The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: https://www.tandfonline.com/loi/ijmf20

Early development of the human placenta and

pregnancy complications

Kjell Haram, Jan Helge Mortensen, Ole Myking, Bodil Roald, Everett F.
Magann & John C. Morrison

To cite this article: Kjell Haram, Jan Helge Mortensen, Ole Myking, Bodil Roald, Everett
F. Magann & John C. Morrison (2019): Early development of the human placenta and
pregnancy complications, The Journal of Maternal-Fetal & Neonatal Medicine, DOI:
10.1080/14767058.2019.1578745

To link to this article: https://doi.org/10.1080/14767058.2019.1578745

Published online: 27 Feb 2019.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2019.1578745

REVIEW ARTICLE

Early development of the human placenta and pregnancy complications

Kjell Harama, Jan Helge Mortensena,b, Ole Mykingc, Bodil Roaldd, Everett F. Maganne and
John C. Morrisonf
a
Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; bDepartment of Public Health and
Primary Health Care, University of Bergen, Bergen, Norway; cDepartment of Internal Medicine, Section of Endocrinology, Haukeland
University Hospital, University of Bergen, Bergen, Norway; dDepartment of Pathology, Center for Pediatric and Pregnancy Related
Pathology, Oslo University Hospital, Oslo, Norway; eDepartment of Obstetrics and Gynecology, University of Arkansas for Medical
Sciences, Little Rock, AR, USA; fDepartment of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA

ABSTRACT ARTICLE HISTORY

An adequately sized placenta at a suitable site with appropriate depth and centripetal progres- Received 18 October 2018
sion of implantation are the major factors for optimal fetal development. The cytotrophoblasts Revised 22 January 2019
surround the blastocyst fuses at the site of the uterine attachment. This forms a second layer of Accepted 1 February 2019
multinucleated syncytiotrophoblasts that constitutes the inner epithelial boundary of the chori-
KEYWORDS
onic villous against the intervillous space. In a normal pregnancy, extravillous cytotrophoblasts Blastocyst; cytotrophoblast;
(EVT) invade and obstruct the spiral arteries and remodel them. Vacuoles in the syncytial cell implantation; placenta;
layer fuse and develop the intervillous space. The inner cell mass (embryoblast) gives rise to the pregnancy complications;
umbilical cord and the mesenchyme in the chorionic villi. Vasculogenesis starts with the forma- spiral artery;
tion of hemangioblastic cords in this mesenchyme. The trophoblastic cell columns anchor the syncytiotrophoblast
placenta. A variety of molecular pathways participate in the placentation process. Placental mor-
phogenesis occurs mainly through complex cellular interactions between the chorionic villous
and the extravillous cytotrophoblasts. The formation of the normal structure of the chorionic
villi, syncytiotrophoblast layer and vasculature is essential for placental function, hormone pro-
duction, and regulation of fetal growth. At each stage of placental development, genetic var-
iants, exposure to infection, poor vascular function, oxidative stress, or failure of normal
development can all lead to abnormal formation resulting in the clinical complications of preg-
nancy such as fetal growth disorders, neonatal neurologic abnormalities, placental adhesions,
and inflammatory problems as well as maternal disease such as preeclampsia.

Introduction information [1,8,9]. Studies regarding placental patho-

The placenta is a complicated organ and several func-
tions are essential for a successful pregnancy outcome
[1]. Abnormalities may cause serious complications,
such as fetal growth restriction, fetal neurologic condi-
tions, placental adhesion disorders, preeclampsia, and
inflammatory processes which remain as challenging
clinical problems [2–6]. A number of longitudinal ana-
tomic studies of the placenta have been performed in
normal as well as abnormal pregnancies and all dem-
onstrate the importance of sequential placental devel-
opment [7,8]. The spiral arteries have been a focus in
many reports, some critically apprizing in vitro examin-
ation of trophoblast invasion and spiral artery remod-
eling [1]. The placenta has been assessed by electron
microscopy, flow cytometry, immunohistochemical,
and endocrinologic methodology to provide additional
physiology have recently provided information on the
complex interactions between normal regulation of
placental growth and spiral artery remodeling as a
function of apoptosis [1,9,10].
The purpose of this review is to describe the main
aspects of placental development in the first half of
pregnancy and obstetric complications, which can
result if pathophysiologic changes in the pla-
centa occur.
Early development of the human placenta
The outer blastocyst layer of trophoblast develops into
the placenta and fetal membranes. The inner cell mass
(embryoblast) develops into the embryo and umbilical
cord. The embryoblast is surrounded by a single layer

CONTACT Everett F. Magann efmagann@uams.edu Department of Obstetrics and Gynecology, UAMS, Markham St. Slot # 518, Little Rock,
AR, USA
This paper honors Dr. Kjell Haram, recently deceased, who was a leading clinical researcher in the field of Obstetrics and Gynecology. His innovative
thought process, keen interest in new ideas, and energetic scientific methods will be missed.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 K. HARAM ET AL.
of mononucleated trophoblasts, which also embraces
the blastocele and the blastocyst cavity. During
human development, between the stages of the mor-
ula and blastocyst (days 4–5 postconception), the
trophoblast is the first cell lineage to differentiate [11].
After the establishment of the trophoblasts, the
blastocyst consists of an inner cell mass that is sur-
rounded by a single layer of mononucleated tropho-
blasts. This outer layer surrounds not only the
embryoblast but also the blastocoel and the blastocyst
cavity. The placental mesenchyme is derived from an
extraembryonic mesoderm outgrowth of the early
embryo. At about days 6–7 postconception, the
blastocyst hatches from the zona pellucida and
attaches to the uterine epithelium and at that stage
formation of the placenta begins [8]. Only the tropho-
blasts overlying the inner cell mass (referred to as
polar trophoblasts) lead to blastocyst implantation [8].
Immediately after implantation, the first invasion of
the endometrium is performed by the early syncytio-
trophoblasts [11,12].
The cytotrophoblasts differentiate along the fusion
or the invasion pathway. The cytotrophoblasts have
the ability to change from the proliferation to invasion
state by adjusting the adhesion molecule phenotype
[13]. Both types of trophoblasts keep a subset of cells
in direct contact with the villous basal membrane.
They retain their generative potential and the ability
to proliferate in response to growth factors [1,3]. The
cytotrophoblasts around the blastocyst fuse at the site
of uterine attachment to form a second layer of multi-
nucleated syncytiotrophoblasts, which constitutes the
inner epithelial boundary of the chorionic villus
against the intervillous space [13,14]. DNA synthesis
does not occur in syncytiotrophoblasts, indicating that
the syncytial nuclei are unable to replicate [14]. Once
formed, the syncytiotrophoblasts grow by means of
steady incorporation of new mononucleated tropho-
blasts from a proximal subset of stem cells, which
renews the syncytiotrophoblasts. The fusion process
integrates the cytoplasm content, proteins, and RNA
as well as membranes and nuclei from cytotropho-
blasts into the syncytiotrophoblast [1,3]. The final
event of the apoptosis cascade process inside the syn-
cytiotrophoblast is the packaging of old and later
apoptotic nuclei into protrusions of the apical mem-
brane of the syncytiotrophoblast, called syncytial knots
[15]. The process of syncytial fusion is linked to the
“initiator stage” of the apoptotic cascade process
within the cytotrophoblast cells. The extrusion of syn-
cytial knots from the syncytiotrophoblast is the result
of final “execution stages” of the apoptotic process
within the syncytiotrophoblast [13,15]. Syncytial fusion
is dependent on commencement of the apoptotic cas-
cade in the chorionic villous cytotrophoblasts and in
the syncytiotrophoblasts [15]. The syncytium has a
high turnover rate and the syncytial knots are shed
into maternal blood. Anomalies in the syncytiotropho-
blast layer may impede placental function and can
lead to fetal growth restriction [16,17].
In the first trimester, cytotrophoblast stem cells
push forward through the syncytiotrophoblastic mass
and reach the maternal side of the placenta. The
maternal tissue reorganizes and develops, with suffi-
cient oxygen, into multilayered structures which will
become the trophoblastic cell columns that anchor
the placenta to the wall of the uterus [18] At around
day 14 postconception, the cytotrophoblasts begin to
invade the underlying decidua (interstitial invasion)
from this anchoring column as extravillous cytotropho-
blasts (EVTs) [19]. The EVTs accumulate around the spi-
ral arteries and expand laterally to form the
cytotrophoblast shell and then they stop proliferation
and begin invasion because of differentiation. The
depth of trophoblast invasion initiated at the center of
the placenta becomes more shallow at the periphery,
which is noted around midgestation. Appropriate
placement of the placenta at a suitable site, with nor-
mal depth and centripetal progression of implantation,
are essential for optimal development of the fetus.
Spiral artery remodeling
EVTs penetrate and invade the media of the spiral
arteries in normal pregnancy. The elastic and add-
itional matrix tissue is enzymatically destroyed and
replaced by fibrinoid material [19] After breaking
through the artery barricade, the cytotrophoblasts
migrate along the inner luminal surfaces of the endo-
thelium and transiently coexist with the endometrium
on the walls of partially modified spiral arteries before
replacing the endothelium. The remodeling of the spi-
ral arteries involves endothelial apoptosis induced by
EVTs through Fas/FASL interactions [20]. Fas expres-
sion is detected in spiral artery endothelial cells,
smooth muscle cells and decidual endothelial cells.
Fas/FASL interactions are involved in trophoblast
induction of endothelial apoptosis. Loss of endothelial
cells from the lumen of the maternal uterine spiral
arteries is a prerequisite for a successful pregnancy
[19]. If abnormalities occur early in the process of spi-
ral artery changes, severe forms of preeclampsia can
occur [21]. The trophoblasts transform their adhesion
receptor phenotype similar to the endothelial cells

they replace and the EVTs obstruct the lumen of the
spiral arteries (endovascular invasion) [19]. During this
process, if oxygen status is suboptimal, embryopathies
can occur [18]. The cytotrophoblast plugging of spiral
arteries may serve as a mechanism to protect the fetus
and the placenta from free radical-mediated stress
[22]. At the same time, the cytotrophoblast obstruc-
tion creates a low-oxygen environment in the placen-
tal tissue, less than 20 mm Hg until 10–12 weeks of
gestation [23].
At the end of the first trimester, the luminal plugs in
the spiral arteries begin to disintegrate [22] and they
are dissolved at about 14 weeks’ gestation with a rise
in placental pO2 to concentrations above 50 mmHg
[18,24]. The remodeling processes normally occur dur-
ing the first 20–22 weeks of pregnancy leading to spiral
artery dilatation, a low-resistance circulatory system and
increased intervillous blood flow [18]. This process has
been termed “physiologic change” which refers to the
combination of cytotrophoblasts, accumulated fibrinoid
material in the spiral artery walls, and loss of musculoe-
lastic tissue in the media of fetal spiral arteries [25].
However, failure of this process can result in pree-
clampsia, growth restriction, and vascular anomalies
[4,6,16]. Trophoblasts may or may not invade the ven-
ous wall, even though free floating endoluminal
trophoblast have been found in these vessels [26].
The intervillous space
Vacuoles develop in the syncytial cell layer. These fuse
and form lacuna (especially at the embryonic pole)
and an intercommunicating vascular network. The
lacuna is observed 11–12 days after conception and is
filled with fluid [9]. The syncytial cells penetrate
deeply into the stroma and erode the lining of the
capillaries, which are congested and dilated, thus
forming sinusoids [11]. Further development of these
sinusoids leads to the creation and expansion of the
intervillous space (second –third gestational week) and
results in the first arterial blood flow from mother to
the intervillous space [27].
Development of chorionic villi, vasculogenesis,
and angiogenesis
The structural and functional unit of the placenta is
the chorionic villus [28]. The formation of the normal
structure of the chorionic villi, syncytiotrophoblast
layer and vasculature is essential for placental func-
tion, hormone production, and regulation of fetal
growth. The relationship between maternal and fetal
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3
circulation in the placenta is crucial for efficient
exchanges of oxygen and nutrition to the fetus and
removal of waste products from the fetus [16].
Chorionic villi formation starts at about 2 weeks after
conception. Finger-like outgrowths of trophoblast tra-
beculae proliferate from the chorionic plate into the
intervillous space developing the chorionic villous
trees. As long as the villi are composed of only troph-
oblasts, they are termed primary villi [28]. At 5 weeks’
gestation (about 21 days after conception), the primary
chorionic villi are invaded by mesenchyme cells
derived from the embryoblast, thereby transforming
the primary villi into secondary chorionic villi. At the
end of the third week, mesenchyme cells begin to dif-
ferentiate into blood cells and small blood vessels
(vasculogenesis) which results in the formation of the
the tertiary chorionic villi. Each tertiary villus has a
connective tissue core that contains fetal blood vessels
and numerous macrophages (Hofbauer cells) [28]. As
the placenta ages, there will be a normal increase in
the stromal connective tissue whereas abnormalities in
this process can result in preeclampsia [7,21,29].
The free-floating chorionic villi can be divided into
five types on the basis of the caliber and stromal char-
acteristics as well as vessel structure and appearance
[28]. Mesenchymal villi (100–250 mm in diameter) are
the forerunners of the intermediate villi and are pre-
dominantly found in the earliest stages of pregnancy.
They become significantly reduced after the first tri-
mester. Immature intermediate villi (100–400 mm in
diameter) developing from differentiating mesenchy-
mal villi are large bulbous villi that dominate the
chorionic villous tree between 8 and 22 weeks of preg-
nancy [28]. Stem chorionic villi derive from differenti-
ation of intermediate villi and are generally the villi
with the largest diameter (100–300 mm). They serve to
support the chorionic villous tree. Their villous core is
characterized by centrally located arteries and veins in
a dense fibrous stroma [28]. Mature intermediate villi
starting at about midgestation are long slender
mature intermediate villi (80–120 mm). Terminal villi
are final branches of the villous tree. They have a
length up to 100 mm, a diameter of about 80 mm, and
originate from mature intermediate chorionic villi [28].
Vasculogenesis is defined as the process in which a
primitive vascular network is established while angio-
genesis is the process of new vessel formation from
preexisting vessels [30]. The chorionic vasculogenesis
starts with the formation of hemangioblastic cords
that are the first precursors of fetal endothelium in
the villous stroma. These so-called hemangioblastic
cell cords can be demonstrated as early as 15–21 days
4 K. HARAM ET AL.
after conception [1]. In the human placenta, the for-
mation of endothelial tubes from hemangiogenic
cords starts at about 21 days after conception by focal
enlargement of centrally located intercellular clefts
which later fuse to become a larger lumen [31].
Apoptosis contributes to physiologic vascular lumen
formation and vascular branching in human placental
vasculogenesis [32]. Abnormalities of placental vaculo-
genesis can cause idiopathic recurrence, spontaneous
miscarriages, although the most frequent cause of
such early losses is chromosomal abnormalities [33,34].
Likewise, if the anchoring villi are abnormal, placenta
abruption can occur later in pregnancy and lead to
stillbirth or an increased prevalence of major fetal con-
genital malformation [35,36].
In the normal human pregnancy, capillary growth is
biphasic, involving an initial phase of branching angio-
genesis (formation of tightly looped capillaries) fol-
lowed by increased nonbranching angiogenesis
(formation of longer capillaries) [7]. New branches may
be created by sprouting angiogenesis (lateral spouting
from existing vessels) or by intussusceptive angiogen-
esis (formation of transvascular epithelial pillars which
partition one lumen into two or more lumina) [7].
These cords develop into a richly branched chorionic
villous capillary bed. Formation of a capillary vascular
network occurs from 32 days after conception until 25
weeks’ gestation by branching angiogenesis.
Regression of terminal capillary webs and formation of
central stem vessels primarily occurs mainly through
15–32 weeks post conception. From about 25 weeks
after conception until term, the patterns of chorionic
villous vascular growth switch from branching angio-
genesis to nonbranching angiogenesis and to the for-
mation of capillary loops [7]. The human placenta
experiences a dramatic growth including elongation of
the terminal villi during the second trimester. The
chorionic villi undergo substantial changes as charac-
terized by an estimated 56-fold increase in capillary
volume in peripheral chorionic villi by term, mostly
due to an increase of the mean length of the villi
[28,37]. The remodeling of the vessels in the chorionic
villi includes loss of elastic membranes, thinner muscu-
lar coats, dispersion of muscle cells and also the loss
of the muscoelastic coat of the vessel wall (disruption
of the tunica media) [28].
Molecules involved early placental formation
and function
Trophoblast invasion of the decidua and maternal vas-
culature is regulated by trophoblastic and decidual
factors in normal and preeclamptic gestations [28,38].
In addition, decidual changes in the endometrial
stoma and myometrium precede trophoblast invasion
and remodeling, which particularly in adolescent preg-
nancies, can result in spontaneous preterm labor and
growth restriction [39,40]. Human cytotrophoblasts
produce both the urokinase-type plasminogen activa-
tor and different matrix metalloproteinases – (MMPs),
particularly important in those who develop pree-
clampsia [2]. The MMP-9 protease activity is required
for cytotrophoblast degradation and invasion through
Matrigel. Cytokines and growth factors modulate the
MMP expression and the proteolytic activity [2]. Either
syncytiotrophoblasts or the inner villous cytotropho-
blast layer expresses a number of transforming growth
factor beta (TGFb) superfamily ligands [41]. By modu-
lating the syncytial fusion, they play important roles in
the decidual regulation of the EVT invasion [4]. Several
hormones such as estrogen, progesterone, human
chorionic gonadotropin (hCG), prolactin, leptin, human
placental lactogen (hPL), and different cytokines par-
ticipate in the regulation of the cytotrophoblast differ-
entiation, proliferation, and invasion [42]. IL-6 also
contributes to the regulation of hormone production
and appears to be involved in angiogenesis. Following
implantation, invasion of the decidua by EVTs is tightly
modulated by cytokines [4]. Plasmin may activate spe-
cific procollagenases and facilitate the EVT invasion in
the decidua.
Activin promotes, while TGFb and macrophage
inhibitory cytokine-1 (MIC-1) (expressed in the
decidua) inhibits trophoblast migration in vitro, sug-
gesting that a relative balance of the TGFb superfamily
members participate in modulating the extent of
decidual cytotrophoblast invasion [43]. By the end of
the first-trimester follistatin is inhibitory whereas acti-
vin A stimulates the invasive potential of cytotropho-
blasts prior to 10 weeks’ gestation [3]. Oxygen is also
a key regulator of placental development. The tropho-
blast migration and invasive capacity are modulated
by oxygen tension and low-tissue PO2 maintains the
trophoblasts in a proliferative, noninvasive state
[18,44]. The localization of the cell columns at the bor-
der between low-oxygen placenta (promoting prolifer-
ation) and the high-oxygen decidua (promoting
invasion) is needed for the shift from the ability to
proliferate in the proximal part of the cell column to
the capability for invasion at the distal part [8].
Hypoxia is a potent stimulus for the induction of VEGF
gene expression, while hypoxia-inducible factor-1 (HIF-
1) is an up-regulating factor. The EVTs express numer-
ous VEGF family members. VEGF ligands and receptors

are deregulated in severe preeclampsia and fetal/pla-
cental vasculopathy [43]. Also, in the face of cytokine
expression, polymorphisms in the tumor necrosis fac-
tor alpha and lectin genes have been related to cere-
bral palsy in the offspring, particularly if they are born
preterm [45–47].
Normally, the expression of cell-cell interaction (e.g.
cadherins, Ig superfamily) and cell-extracellular matrix
(e.g. integrin receptors), as well as adhesion molecules
(syncytin), are extensively modulated as the EVTs
invade the uterine wall from the outside of the spiral
arteries and also retrograde from the cytotrophoblastic
shell [48]. The invasive pathway of trophoblast differ-
entiation is associated with a change in adhesion
receptor phenotype away from epithelial cell type
adhesion molecules (integrin b4 and b5), to adhesion
receptors typical for invasive and endothelial cells
(vascular endothelial (VE)-cadherin), b1 and b3 integrin,
vascular cell adhesion molecule 1 (VCAM-1), platelet-
endothelial adhesion molecule 1 (PECAM-1), and intra-
cellular adhesion molecule-1 (ICAM). The cytotropho-
blast cell-cell fusion into syncytiotrophoblasts during
human placentogenesis is tightly regulated [13].
Syncytin probably plays a key role in the cell-cell
fusion [13,48]. Syncytin is a membrane protein derived
from the envelope gene of an endogenous retrovirus
of the HERV-W family, almost exclusively expressed in
the syncytiotrophoblasts [49]. Initiation of the cell-cell
fusion takes place either through up-regulation of syn-
cytin in differentiating cytotrophoblasts, through local
down-regulation of receptors in the syncytiotropho-
blasts or through local up-regulation of syncytin in the
syncytiotrophoblasts themselves [47].
The circulating renin-angiotensin system (RAS) plays
a key role in regulating blood pressure and electrolyte
balance [50]. There is a local renin-angiotensin system
(RAS) in the placenta. RAS has a critical regulatory role
in vascular remodeling and in the fetoplacental circula-
tion facilitating adequate placental blood flow [50,51]. If
the blood flow is abnormal, preeclampsia may occur,
particularly in the presence of polymorphisms [51].
Decidual tissues are a source of angiotensin II (ANG-II)
production and trophoblasts serve as paracrine targets
of ANG-II signaling through angiotensin AT1 receptor
activation. Multiple genes are regulated by AT1 recep-
tors associated with trophoblast invasion (e.g. plasmino-
gen-activator inhibitor-1 (PAI-1) and sFlt-1) [47]. The
peroxisome proliferator-activated receptor-c (PPARc) is
a member of the nuclear receptor superfamily
expressed in the chorionic villi, EVTs, and in the syncy-
tiotrophoblasts [27]. PPARc has a major role in the con-
trol of human trophoblast invasion during early
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5
pregnancy. Ligands such as oxidized low-density lipo-
proteins (LDLs) at the implantation site might contrib-
ute to the modulation of trophoblast invasion through
activation of PPARc and liver  nuclear receptor
b [21,27].
Development of the chorionic vasculature in the
placenta depends on the actions of angiogenetic
growth factors and their receptors produced by cells
and extracellular matrix ingredients near the fetal ves-
sels. These vessels lack autonomic innervations, so
resistance to flow in the maturing vasculature must be
regulated by local vasoactive effectors [30]. The bal-
ance of various angiogenetic factors and several
angiogenetic inhibitors mainly regulates angiogenesis.
Most of the angiogenetic regulators are extrinsic to
endothelial cells. Vasohibin, a novel endothelium-
derived angiogenesis inhibitor, is selectively expressed
in endothelial cells and is induced by well-known
angiogenetic factors such as VEGF and fibroblast
growth factor 2 (FGF-2) [2,52]. Angiogenesis enhances
the development of the vascularity in the chorionic
villi and the main factors are VEGF, PlGF, FGF, and the
angiopoietin (Ang) protein family as well as their
receptors [53]. The extracellular portion of VEGF-A
molecule (i.e. the soluble VEGF antagonist, sflt-1) is
required for placental vascular development.
Histochemical studies have found that the receptor is
expressed on human villous endothelium, villous mac-
rophages, and trophoblasts during fetoplacental
angiogenesis [37]. PlGF is expressed both in villous
syncytiotrophoblasts and in the media of larger stem
vessels [54].
The vasculogenesis and angiogenesis early in the
placental development are stimulated by VEGF, PlGF,
FGF, and their receptors [54]. PlGF in vivo stimulates
proliferation of microvascular endothelial cells in the
term placenta and PlGF is also a potent stimulator of
angiogenesis [8]. PlGF is down-regulated by hypoxia
and becomes increasingly significant towards the third
trimester as angiogenesis changes from branching to
non-branching type [53].
Basic FGF-2 (or bFGF) is thought to be involved in
the recruitment of hemangiogenic progenitor cells
and their expression in human placental villi [30].
Vascular endothelial growth factor A (VEGF-A of VEGF)
is responsible for the growth and aggregation of the
endothelial precursors for the formation of hemangio-
genic cords and is highly expressed in early pregnancy
[54]. Chorionic villous trophoblasts and villous macro-
phages are the main sources of this cytokine [53].
Angiogenesis is also mediated, in part, by the endo-
thelial cell receptor tyrosine kinases (RKTs), Tie-1
6 K. HARAM ET AL.
(expressed in decidual endothelial cells), Tie-2
(expressed in the vascular endothelium), and the Tie-2
agonist ligand Ang-1, which are essential for a suc-
cessful pregnancy [54]. When these receptors are defi-
cient, angiogenesis is reduced and growth restriction,
diabetes, as well as preeclampsia becomes more
prevalent. Ang-1 and Ang-2 have been detected in
perivascular cells of the intermediate chorionic villi
[55]. In the chorionic villous, establishment and main-
tenance of the outer part of the vessel walls is, in
part, controlled by the balance of Ang-1 and Ang-2
interacting with the Tie-2 receptor [56]. The Ang-2 and
Tie-2 receptor ligand system may play a pivotal role in
the remodeling of the vessels of the fetal-maternal
interface [30]. Endothelial growth factor receptor kin-
ase 1 and 2 (VEGFR-1 and VEGFR-2) are also involved
in vasculogenesis [42]. The placental-specific transcrip-
tion factor glial cell missing gene (GCM1) is a transac-
tivator for syncytin expression in the placenta [57].
GCM1 promotes vasculogenesis and vascular branch-
ing and has a distinct role in the maintenance, devel-
opment, and turnover of the trophoblasts.
Conclusion
The placenta is a unique organ whose vital functions
determine fetal and maternal health. An extensive lit-
erature on placental development began in the eight-
eenth century. The classic publication by Grosser
published in 1927 reviewed existing knowledge of
implantation at that time [8]. Since that time, a great
number of publications confirming the importance of
placenta development have been published. The pre-
sent survey highlights the changes in early placental
development and the clinical problems during preg-
nancy which can occur if this process is abnormal.
Formation of the chorionic villi and angiogenesis are
important steps in the creation of a normal structure,
which is essential for a placental function such as hor-
mone production, removal of waste products from the
fetus, and regulation of fetal growth. The relationship
between maternal and fetal circulation in the placenta
is crucial for efficient exchanges of oxygen and nutri-
tion to the fetus. Inadequate vascularity in the chori-
onic villi may cause reduced fetal growth, lead to
placental abruption, adhesion problems, stillbirth, pre-
eclampsia, HELLP syndrome, fetal respiratory problems,
and inflammation [2–5,58,59].
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Everett F. Magann http://orcid.org/0000-0001-6823-7635
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