-fetal
interface, were capable of regulating ADAMTS-5
mRNA and protein expression levels in these
cells in vitro. According to their observations,
they concluded that the regulated expression of
mem-bers of the ADAMTS gene family of matrix
metalloproteinases contributed to the cytokine-
mediated degradation of decidual extracellular
matrix during pregnancy in humans.10 In the de-
velopment of preeclampsia during the last trimes
ter of pregnancy, ADAMTS-5 is also known as
aggrecan-2, a major component of extracellular
matrix and ADAMTS-5 gene known to be ex-
pressed in the bladder, cervix, esophagus, pla
centa, and uterus.11 Previous studies showed that
the ADAMTS family plays a regulatory role in im-
plantation and maintenance of pregnancy.12
In this study, we aimed to investigate the role of
Caspase-12 and ADAMTS-5 expression in samples
of placentas from women with placenta previa and
normotensive healthy women.
Materials and Methods
Patient Follow-Up
This study was performed at the Department of
Obstetrics and Gynecology, Memorial Hospital,
between May 2018 and April 2019. It was ap-
proved by the ethics committee of Memorial Hos
pital (ID 15/02.04.2018), Diyarbakır, Turkey, and
all patients gave informed written consent. This
clinical trial consists of 15 placentas of women
with placenta previa and 15 placenta samples
from normotensive healthy women between 29
and 38 weeks of gestation. The gestational weeks
of the women were determined according to the
last date of menstruation and/or ultrasonographic
measurements. In this clinical study, pregnant
women with an infection, patients with chronic
cardiac disease, and those with other chronic dis-
eases were excluded from the study. Embryologi
cally, patients with intrauterine growth restriction
were also not included in the evaluation.
Table I shows the clinical features of the pla
centas from the women with placenta previa (pla-
centa previa group) and the normotensive heal
thy women (control group). Pregnant women with
systolic >140 mmHg, diastolic >90 mmHg, and
proteinuria 0.3 g/24 h were included in the pla
centa previa group. For both groups, portions of
the central and edge zones of the placenta were
collected for histopathologic and immunohisto
chemical examinations.
Placental Tissue Collection and Hematoxylin-Eosin
Staining Procedure
Immediately after birth, normal and placenta pre-
via tissues were moved from the delivery room
to the laboratory and, after preliminary histopa
thological examination, 2 series of tissue sam-
192 Analytical and Quantitative Cytopathology and Histopathology®
Çavus
and Değer
3. ples were obtained. Samples of placental tissue
(1×1×1 cm) obtained from healthy patients and
patients with placenta previa were cut out im-
mediately after cesarean delivery from the ma-
ternal side around the umbilical cord under ster
ile conditions. Tissue sections of 4–6 µm thickness
(RM2265 rotary microtome; Leica, Germany) were
prepared in the transverse plane and stained
using hematoxylin-eosin (H-E) staining for light
microscopy examination.
The H-E staining procedure was as follows.
After the deparaffinizing procedure of sections
with 2 changes of xylene for 10 minutes each,
they were rehydrated in 2 changes of absolute
alcohol, 5 minutes each. Applied with 95% al-
cohol for 2 minutes and 70% alcohol for 2 min
utes, the sections were then washed briefly in
distilled water. Then, they were stained in Harris
Hematoxylin solution for 8 minutes. After wash-
ing in running tap water for 5 minutes, sections
were differentiated in 1% acid alcohol for 30
seconds. After bluing in 0.2% ammonia water
for 30 sec
onds, they were washed in running tap
water for 5 minutes and rinsed in 95% alcohol.
They were counterstained in eosin-phloxine solu
tion for 30 seconds and dehydrated through 95%
alcohol, 2 changes of absolute alcohol, 5 minutes
each. They were cleared in 2 changes of xylene,
5 minutes each, and mounted with xylene-based
mounting medium.
Immunohistochemical Staining
Sections were brought to distilled water and
washed 3×5 min in phosphate-buffered saline
(PBS) (Catalog no. 10010023, Thermo Fisher Scien
tific, Fremont, California, USA). Antigen retrieval
was done in a microwave (Bosch, 700 watt) for 3
min×90°C. They were subjected to a heating pro
cess in a microwave oven at 700 watts in a citrate
buffer (pH 6) solution for proteolysis. Sections
were washed 3×5 min in PBS and incubated with
hydrogen peroxide (K-40677109, 64271 hydrogen
peroxide [H2O2], Merck Germany) (3 mL 30%
H2O2+27 mL methanol) for 20 minutes. Sections
were washed 3×5 min in PBS and blocked with
Ultra V Block (lot: PHL150128, Thermo Fisher)
for 8 minutes. After draining, primary antibodies
Caspase-12 antibody, mouse monoclonal (1/100),
and ADAMTS-5 antibody, mouse monoclonal
(1/100), were applied. Sections were incubated
and left overnight at 4°C. Sections were washed
3×5 min in PBS and then incubated with sec-
ondary antibody (Histostain-Plus Kit, Invitrogen,
Carlsbad, California) applied for 20 minutes. Af-
ter washing with PBS, Streptavidin Peroxidase
(lot: PHL150128, Thermo Fisher) was applied to
sections for 20 minutes. Sections were washed in
3×5 min PBS and DAB (lot: HD36221, Thermo
Fisher) was applied to the sections for up to 10
minutes. Slides showing reaction were stopped
in PBS. Counterstaining was done with Harris
Volume 41, Number 6/December 2019 193
ADAMTS-5 and Caspase-12 in Placenta Previa
Table I Independent t Test Analysis Results of Clinical Features of the Groups
Placenta previa
Control group group p Value
Age 28.2±0.68 33.88±0.85 <0.01*
Gestational age 38.18±0.03 35.79±0.28 <0.01*
Gravida 2.07±0.06 4.48±0.09 <0.01*
Parity 0.97±0.07 2.00±0.06 <0.01*
Birth weight (g) 3,110.24±150.26 2,980.62±160.42
>0.05
Systolic blood pressure (mmHg) 122.1±8.2 142.5±1.4 <0.01*
Diastolic blood pressure (mmHg) 75.8±6.4 92.6±1.2 <0.01*
Hemoglobin (g/dL) 10.8±0.8 12.2±1.6 <0.01*
Hematocrit (%) 37.4±3.8 36.9±2.9
>0.05
Thrombocyte 238.2±66.4 249.3±85.8
>0.05
AST (U/L) 23.2±3.9 43.8±10.8 <0.01*
ALT (U/L) 17.8±8.4 63.2±6.8 <0.01*
Proteinuria (g/24 h) — 0.52±0.22 —
C/S (n) 8 9
>0.05
NB (n) 7 6
>0.05
Results are expressed as mean±SEM.
*p<0.05 was considered statistically significant.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, C/S = cesarean section, NB = normal birth.
4. Hematoxylin for 45 seconds, dehydrated through
ascending alcohol, and cleared in xylene (product
number: HHS32 SIGMA, Hematoxylin Solution,
Harris Modified, Sigma-Aldrich, St. Louis, Mis
souri, USA). Slides were mounted with Entellan
(lot: 107961, Sigma-Aldrich) and examined under
an Olympus BH-2 light microscope.
Statistical Analysis
Statistical analyses were carried out using the
statistical package SPSS 15.0 for Windows (SPSS
Inc., Chicago, Illinois, USA). Independent t test
was performed to compare data from control and
placenta previa patients.
Results
Clinical Findings
Independent t test analysis was used to analyze
significance between the groups. Mean ranks of
each group and p values were evaluated. Statis
tically, p<0.05 was accepted as significantly dif
ferent. The characteristics of patients including
clinical features are summarized in Table I.
Histopathological Observations
Control Group. Syncytial cells in the root were well-
organized with chromatin-rich nuclei. In the villi,
lumens of blood vessels were normal with regular
squamous endothelial cells. In the few syncytial
nodes and bridges, connective tissue cells and
fibers showed regular arrangement within the villi
(Figure 1A).
Placenta Previa Group. Significant degeneration and
apoptotic changes in syncytial cells of root villi,
excessive dilation and congestion of blood vessels,
and hyperplastic endothelial cells were observed.
Thinning and degenerative changes in the con
nective tissue fibers in the villi, increased syncytial
nodes, accumulated fibrin between the syncytial
bridges, and intense erythrocyte and inflammatory
cell infiltration were observed (Figure 1B).
Immunohistochemical Findings
Control Group (ADAMTS-5 Immunostaining). In the
root and free villi, the syncytial cell structure
was regular and mild ADAMTS-5 expression was
observed, while negative ADAMTS-5 expression
was observed in the vascular endothelial cells and
connective tissue cells (Figure 2A).
Placenta Previa Group (ADAMTS-5 Immunostaining).
Increased expression of ADAMTS-5 was observed
in large root villi and mature chorionic villi in
the maternal region. Also, ADAMTS-5 expression
was positive in Hofbauer cells, endothelial cells,
connective tissue cells, and fibers in medium and
small blood vessels (Figure 2B).
Control Group (Caspase-12 Immunostaining). In some
of the maternal decidual cells, mild Caspase-12
expression was observed but was negative in the
syncytial cells, vascular endothelial cells, and con
nective tissue cells (Figure 3A).
Placenta Previa Group (Caspase-12 Immunostaining).
Increased expression of Caspase-12 in the mater
nal decidual cells was generally seen. Expression
was also observed to be sparse over the entire
cytoplasm. Expression of Caspase-12 was positive
in syncytiotrophoblast cells, vascular endothelial
cells, and some connective tissue cells (Figure 3B).
194 Analytical and Quantitative Cytopathology and Histopathology®
Çavus
and Değer
Figure 1
(A) H-E staining (control
group). Scale bar=50 µm.
(B) H-E staining (placenta
previa group). Scale bar=20
µm.
5. Discussion
Placenta previa is a negative condition which oc-
curs in the lower segment of the uterus. The im-
plantation of the placenta into the weakly vascu
larized lower uterine segment is reported to cause
inadequate uteroplacental perfusion, affecting fe-
tal oxygenation and growth. Chorionic villi have
been reported to cause severe postpartum hemor
rhage as placental separation progresses by deep-
ly invading the myometrium with weakly formed
decidua basalis. Authors emphasized that placen
tas with neonatal mortality and morbidities in the
placenta previa group were lighter in weight than
those in normotensive placentas. In addition, it
has been shown that chorionic plaque diameters,
chorionic plaque areas, and marginal cord inser
tion are significantly higher in the placenta of
women diagnosed with placenta previa in the
third trimester.13 There are few studies on the mo-
lecular mechanisms underlying placenta previa
recently; there are studies mostly on the molecular
regulation of trophoblast cell infiltration and pla
cental angiogenesis.14
Diameters of small villi, blood vessels, and de-
cidual cells were significantly decreased in the
placenta previa group as compared to the control
group. However, villous epithelial thickness was
not statistically significant (Table II) (Figure 4).
Expression of Caspase-12 and ADAMTS-5 were
increased in the previa group as compared to the
control group (Table III) (Figure 5). Diameters of
small villi, blood vessels, and decidual cells were
significantly decreased in the placenta previa group
as compared to the control group. An increase in
syncytial knot, vascular congestion, fibrin accu
mulation, inflammation, and decidual cells were
observed in the placenta previa group relative to
the control group (Table IV) (Figure 6).
The pathogenesis of placenta previa includes
an abnormal interaction between decidua and the
invasive extravillous trophoblast, and many hy-
potheses have been proposed to explain this ab-
Volume 41, Number 6/December 2019 195
ADAMTS-5 and Caspase-12 in Placenta Previa
Figure 2
(A) ADAMTS-5
immunostaining (control
group). Scale bar=50 µm.
(B) ADAMTS-5
immunostaining (placenta
previa group). Scale bar=50
µm.
Figure 3
(A) Caspase-12
immunostaining (control
group). Scale bar=50 µm.
(B) Caspase-12
immunostaining (placenta
previa group). Scale bar=50
µm.
6. normality. Coordinated disintegration and syn
thesis of the extracellular matrix also plays an
important role in trophoblastic invasion during
insertion. ADAMTS proteases play an important
role in defective trophoblast invasion, hypoxic
spiral artery formation, and impaired extracellu-
lar matrix formation and the rearrangement of
these structures. One of these is the deficiency of
the metalloproteinases, which are antagonists of
matrix metalloproteinases or secreted by decidual
cells, in the decidualization areas of anti-invasive
factors which are activators of the tissue inhibi-
tor. Decidua plays a primary role in embryonic
implantation and pregnancy maintenance during
early pregnancy by means of controlling the tro
phoblastic invasion depth and vascularization.15
Namli Kalem et al16 studied immunohistochemi
cally to investigate the presence and localization
of ADAMTS 1, 4, 5, 8, and 9 in decidual and cho
rionic tissues in first trimester pregnancy losses.
They conducted their research with chorionic
and decidual tissues from the first trimester in
early pregnancies and early pregnancy losses and
showed the presence, localization, staining inten-
sity, and staining distribution of ADAMTS 1, 4,
5, 8, and 9 immunohistochemically. They also ob-
served that the decidual and chorionic tissue lev-
els of ADAMTS 1, 4, 5, and 8 in ongoing pregnan
cies were more intensely expressed as compared
to in miscarried pregnancies.16 ADAMTS-5 affects
angiogenesis via downregulation of proangio-
genic factors such as VEGF, PGF, and platelet-
derived endothelial growth factor.17 Ozler et al18
investigated the role of ADAMTS-5 in unexplained
fetal growth restriction. They stated that the ex-
196 Analytical and Quantitative Cytopathology and Histopathology®
Çavus
and Değer
Table II Independent t Test Analysis Results of Diameter of
Floating Small Villi, Diameter of Blood Vessels in Villi,
Diameter of Decidual Cells, and Epithelial Thickness in
Villi
Placenta
Control previa
group group
(µm) (µm) p Value
Diameter of floating
small villi 13.4±0.17 12.4±0.16 <0.01*
Diameter of blood
vessels in villi 9.37±0.13 6.26±0.10 <0.01*
Diameter of decidual
cells 14.78±0.41 9.29±0.23 <0.01*
Epithelial thickness
in villi 1.74±0.07
1.69±0.08
>0.05
Results are expressed as mean±SEM.
*p<0.05 was considered statistically significant.
Figure 4 Independent t test analysis results of diameter of
floating small villi, diameter of blood vessels in villi, diameter of
decidual cells, and epithelial thickness in villi measurement of
the groups. *Indicates significant difference between control and
placenta previa groups (p<0.01).
Table III Independent t Test Results of Caspase-12 Expression
and ADAMTS-5 Expression
Placenta
Control previa
group group p Value
Caspase-12 expression 1.40±0.16 3.25±0.11 <0.01*
ADAMTS-5 expression 0.93±0.18 3.63±0.15 <0.01*
Results are expressed as mean±SEM.
*p<0.05 was considered statistically significant.
Figure 5 Independent sample t test result of Caspase-12 and
ADAMTS-5 expression scores of the groups. *Indicates significant
difference between control and placenta previa groups (p<0.01).
The quantification of all parameters: 0 = no change, 1 = too
weak, 2 = weak, 3 = middle, 4 = strong. (Scoring was determined
by examining histological parameters in 15 different regions
within the microscope field, and 10 cells counted in each area.)
7. pression of ADAMTS-5 was increased in placen-
ta decidua and syncytiotrophoblast cells, leading
to the destruction of collagen and proteoglycans
in the extracellular matrix. An additional finding
of the same work revealed increased ADAMTS-5
levels with anti-angiogenic and aggrecanase ac-
tivities in plasma in fetal growth restricted preg
nancies. In our study, moderate ADAMTS-5 ex-
pression was observed in the syncytial region of
the control group placental sections, while nega
tive expression was observed in blood vessels,
endothelial cells, and connective tissue cells (Fig-
ure 5A). In the placenta previa group, an increase
in ADAMTS-5 expression was observed in syncy
tial structures, blood vessel endothelial cells, con
nective tissue cells, and Hofbauer cells in the root
villus and small villi in the maternal region (Fig
ure 2B). ADAMTS-5, which has anti-angiogenic
and aggrecan activity, was thought to prevent the
development of the fetus with placental previa and
placental insufficiency and increased inflammation,
which may adversely affect maternal function.
A hot prominent topic in placental biology is
villous trophoblasts and their response to oxi
dative stress, hypoxia/reoxygenation, irregular
inflammation, or mechanical damage.19 Hypoxia-
induced placental oxidative stress activates apo
ptosis. Apoptosis by hypoxia is activated by the
mitochondrial pathway.20
Caspase-12 is phylogenetically a member of the
inflammatory group of the caspase family and is
proteolytically activated under specific ER stress-
induced cell death.21 Shiraishi et al22 investigated
the relationship between ER stress-induced cell
death and mitochondria and demonstrated that
cytochrome c was released from mitochondria
during ER-induced cell death. In addition, they
indicated that ER stress-induced apoptosis could
activate different signaling pathways in different
cell types and under different stresses. Fu et al23
investigated markers of ER stress-induced apo
ptosis in placentas of women with early and late
onset severe preeclampsia. These authors report
that ER stress-induced apoptosis is associated
with severe preeclampsia and is characterized by
the activation of 3 signaling pathways. Molecu
lar and morphological evidence confirmed that
syncytiotrophoblasts are vulnerable to ER stress
because of their wide secretory activity, and this
was shown by high levels of plasma in early-
onset preeclampsia.23 It was emphasized that the
reduction in cell proliferation that causes growth
restriction is important for activation of proin
flammatory pathways and for placental develop
ment and function.24 It was stated that it is es-
sential to regulate the activity of caspases for cell
survival and proper cell death process. Increased
trophoblast apoptosis is seen in clinical obstetric
pathology such as preeclampsia and intrauterine
growth restriction.25 In the placenta previa group
of our study, Caspase-12 expression was observed
in the syncytial regions and bridges and villous
connective tissue (Figure 3B).
Conclusion
ADAMTS-5, which has anti-angiogenic and aggre
can activity, was thought to play an important
Volume 41, Number 6/December 2019 197
ADAMTS-5 and Caspase-12 in Placenta Previa
Table IV Independent t Test Analysis Results of Syncytial
Knots, Congestion in Blood Vessels, Accumulation of
Fibrin, Inflammation, and Degeneration in Decidual
Cells
Placenta
Control previa
group group p Value
Syncytial knot 1.13±0.17 3.69±0.12 <0.01*
Congestion in blood
vessels 0.47±0.13 3.56±0.13 <0.01*
Accumulation of fibrin 0.73±0.15 3.56±0.13 <0.01*
Inflammation 0.60±0.13 3.50±0.16 <0.01*
Degeneration in de-
cidual cells 0.53±0.13 3.38±0.15 <0.01*
Results are expressed as mean±SEM.
*p<0.05 was considered statistically significant.
Figure 6 Independent sample t test result of syncytial
knots, congestion in blood vessels, accumulation of fibrin,
inflammation, and degeneration in decidual cells scores of
the groups. *Indicates significant difference between control
and placenta previa groups (p<0.01). The quantification of all
parameters: 0 = no change, 1 = too weak, 2 = weak, 3 = middle,
4 = strong. (Scoring was determined by examining histological
parameters in 15 different regions within the microscope field,
and 10 cells counted in each area.)
8. role in the development of extracellular matrix de-
velopment, inflammation, and angiogenesis and
may adversely affect maternal function and devel
opment of the fetus with placental previa and
placental insufficiency. The intense presence of
Caspase-12 activity in secretory cells such as de-
cidual cells and syncytiotrophoblast cells empha
sizes the importance of Caspase-12 in inducing
apoptotic change due to endoplasmic reticulum
stress and in the cell cytoplasmic domain. We
observed intense Caspase-12 activity in secretory
cells such as decidual cells and syncytiotropho-
blast cells, and we postulate that Caspase-12 is
important in inducing ER stress-induced apoptotic
change.
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