Beruflich Dokumente
Kultur Dokumente
http://www.kidney-international.org
& 2009 International Society of Nephrology
Division of Matrix Biology, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston,
Massachusetts, USA; 2Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA and 3Department of
Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
HISTORY OF PREECLAMPSIA
Hypertension in preeclampsia can lead to serious complications in both maternal and neonatal health. However, the
etiology of hypertension in preeclampsia remains unclear. In
normal human pregnancy, there is increased cardiac output
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Normal pregnancy
Preeclampsia
Dilation of
vasculature
Blood
Blood
Vascular
contraction
PRA
Low
Vascular resistance
High
High
Plasma volume
Low
Decreased
Sensitivity to vasoactive
substance
Increased
()
Autoantibodies for
AT1 receptor
(+)
High
2-ME
Low
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occur in some women with low sFlt1 and high PlGF levels.28
Therefore, although the involvement of placenta-derived
sFlt1 in the pathogenesis of preeclampsia is still being
explored, the utility of sFlt1 and PlGF levels as diagnostic
biomarkers for predicting preeclampsia is independently
being evaluated. In the AT(1)-AA-induced preeclampsia-like
disease in mice, elevation of sFlt1 is also found and is
speculated to contribute to the renal glomerular endothelial
damage; however, a connection to hypertension was not
found.12 Therefore, additional in-depth mechanistic studies
are required to elucidate the contribution of sFlt1 and
PlGF to the pathogenesis of preeclampsia.
Soluble endoglin (sEndoglin), which is also increased in
maternal serum in preeclampsia, is another circulating factor
that causes a preeclampsia-like phenotype in rodents.29 It is
speculated that adenoviral expression of sEndoglin induces a
preeclampsia-like phenotype in rats through the inhibition of
angiogenesis and activation of endothelial nitric oxide
synthase. Such effects of adenoviral-delivered sEndoglin
can be enhanced by co-infection with sFlt1-expressing
adenovirus,29 suggesting that sEndoglin may augment the
effects of sFlt1. Although such investigations may shed light
on the pathogenesis of preeclampsia, it is important to
consider that using an adenovirus system to deliver factors
relies on its capacity to infect many organs throughout the
body, including the liver. Adenoviral delivery leads to
concentrations of sFlt1 and sEndoglin that are substantially
higher in these animal models when compared with
physiological levels observed in preeclampsia.28,30 These data
in rats were analyzed using an enzyme-linked immunosorbent assay system specific for mouse sFlt1 and human
sEndoglin in rats infected with adenovirus carrying cDNA for
mouse sFlt1 and human sEndoglin. There was no evaluation
of endogenous rat-specific sFlt1 or sEndoglin. In addition,
increased viral infections may cause liver dysfunction in a
non-specific manner and may contribute to the vascular
dysfunction. Furthermore, the duration and change in the
rate of exposure to these molecules may be different in a
physiological condition observed in human preeclampsia.
Therefore these models need further characterization
to determine their physiological relevance to human
preeclampsia.26,29
Role of hypoxia-inducible factors in preeclampsia
Normal pregnancy
Estradiol
CYP450
17-hydroxyestradiol
COMT
HIF-1 suppression
Placental perfusion
2-ME
Low inflammatory
response
Vascular homeostasis
Preeclampsia
Estradiol
Placental defect
CYP450
17-hydroxyestradiol
COMT
Placental hypoxia
HIF-1 accumulation
Low
2-ME
Vascular defect
Inflammatory
response
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Genetic factors
Environment factor
(deficiency in nutrition?)
?
NK cell
Oxidative
stress
AT(1)-AAs
Vasoactive
substances
Low 2-ME
Inflammation
Hypoxia
HIFs
sEndoglin
Low vasodilators
sFlt1
VEGF
sFlt1-14
Increased demand
from embryo?
Endothelial damage
?
Placental deficiency
?
DISCLOSURE
REFERENCES
1.
2.
PERSPECTIVE
Although decreased placental perfusion due to poor placentation is likely a key factor in the onset of preeclampsia, it is
unlikely to be the only factor that leads to preeclampsia
(Figure 3). For example, perfusion defects can also lead to
fetal growth restriction even in the absence of preeclampsia.
Furthermore, only one-third of the babies born to preeclamptic women show growth restriction even in the
presence of placental defects.56 Placental perfusion defects
(vide supra) are often the consequence of abnormal
implantation and shallow invasion of trophoblasts; however,
these findings are also found in the placentae of pregnant
women with intrauterine growth restriction and in preterm
babies of non-preeclamptic women.57 Preeclamptic placentae
are sometimes larger than in normal pregnancy, and large
babies in women with obesity and gestational diabetes have
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explain all of the symptoms associated with preeclampisa.
An interesting alternate possibility is the consideration
of the fetal/placental weight ratio (FP ratio) as an important
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