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Abnormal Placentation, Angiogenic Factors, and The Pathogenesis of Preeclampsia
Abnormal Placentation, Angiogenic Factors, and The Pathogenesis of Preeclampsia
Placentation,
Angiogenic Factors,
a n d th e P a t h o g e n e s i s
o f P re e c l a m p s i a
Michelle Silasi, MDa, Bruce Cohen, MDa,
S. Ananth Karumanchi, MDa,b,c, Sarosh Rana, MD
a,d,
*
KEYWORDS
Pregnancy Preeclampsia Hypertension
Angiogenic factors
S.A.K is listed as a coinventor on multiple patents filed by the Beth Israel Deaconess Medical
Center for the use of angiogenic proteins for the diagnosis and therapy of preeclampsia.
S.A.K. is a consultant to Abbott Diagnostics (Abbott Park, IL, USA), Beckman Coulter (Chaska,
MN, USA), Roche diagnostics (Mannheim, Germany) and Johnson & Johnson (New Brunswick,
NJ, USA). SR is funded by 5K12 HD001255-08 (National Institutes of Health/National Institute of
Child Health and Human Development).
a
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel
Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Kirstein 3182,
Boston, MA 02215, USA
b
Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center,
Harvard Medical School, 330 Brookline Avenue, Kirstein 3182, Boston, MA 02215, USA
c
Howard Hughes Medical Institute, 25 Francis Avenue, Cambridge, MA 02138, USA
d
Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard
Medical School, 330 Brookline Avenue, Kirstein 3182, Boston, MA 02215, USA
* Corresponding author. Department of Obstetrics and Gynecology, Beth Israel Deaconess
Medical Center, 330 Brookline Avenue, Kirstein 3182, Boston, MA 02215.
E-mail address: srana1@bidmc.harvard.edu
and demonstrated how they contribute to the maternal endothelial dysfunction and
clinical features of PE. This article will include a review of information on the clinical
aspects, management, and molecular pathogenesis of PE, specifically focusing on
the role of these recently characterized angiogenic factors.
Complications
PE is a complex disease that can lead to complications in multiple organ systems.
Central nervous system complications include eclampsia (generalized tonic clonic
seizures), which complicates approximately 2% of PE cases in the United States.
Although most cases of eclampsia occur as a progression from PE, it can happen
without evidence of hypertension or proteinuria. Up to one third of eclampsia cases
occur postpartum, even days to weeks after delivery.14 Acute renal failure, liver failure,
pulmonary edema, and HELLP syndrome are additional complications. HELLP
syndrome is characterized by hemolysis, elevated liver enzymes, and low platelets.
It is considered a severe variant of PE, and is associated with a higher risk of maternal
and neonatal adverse outcomes than PE alone.
Recently literature has accumulated about long-term consequences of PE including
increased risk of cardiovascular disease, renal disease, and stroke. Approximately
20% of women with PE develop hypertension or microalbuminuria within 7 years,
compared with only 2% of women with normotensive pregnancies.15 The long-term
risk of cardiovascular and cerebrovascular disease is doubled in women with PE
and gestational hypertension compared with age-matched controls.16,17 Severe PE,
recurrent PE, PE with preterm birth, and PE with growth restriction are most strongly
associated with adverse cardiovascular outcomes. This increased risk of long-term
cardiovascular disease is independent of whether the woman had vascular risk factors
before the development of PE.
Fetal complications secondary to PE include intrauterine growth restriction, prema-
turity, placental abruption, and increased risk of perinatal death. PE is a leading cause
of iatrogenic premature delivery and contributes significantly to increasing health cost
associated with prematurity.
develop, the patient is delivered at 37 weeks. Very preterm pregnancies (<32 weeks)
with severe PE may be appropriate candidates for expectant management to admin-
ister antenatal steroids. This protocol, proposed by Sibai18,19 involves giving magne-
sium sulfate for seizure prophylaxis, checking serial laboratory values, and close
monitoring of blood pressures for 48 hours. After 48 hours, the magnesium can be dis-
continued, but close in-house observation must continue to monitor for declining clin-
ical status or signs of severity. Once this happens, delivery is indicated. Otherwise, the
patient may remain pregnant until 34 weeks. PE at term (at least 37 weeks) is managed
by immediate delivery. A recent large multicenter randomized controlled trial (HYPI-
TAT) in the Netherlands enrolled patients with a singleton pregnancy at 36 to 41
weeks gestation with either gestational hypertension or mild PE and randomized
them to undergo either induction of labor or expectant monitoring. This study found
that women in the induction of labor group had a lower rate of development of poor
maternal outcome (relative risk 0.71, 95% confidence interval [CI] 0.59 to 0.86,
P<.0001).20
PATHOGENESIS OF PE
Placental Vascular Development in Health and in Disease
Evidence implicates the placenta is a major determinant in the development of PE.
This evidence includes
Resolution of most signs and symptoms of PE within 48 hours following delivery of
the placenta
PE has been reported in molar pregnancies where there is no fetus present
PE can occur postpartum in the presence of retained placental fragments.19,2126
blood supply of blood. Plugs of endovascular trophoblast cells form within the distal
segments of the maternal arteries. These plugs serve as barriers, preventing maternal
blood from flowing into the intervillous space. As vascular remodeling of the spiral
arteries continues; the trophoblast plugs become loose, allowing blood flow, and
subsequently, oxygen transport between the mother and the intervillous space.
Oxygen tension measurements in the intervillous space up to 10 weeks of gestation
are approximately 20 mm Hg.30 This relatively hypoxic environment switches to
a more normoxic environment as maternal blood supplies oxygen to the intervillous
space. Oxygen tension levels rise threefold, with highest levels in the peripheral areas
of the developing placenta and lowest levels toward the center. Peak pO2 is about 60
mm Hg at 16 weeks of gestation. The rise in oxygen levels not only stimulates the
growth of the fetus, but also causes an upregulation of a range of adhesion molecules
by cytotrophoblast cells that facilitate trophoblast invasion. When there is a deficient
blood supply from the mother, prolonged hypoxia occurs, with detrimental effects to
the formation of the placental vasculature.
Abnormal placentation occurs in preeclamptic patients as evidenced by shallow
or absent remodeling of the maternal spiral arteries.31 Histologic studies show that
the physiologic remodeling of the spiral arteries is incomplete.32,33 The spiral
arteries in the myometrium retain their endothelial linings and muscular walls,
thereby retaining their high-resistance phenotype. This failure of vascular remodel-
ing may be the initial insult in the pathogenesis of PE. In addition, defects in the
phenotypic switching of cellular adhesion molecules have been characterized in
preeclamptic patients. For example, trophoblast cells from preeclamptic pregnan-
cies fail to switch the expression of epithelial cell-associated cell surface integrins
to an endothelial phenotype, thereby limiting their invasive potential.34 It also has
been hypothesized that decidual natural killer (NK) cells or activated macrophages
may play a role in the vascular remodeling noted during pregnancy, and this
process may be altered in PE.35
and is important for vasculogenesis and angiogenesis during the embryonic period of
development.
The VEGF subfamily of factors exerts its effect by binding with receptors. The VEGF
receptors (VEGFR-1 [Flt-1], VEGFR-2 [KDR/Flk1], and VEGFR-3) are tyrosine kinase
receptors. Tyrosine kinase receptors are a specific type of protein kinase receptor,
which work by phosphorylating the substrate to stimulate cellular responses. The
VEGF receptor consists of an extracellular domain, a single transmembrane spanning
region, and an intracellular component containing a split tyrosine kinase domain.
Although VEGF-A, VEGF-B and PLGF bind and interact with VEGFR-1, only VEGF-A
interacts with VEGFR-2.4448 VEGF-C and VEGF-D interact with VEGFR-3, which is
mostly expressed in lymphatic endothelium. The soluble form of VEGFR-1 (sFlt1 or
sVEGFR1) is a splice variant lacking the transmembrane and cytoplasmic domains.
Therefore, it circulates and acts as a potent VEGF and PlGF antagonist by preventing
their reaction with their endogenous receptors.49,50
Endoglin is a cell surface coreceptor for the transforming growth factor (TGF) family
members such as TGF-beta 1 and TGF-beta 3. These two factors are potent inhibitors
of trophoblast differentiation and migration.51 Soluble endoglin (sEng) is a truncated
form of the extracellular domain of endoglin that is expressed at high levels by the syn-
cytiotrophoblast layer and by cytotrophoblast cells undergoing differentiation to an
invasive phenotype. It is up-regulated in PE in a pattern similar to sFlt1. sEng acts
by inhibiting TGF-beta signaling in the vasculature. The precise role of sEng during
normal placental development is unknown.
Fig. 1. Summary of the pathogenesis of preeclampsia. Immune factors such AT1-AA, NK cell
dysfunction, and other factors may cause placental disease, which in turn leads to the
release of antiangiogenic factors (such as sFlt1 and sEng) and other inflammatory mediators
to induce hypertension, proteinuria, and other complications of preeclampsia. (Reproduced
from Wang A, Rana S, Karumanchi SA. Preeclampsia: the role of angiogenic factors in its
pathogenesis. Physiology 2009;24:14758; with permission.)
Ahmed68 showed that the ratio of VEGF and PlGF to sFlt1 is lower in explants derived
from preeclamptic patients. Conditioned media from normal villous explants induced
endothelial cell migration and in vitro tube formation, which was attenuated by exog-
enous sFlt1, while removal of sFlt1 from preeclamptic conditioned media restored
migration and tube formation. These findings suggest that elevated levels of sFlt1
lead to impaired VEGF/PLGF signaling leading to an antiangiogenic state.
246 Silasi et al
In light of the changes noted in angiogenic factors seen in women with PE, multiple
studies have proposed using angiogenic factors for screening. Data from retrospec-
tive studies have shown significant elevations in both maternal sFlt1 and sEng from
midgestation onward, and this rise seems to occur 5 to 8 weeks before PE
onset.52,53,59,78 Elevations in both sEng and the sFlt1:PlGF ratio seen in the late
second and early third trimester are associated with a significantly high risk for the
development of preterm PE.59 Also, the sFlt1/PlGF ratio has been suggested as an
index of antiangiogenic activity that reflects changes in both biomarkers79 and is
a better predictor of PE compared with either measure alone.59 In a recent large
prospective longitudinal cohort study for risk assessment for PE, midtrimester
PLGF/sEng X sFlt1 had a sensitivity of 100%, specificity of 95.3%, negative predictive
value (NPV) of 100%, and positive likelihood of 57.6.80 In all the studies, levels of
angiogenic proteins were measured by enzyme-lined immunosorbent assay (ELISA);
however, recently automated assays for sFlt1 and PlGF have been reported that
have coefficient of variation under 5%, and results are available in less than 30
Angiogenic Factors and Preeclampsia 247
SUMMARY
development of PE, but future studies using the time sequence of the changes seen in
these factors may lead to a much needed and valuable screening method to be used in
routine clinical practice. Furthermore, strategies looking at restoring the balance of
these dysregulated factors may pave the way toward variable treatment options for
this devastating disease.
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