Perturbation of trophoblast functions may result in a range of
adverse pregnancy outcomes such as malformation, fetal growth
retardation, spontaneous abortion and stillbirth. For instance, a
limited trophoblast invasion of maternal vessels has been correlated to
both preeclampsia and fetal growth restriction, whereas an excessive
trophoblast invasion is associated with invasive mole, placenta accreta
and choriocarcinoma.
However, in spite of the the quantity of literature regarding the
physiopathology of trophoblastic functions, the mechanisms leading to a
successful pregnancy are far from fully understood. A modern approach
to the matter is represented by the attempt to investigate the
behaviour of the regulatory factors which are known to carry a high
risk of spontaneous abortion in pregnancies, such as those complicated
by fetal aneuploidy. Results obtained in this field demonstrate that
chromosomal alterations in the embryo are correlated with anomalous
amniotic and maternal plasma levels of growth factors and
proinflammatory cytokines [84,85]
which may impair trophoblast function. This concept is supported by the
demonstration that trisomy 21 is associated with various defects in CT
differentiation represented by down-regulation of adhesion molecules
such as integrin α1 and, possibly as a
compensatory mechanism, upregulation of MMP-9. These alterations may be
responsible for the increase in CT apoptosis at the maternal-fetal
interface [86].
Preeclampsia, a multifactorial syndrome thought to be caused by a
combination of genetic, environmental, immunological and nutritional
factors affects approximately 2–3% of all pregnant women and is a major
cause of maternal and fetal morbidity and mortality. It is generally
diagnosed in the third trimester and it is frequently, though not
necessarily, responsible for pregnancy-induced hypertension and
proteinuria. The pathological basis behind the clinical symptoms is
represented by generalized vasoconstriction, increased vascular
reactivity, parenchymal hypoperfusion, excessive edema, and platelet
activation triggering the coagulation cascade [87].
In normal pregnancy, as described above, EVT cells transform the
spiral arteries into low-resistance vessels. In preeclampsia, however,
spiral artery remodeling is defective and the utero-placental
circulation remains in a state of high resistance (Fig. 4). It has been hypothesized that poor placental perfusion per se is
an insufficient prerequisite for preeclampsia; as a matter of fact,
this pathologic condition appears only when altered placentation occurs
together with maternal constitutional factors [69]. Both the mother and fetus contribute to preeclampsia, the fetal contribution being affected by paternal genes. Indeed, Hiby et al [88]
recently indicated the following factors correlated to preeclampsia:
HLA-C, on fetal trophoblast cells and KIRs, on maternal decidual NK
cells. Both of these factors are characterized by an extensive
polymorphism of immunological importance in this condition. In
particular they suggest that mothers lacking most or all activating KIR
are at a greatly increased risk of preeclampsia when the fetus
possesses HLA-C belonging to the HLA-C2 group. In preeclampsia the
dialogue between EVT and NK cells necessary for a correct spiral artery
remodeling during early pregnancy cannot take place.
Several other factors have been implicated in the poor remodeling of
spiral arteries, such as a defect in EVT cell differentiation toward
the invasive phenotype, an increase in apoptosis, an imbalanced control
of migratory and invasive EVT functions, and the inability of cells to
adopt an endovascular phenotype [69,89,90]. In contrast, Brosens et al [3]
proposed the scarce myometrial artery transformation may be due to a
deficient myometrial decidualization, rather than to defective
trophoblast invasion. Nevertheless, it has been reported that in
preeclampsia CT cells fail to down-regulate α6β4, to up-regulate α1β1
integrins and to enhance MMP and HLA-G expression, whereas they
maintain an elevated production of E-cadherin and of the anti-invasive
factor, TGF-β [52]. Moreover, Redline et al [91]
demonstrated that this pathological condition is associated with an
excess of proliferative immature intermediate trophoblast cells,
probably due to dysregulation of some cytokine and growth factor
secretion. Indeed altered levels of several cytokines, produced at the
maternal-fetal interface and involved in the physiological control of
EVT cell proliferation, differentiation and function, have been found
in the blood of preeclamptic women [87].
It has also been hypothesized that enhancement of IL-2 production, due
to the reduced placental HLA-G expression, is responsible for the
scarce invasiveness of preeclamptic trophoblast [92], and that deficiency of IL-10 may contribute to enhanced inflammatory responses elicited by TNF-α and interferon-γ towards the trophoblast [50].
The enhanced pro-inflammatory/anti-inflammatory cytokine ratio is
mainly due to the shift to a Th1-predominant state, clearly
demonstrated in preeclampsia, and probably associated to an excessive
production of inflammatory agents, among which IL-12 [14]. Abnormalities in TGF-β3
expression are also associated with preeclampsia and it has been
demonstrated that down-regulation of this growth factor restores the
invasive capability of preeclamptic trophoblast cells [34]. Caniggia et al [33] hypothesized that an up-regulation of both TGF-β3 and HIF-1 expression, secondary to a failure in the change in O2 tension
during early placentation or to a defect in the ability of trophoblast
cells to respond to this change, could arrest trophoblast
differentiation along the invasive pathway. Alterations in the
invasion-regulating system, uPA/uPAR/PAI, may also contribute to the
development of preeclampsia since reduced levels of uPA and increased
concentrations of PAI-1 have been reported in preeclamptic mothers.
Such an observation is in line with the demonstration that most of the
MMP-9 secreted by the preeclamptic trophoblast is in an inactive form,
and that antibodies against uPAR are found in pregnant women with a
history of fetal loss [69].
Placental ischemia, consequent to poor spiral artery remodeling [87], enhanced Th1/Th2 ratio [93] and pro-angiogenic/anti-angiogenic factor imbalance [94]
may promote inflammatory changes through the release of Th-1 cytokines
and ROS with consequent endothelial dysfunction, leading to the release
of humoral factors responsible for the clinical symptoms of
preeclampsia [69].
Several pieces of evidence suggest an involvement of ROS in endothelial alterations of the syndrome [69,83,95,96]. High decidual levels of oxidative stress markers have been found in preeclamptic decidua [95], and some of these are able to inhibit EVT cell invasiveness [96].
Moreover a reduction in glutathione peroxidase has been demonstrated in
the preeclamptic placenta, probably correlated with increased in vitro placental production of lipid hydroperoxides and thromboxane A2 (TXA2), a vasoconstrictive and pro-aggregatory compound, normally counterregulated by prostacyclin (PGI2). The consequent TXA2/PGI2 imbalance
could contribute to the state of high resistance of the utero-placental
circulation in preeclampsia. Since NO enhances vasodilatatory action of
PGI2 and inhibits TXA2-mediated-vasoconstriction, its reported decrease in preeclampsia could worsen vascular dysfunction [97].
An enhancement of placental NAD(P)H oxidase activity, possibly
stimulated by the increased vascular resistance, has recently been
implicated in preeclampsia. Excessive superoxide production could be
detrimental, both directly and indirectly, through an increase of
cytokine expression [77].
It has been reported that trophoblast cell-derived debris, a
by-product of apoptosis in the outer layers of the developing and
mature placenta, is present in maternal blood during normal pregnancy.
It increases in the blood of preeclamptic women, probably due to an
exaggerated apoptosis or even ischaemic necrosis of the oxidatively
stressed placenta. This event could represent a further pathogenic
mechanism of preeclampsia, through the release of pro-inflammatory
cytokines [98].
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