Preeclampsia: The Role of Angiogenic Factors in Its Pathogenesis

Preeclampsia: The Role of Angiogenic Factors in Its
Pathogenesis
Alice Wang, Sarosh Rana and S. Ananth Karumanchi
Physiology
doi:10.1152/physiol.00043.2008
24:147-158, 2009.
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Role of Endothelin in Mediating Soluble fms-Like Tyrosine Kinase 1-Induced Hypertension
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PHYSIOLOGY 24: 147–158, 2009; doi:10.1152/physiol.00043.2008
the numerous
Preeclampsia: The Role of Angiogenic
Alice Wang,1 Sarosh Rana,2
obesity could
Factors in Its Pathogenesis
and S. Ananth Karumanchi2–4
1Division of Neonatology, Children’s Hospital Boston
and Harvard Medical School, Boston; Departments of
Preeclampsia, a systemic syndrome of pregnancy clinically characterized by
2Obstetrics and Gynecology and 3Medicine, Beth Israel
Deaconess Medical Center and Harvard Medical School,
new onset of proteinuria and hypertension, is associated with significant mor-
Boston, Massachusetts; and 4Howard Hughes Medical
es lifespan in
Institute, Chevy Chase, Maryland
. Am J Physiol
bidity and mortality to both mothers and fetuses. The pathogenesis of
sananth@bidmc.harvard.edu
E627 2009.
preeclampsia has been enigmatic; this review will focus on understanding the
origins of this disorder. Preeclampsia originates in the placenta, starting with
dicine
inadequate cytotrophoblast invasion and ending with widespread maternal
endothelial dysfunction. Production of placental anti-angiogenic factors,
ation between
specifically soluble fms-related tyrosine kinase 1 and soluble endoglin, have
vity in rodents?
rm used to des-
been shown to be upregulated in preeclampsia. These placental anti-angio-
by which the
genic factors are released into the maternal circulation; their actions disrupt
ustion of a sub-
Downloaded from
an end point in
the maternal endothelium and result in hypertension, proteinuria, and the
trons are trans-
other systemic manifestations of preeclampsia. The molecular basis for pla-
ory chain. The
the respiratory
cental dysregulation of these pathogenic factors remains unknown, remains
mitochondria,
unknown. Hypoxia is likely an important regulator. Other factors such as alter-
ynthase to syn-
physiologyonline.physiology.org
es not occur via
ations in the renin-angiotensin-aldosterone axis, immune maladaption, exces-
ugh uncoupling
sive shedding of trophoblast debris, oxidative stress, and genetic factors
siological roles
reactive oxygen
likely contribute to the pathogenesis of the abnormal placentation. As of
P2 has led to the
2009, the only successful treatment for preeclampsia is delivery. No definitive
le in regulating
y substantiated
preventive strategies have been identified. However, several of the recent
observations related to phenotypic causality provide stimuli for the develop-
, Andrews and
mitochondrial
ment of novel therapies.
on April 10, 2011
e of the longer
mice (rats live
Preeclampsia, a pregnancy-specific disorder charac-
Epidemiology and Risk Factors
r than mice).
terized clinically by new onset hypertension and pro-
ious tissues in
teinuria after 20 wk of gestation, is the most frequently
The worldwide incidence of preeclampsia is 3–4% of
hey found that
encountered medical complication during pregnancy,
all pregnancies (108b). Most cases of preeclampsia
coupled respi-
affecting ~3–5% of pregnant women worldwide (108b).
occur in healthy nulliparous women, in whom the
o significantly
In developing countries where access to health care is
incidence of preeclampsia may be as high as 7.5%
xidative stress.
limited, preeclampsia is a leading cause of maternal
(108a). Multiparous women pregnant with a new part-
UCP2 mutant
mortality, with estimates of >60,000 maternal
ner have a similar preeclampsia risk as nulliparous
of UCP2 have a
deaths/yr (108b). In the developed world, the burden
women (95); this has been ascribed to factors associat-
of this disease falls on the neonate because of prema-
ed with a change in paternity or increased interpreg-
e finding that
ture deliveries performed to preserve the health of the
nancy interval (90). In addition, women with
es implies that
mother. Worldwide, preeclampsia is associated with a
preeclampsia in a prior pregnancy continue to have a
ey mechanism
perinatal and neonatal mortality rate of 10% (4).
high risk of preeclampsia in subsequent pregnancies.
and ROS and
Delivery of the placenta results in resolution of the
Although most cases of preeclampsia occur in the
orie restriction,
condition, implicating the placenta as a central culprit
absence of a family history, the presence of
aging process,
in the pathogenesis of preeclampsia. This has led to a
preeclampsia in a first-degree relative increases a
2 and UCP3,
two-stage theory whose proponents hypothesize
woman’s risk of severe preeclampsia two- to fourfold
independently
preeclampsia to be a systemic syndrome that origi-
(16). A history of preeclampsia in the father’s mother
e, we await fur-
nates in the placenta and is characterized by maternal
also confers an increased risk (27).
er it is possible
widespread endothelial dysfunction (101). This article
Several medical conditions are associated with
lly extend lifes-
considers the pathogenesis as well as the diagnostic
increased preeclampsia risk, including chronic hyper-
P2 activity. 
and therapeutic advances in preeclampsia.
tension, diabetes mellitus, renal disease, obesity, and
1548-9213/09 8.00 ©2009 Int. Union Physiol. Sci./Am. Physiol. Soc.
147

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REVIEWS
hypercoagulable states, such as antiphospholipid
maternal complications of preeclampsia include acute
Pathogen
syndrome and factor V Leiden. Advanced maternal
renal failure, placental abruption, seizures, pulmonary
age is also an independent risk factor for preeclamp-
edema, acute liver injury, hemolysis, and/or thrombo-
The first deca
sia (22). Conditions associated with increased cytopenia. The latter three signs frequently occur
major advan
placental mass, such as multifetal gestations and
together as part of the HELLP (hemolysis, elevated
pathophysiolo
hydatidiform mole also predispose women to
liver enzymes, and low platelets) syndrome. Consid-
as the “diseas
preeclampsia. There seems to be no clear association
ered by many to be a severe variant of preeclampsia,
molecular pat
between consanguinity and the incidence or severity
HELLP syndrome is associated with a higher risk of
to be unravele
of preeclampsia (9); however, there are reports of
maternal and neonatal adverse outcomes than
in placental a
familial aggregation of preeclampsia and intrauterine
preeclampsia alone. Eclampsia complicates ~2% of
genic factors,
growth restriction in a genetically isolated popula-
preeclampsia cases in the United States. Up to one-
duce systemic
tions (12). Interestingly, smoking during pregnancy
third of eclampsia cases occur postpartum, up to 6 wk
hypertension,
appears to reduce the risk of preeclampsia (24).
after delivery (88). Complications affecting the devel-
manifestation
Although none of these epidemiological risk factors
oping fetus include both iatrogenic and spontaneous
lar basis fo
are well understood, they have helped to provide
prematurity (111), intrauterine fetal growth restric-
pathogenic fa
insight into the pathogenesis of preeclampsia.
tion (IUGR), oligohydramnios, and increased risk of
angiogenic pr
perinatal death.
opment and t
Clinical Features
Although the acute symptoms of preeclampsia will
be explored. H
remit after delivery, there are epidemiological studies
Downloaded from
lator. In additi
The cardinal features of preeclampsia are de novo
suggesting that there may be long-term cardiovascular
axis, excessiv
onset of hypertension (defined as systolic blood pres-
consequences. Approximately 20% of women with
phoblast debr
sure
140 mmHg or diastolic blood pressure 90
preeclampsia develop hypertension or microalbumin-
sucsceptibility
mmHg, and proteinuria ( 0.3 g in a 24-h urine speci-
uria within 7 years of a pregnancy complicated by
esis of preecla
men and/or protein to creatinine ratio of >0.30).
preeclampsia compared with only 2% among women
Role of the p
Historically, edema was part of the diagnostic triad for
with uncomplicated pregnancies (68). A study pub-
physiologyonline.physiology.org
preeclampsia; however, edema was too nonspecific to
lished by Smith et al. (91) reported that that at 1 year
The placenta i
be disease defining. Still, the sudden onset of severe
~20% of women have residual microalbuminuria.
only occurs in
edema, especially edema of the hands and face, is
In addition, the long-term risk of cardiovascular
always remits
often the only change detectable by the patient in this
and cerebrovascular disease is doubled in women
hydatidiform m
otherwise insidious disease. Preeclampsia develops
with preeclampsia and gestational hypertension
essary for the
from 20 wk of gestation onward until term, although
compared with age-matched controls (39, 76). This
in a case of pr
most cases are diagnosed preterm. In some cases,
increase in subsequent cardiovascular disease is
nancy, remov
preeclampsia may even first present after delivery.
observed for both preeclampsia and gestational
and symptom
The spectrum of preeclampsia varies widely. For
hypertension (76). Severe preeclampsia, recurrent
ered (87). Cas
clinical purposes, it is classified as mild or severe, but
preeclampsia, preeclampsia with preterm birth, and
associated wi
on April 10, 2011
such classifications may be misleading. Although the
preeclampsia with IUGR are most strongly associated
rapid improve
classification of severe preeclampsia serves to empha-
with future adverse cardiovascular outcomes. A
Severe pree
size the more ominous features of the syndrome (see
recent study by Vikse et al. showed that preeclampsia
evidence of p
Table 1), some have suggested a more nuanced dis-
is also a marker for increased risk for subsequent
Findings inclu
ease categorization (55a) or a classification of the dis-
end-stage renal disease (ESRD), although the
cular obstruc
ease based on the gestational age of presentation (98).
absolute risk of ESRD in this population is low (97).
intimal thick
The degree of proteinuria varies from minimal to
Preeclampsia and cardiovascular disease share many
endothelial da
nephrotic range; however, the amount of proteinuria
common risk factors, including chronic hyperten-
to occlusion
does not appear to have an effect on maternal or fetal
sion, diabetes, obesity, renal disease, and metabolic
Abnormal ute
outcomes (106). The approach to pregnant women
syndrome. Smith et al. (91) showed that, by 1 year
tent with de
with hypertension but without proteinuria is uncer-
postpartum, women who developed preeclampsia
observed befo
tain, but close follow-up is prudent. This recommen-
had increased blood pressure, total cholesterol, high-
The severity of
dation is supported by the observation that mild
er LDL cholesterol, triglycerides, increased BMI,
be correlated
gestational hypertension that occurs remote from
fasting insulin, HOMA index, and urinary microalbu-
although these
term may subsequently develop into preeclampsia
min/creatinine ratio. The increase in long-term car-
Abnormal p
(10). Ten percent of women with other clinical and/or
diovascular mortality holds even for previously
histological manifestations of preeclampsia have min-
healthy women without any overt vascular risk fac-
Because of the
imal or no proteinuria (29), and 20% of women who
tors who develop preeclampsia (20). Thus the
sia, there has b
develop eclampsia (seizures) have no proteinuria (88).
increase in long-term cardiovascular events in
malities in pla
Lafayette et al. showed that, in women with pre-
women with a history of preeclampsia may either be
role in the dise
eclampsia, the GFR is depressed, whereas the renal
the result of shared risk factors or the result of subtle
Early in nor
plasma flow and oncotic pressure is similar to healthy
vascular damage or persistent endothelial dysfunc-
cytotrophobla
pregnant woman (49). Uncommon but serious tion caused by preeclampsia.
ral arteries of
148
PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org

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REVIEWS
include acute
Pathogenesis
invasive cytotrophoblasts replace the endothelial layer
es, pulmonary
of the maternal spiral arteries, transforming them
d/or thrombo-
The first decade of this millennium has witnessed
from small, high-resistance vessels to high-caliber
quently occur
major advances in our understanding about the
capacitance vessels (see FIGURE 1) capable of provid-
lysis, elevated
pathophysiology of preeclampsia. Historically known
ing adequate placental perfusion to sustain the grow-
ome. Consid-
as the “disease of theories,” the mystery about the
ing fetus. In preeclampsia, this transformation is
preeclampsia,
molecular pathogenesis of preeclampsia is beginning
incomplete. Cytotrophoblast invasion of the spiral
higher risk of
to be unraveled with a key discovery about alterations
arteries is limited to the superficial decidua, and the
tcomes than
in placental antiangiogenic factors. These antiangio-
myometrial segments remain narrow (65). Fisher et al.
icates ~2% of
genic factors, such as sFlt1 and soluble endoglin, pro-
showed that in normal placental development the
es. Up to one-
duce systemic endothelial dysfunction, resulting in
cytotrophoblasts assume an endothelial phenotype in
um, up to 6 wk
hypertension, proteinuria, and the other systemic
a process called pseudovasculogenesis (114), or vas-
ing the devel-
manifestations of preeclampsia (63, 96). The molecu-
cular mimicry, by downregulating the expression of
d spontaneous
lar basis for placental dysregulation of these adhesion molecules characteristic of their epithelial
rowth restric-
pathogenic factors remains unknown, and the role of
cell origin and adopting an endothelial cell surface
reased risk of
angiogenic proteins in early placental vascular devel-
adhesion phenotype. In preeclampsia, cytotro-
opment and trophoblast invasion is just beginning to
phoblasts do not undergo this switching of cell-surface
eclampsia will
be explored. Hypoxia is likely to be an important regu-
molecules and thus are unable to adequately invade
logical studies
lator. In addition, the renin-aldosterone-angiotensin II
the myometrial spiral arteries (113).
Downloaded from
cardiovascular
axis, excessive oxidative stress and syncytiotro-
women with
phoblast debris, immune maladaption, and genetic
“Although there is not yet any definitive therapeutic or
microalbumin-
sucsceptibility may also all have roles in the pathogen-
omplicated by
esis of preeclampsia.
preventative strategy for preeclampsia, clinical experi-
mong women
Role of the placenta
A study pub-
ence suggests that early detection, monitoring, and sup-
physiologyonline.physiology.org
that at 1 year
The placenta is central to preeclampsia. Preeclampsia
uminuria.
only occurs in the presence of a placenta and almost
portive care are beneficial to the patient and the fetus."
ardiovascular
always remits after its delivery. As in the case of the
ed in women
hydatidiform mole, the presence of a fetus is not nec-
hypertension
essary for the development of preeclampsia. Similarly,
Angiogenic factors are thought to be important in
(39, 76). This
in a case of preeclampsia with an extra-uterine preg-
the regulation of placental vascular development (96).
ar disease is
nancy, removal of the fetus alone was not sufficient,
Flt1 (VEGFR-1), VEGFR-2, Tie-1, and Tie-2 are essen-
d gestational
and symptoms persisted until the placenta was deliv-
tial for normal placental vascular development.
sia, recurrent
ered (87). Cases of postpartum eclampsia have been
Alterations in these pathways in early gestation may
rm birth, and
associated with retained placental fragments, with
contribute to inadequate cytotrophoblast invasion
on April 10, 2011
gly associated
rapid improvement after uterine curettage (62).
observed in the placentas of women with preeclamp-
outcomes. A
Severe preeclampsia is associated with pathological
sia. Mice with these gene deletions have defective pla-
preeclampsia
evidence of placental hypoperfusion and ischemia.
cental vasculogenesis and early embryonic mortality
r subsequent
Findings include acute atherosis, a lesion of diffuse vas-
(17a). Invasive cytotrophoblasts express vascular
although the
cular obstruction that includes fibrin deposition,
endothelial growth factor (VEGF), placental growth
on is low (97).
intimal thickening, necrosis, atherosclerosis, and
factor (PlGF), and VEGFR-1 (Flt-1); expression of these
se share many
endothelial damage (82). Placental infarcts, likely due
proteins by immunolocalization is altered in
nic hyperten-
to occlusion of spiral arteries, are also common.
preeclampsia (115).
and metabolic
Abnormal uterine artery Doppler ultrasound, consis-
sFlt1 has been shown to decrease cytotrophoblast
hat, by 1 year
tent with decreased uteroplacental perfusion, is
invasiveness in vitro (115), and circulating sFlt1 levels
preeclampsia
observed before the clinical onset of preeclampsia (69).
stay relatively low early in pregnancy and begin to rise
lesterol, high-
The severity of the gross placental pathology appears to
in the third trimester. This may reflect a physiological
creased BMI,
be correlated with the severity of the clinical disease,
anti-angiogenic shift in the placental milieu toward
ry microalbu-
although these findings are not universal (82).
the end of pregnancy, corresponding to the comple-
ong-term car-
tion of the vasculogenic phase of placental growth.
Abnormal placentation
or previously
Alterations in these angiogenic pathways in early ges-
cular risk fac-
Because of the necessity of the placenta in preeclamp-
tation could contribute to the inadequate cytrotro-
0). Thus the
sia, there has been much scrutiny on how early abnor-
phoblast invasion seen in preeclampsia, thereby
ar events in
malities in placental vascular remodeling may play a
sparking a cycle of continued derangement in angio-
may either be
role in the disease.
genic balance; however, there is no definitive evidence
esult of subtle
Early in normal placental development, extravillous
for this hypothesis so far. By the third trimester, excess
elial dysfunc-
cytotrophoblasts of fetal origin invade the uterine spi-
placental sFlt1 accumulates in the maternal circula-
ral arteries of the decidua and myometrium. These
tion, produces end-organ effects, and reflects the
PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org
149

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REVIEWS
Target effects
degree of placental ischemia. Similar to sFlt1, both
Therefore, it is possible that soluble endoglin produced
monoclonal antibodies to endoglin and antisense
by the placenta may be a compensatory mechanism to
Although pree
endoglin oligonucleotides stimulated trophoblast out-
limit the effects of membrane-bound or surface
centa, the tar
growth and migration in experiments using tro-
endoglin. In preeclampsia, excessive production of sur-
(79). Many se
phoblasts from 5 to 8 wk of gestation (14). Endoglin
face endoglin leads to increased sEng in the maternal
and endotheli
(CD105) is a cell surface receptor for TGF-beta. TGF-
circulation. sEng together with sFlt1 may be responsible
with preeclam
beta 1 and/or TGF-beta 3 inhibit trophoblast migration
for the maternal endothelial dysfunction and the clini-
cellular fibron
and invasion; endoglin may mediate this effect (14).
cal manifestations of preeclampsia (see below).
selectin, plate
lin. The incub
women with
dysfunction (9
lating factors o
sible for the p
renal, and cer
Hemodynam
there are physi
resistance and
increases in c
Downloaded from
Inversely, pree
vasoconstricti
decreased car
Some studies
be higher in p
overt signs an
physiologyonline.physiology.org
noted in wom
gerated sensiti
II and norepin
op preeclamp
ent vasorelaxa
pressure and p
hypertension a
Renal patho
most clearly v
the characteri
sia. In 1959, S
on April 10, 2011
endotheliosis
in renal glome
vacuolization
capillary spac
deposits of fib
cells. Electron
endothelial fe
eases, endothe
with modest d
Although glom
ered pathogno
by Strevens
endotheliosis
preeclampsia,
gestational hy
endothelial dy
exaggeration
FIGURE 1. Abnormal placentation in preeclampsia
occurs near th
In normal placental development, invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries, trans-
Cerebral ed
forming them from small-caliber resistance vessels to high-caliber capacitance vessels capable of providing placental
perfusion adequate to sustain the growing fetus. During the process of vascular invasion, the cytotrophoblasts differ-
parenchymal
entiate from an epithelial phenotype to an endothelial phenotype, a process referred to as “pseudovasculogenesis”
ings in women
or “vascular mimicry” (top). In preeclampsia, cytotrophoblasts fail to adopt an invasive endothelial phenotype.
considerable
Instead, invasion of the spiral arteries is shallow, and they remain small caliber, resistance vessels (bottom). Figure
adapted from Ref. 50.
finding of cer
150
PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org

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REVIEWS
Target effects: maternal endothelial dysfunction
glin produced
mechanism to
Although preeclampsia appears to begin in the pla-
d or surface
centa, the target organ is the maternal endothelium
duction of sur-
(79). Many serum markers of endothelial activation
n the maternal
and endothelial dysfunction are deranged in women
be responsible
with preeclampsia, including von Willebrand antigen,
and the clini-
cellular fibronectin, soluble tissue factor, soluble E-
below).
selectin, platelet-derived growth factor, and endothe-
lin. The incubation of serum taken from preeclamptic
women with endothelial cells results in endothelial
dysfunction (96). It has been hypothesized that circu-
lating factors originating from the placenta are respon-
sible for the profound effects on the cardiovascular,
renal, and cerebral systems (80).
Hemodynamic changes. During normal pregnancy,
there are physiological decreases in peripheral vascular
resistance and arterial blood pressure, accompanied by
increases in cardiac output and vascular compliance.
Inversely, preeclampsia is characterized by widespread
Downloaded from
vasoconstriction, increased vascular resistance, and
decreased cardiac output and vascular compliance.
Some studies have suggested that cardiac output may
be higher in preeclamptic subjects before the onset of
overt signs and symptoms (16). This is particularly
noted in women with higher BMI. There is also exag-
physiologyonline.physiology.org
gerated sensitivity to vasopressors such as angiotensin
II and norepinephrine (80). Women who go on to devel-
op preeclampsia have impaired endothelium-depend-
ent vasorelaxation (44) and subtle increases in blood
pressure and pulse pressure before the onset of overt
hypertension and proteinuria (22).
Renal pathology. Injury to maternal endothelium is
most clearly visualized in the kidney, which reveals
the characteristic pathological changes of preeclamp-
sia. In 1959, Spargo et al. coined the term glomerular
on April 10, 2011
endotheliosis to describe the ultrastructural changes
in renal glomeruli, including generalized swelling and
vacuolization of the endothelial cells and loss of the
capillary space (see FIGURE 2) (29). There are also
deposits of fibrin within and under the endothelial
cells. Electron microscopy shows loss of glomerular
endothelial fenestrae (49). Unlike other nephrotic dis-
eases, endothelial cells appear to be primarily injured,
with modest damage to the podocyte foot processes.
Although glomerular endotheliosis was once consid-
ered pathognomonic for preeclampsia, recent studies
by Strevens et al. showed that mild glomerular
endotheliosis also occurs in pregnancy without
preeclampsia, especially in a subset of subjects with
gestational hypertension (92). This suggests that the
endothelial dysfunction of preeclampsia may be an
exaggeration of a normal physiological process that
occurs near the end of a term pregnancy.
FIGURE 2. Glomerular endotheliosis
eries, trans-
Normal human glomerulus, light microscopy 40 (PAS stain). Human preeclamptic
Cerebral edema. Cerebral edema and intracerebral
ing placental
glomerulus, light microscopy 40 (PAS stain). Note enlarged glomeruli and occluded
oblasts differ-
parenchymal hemorrhage are common autopsy find-
capillary lumen. Electron microscopy of glomerulus of the above patient described in B.
culogenesis”
ings in women who died from eclampsia, but there is
Note occlusion of capillary lumen cytoplasm and expansion of the subendothelial space
otype.
with some electron dense material. Podocyte cytoplasms show protein resorption
considerable controversy in the literature on the
m). Figure
droplets and relatively intact foot processes, Original magnification, 7,500. (Courtesy,
finding of cerebral edema. The cerebral edema in
I. Stillman)
PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org
151

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REVIEWS
eclampsia does not correlate with the severity of
cally acute hypertensive encephalopathy in the setting
knockout mou
hypertension, suggesting that the edema may be sec-
of renal disease or immunosuppression (36) as well as
in renal dise
ondary to endothelial dysfunction rather than a direct
with the use of anti-angiogenic agents for cancer ther-
glomerular en
result of blood pressure elevation (84). Findings on
apy (71). This syndrome is called reversible posterior
genesis cance
head CT and MRI are similar to those seen in hyper-
leukoencephalopathy (RPLS) or posterior reversible
led to proteinu
tensive encephalopathy, with vasogenic cerebral
encephalopathy syndrome (PRES). This association
lar endothelia
edema and infarctions in the subcortical white matter
supports the involvement of innate antiangiogenic
glomerulonep
and adjacent gray matter, predominantly in the pari-
factors in the pathophysiology of preeclampsia/
capillary repa
etal and occipital lobes (88). An eclampsia-type syn-
ecclampsia, as detailed in the next section.
important in
drome with these characteristic MRI changes have
endothelium
Mechanisms of preeclampsia
been associated with other clinical scenarios, specifi-
in the renal
Altered angiogenic balance. Imbalance of endoge-
hepatic sinuso
nous angiogenic factors plays a key role in the patho-
affected in p
genesis of preeclampsia. Increased expression of sol-
whether induc
uble fms-like tyrosine kinase-1 (sFlt1), associated
tion, or excess
with decreased placental growth factor (PlGF) and
uria and glom
VEGF signaling, were the first abnormalities
The physio
described (3, 63). VEGF stabilizes endothelial cells in
stood than tha
mature blood vessels and is particularly important in
Downloaded from
angiogenesis
maintaining the endothelium in the kidney, liver, and
mation, and w
brain. VEGF signals through two major receptors: Flk
to atherosclero
and Flt1. sFlt1 is a truncated splice variant of the
to VEGF-A, is
membrane-bound VEGF receptor Flt1, also called
thought to am
VEGFR1. sFlt1 consisting of the extracellular ligand-
from the Flt1
binding domain without the transmembrane and
physiologyonline.physiology.org
more potent K
intracellular signaling domains, is secreted by prima-
inhibition of b
rily syncytiotrophoblasts into the maternal circulation
duce preeclam
(18). sFlt1 has also been found to be made in mono-
Derangeme
cytes (75). sFlt1 antagonizes both VEGF and PlGF by
been observed
binding them in the circulation and preventing
urally occurrin
interaction with their endogenous receptors (see
been identified
FIGURE 3) (43).
but its role in
Placental expression of soluble Flt1 is increased in
maternal seru
preeclampsia and is associated with a marked
angiogenesis,
increase in maternal circulating sFlt1 (63). Several
Soluble endog
on April 10, 2011
investigators have confirmed that the increase in
which binds an
maternal circulating sFlt1 precedes the onset of clini-
upregulated in
cal disease (52, 64, 105) and is correlated with disease
of sFlt1. Endog
severity (17, 52). In addition, in molar gestations, lev-
cytriotrophob
els of sFlt1 are found to be elevated and may play a role
Levels of en
in early onset preeclampsia reported in such pregnan-
preeclamptic
cies (47). In vitro effects of sFlt1 include vasoconstric-
fies the vascul
tion and endothelial dysfunction. Exogenous sFLT1,
rats, inducing
delivered via an adenovirus vector to pregnant rats
with feature
produced a syndrome resembling preeclampsia,
Overexpressio
including hypertension, proteinuria, and glomerular
found to indu
endotheliosis (63). Several variants of sFlt1 have been
increased vas
FIGURE 3. sFlt1 and sEng cause endothelial
discovered, including a primate-specific variant that is
with brain ed
dysfunction by antagonizing VEGF and
TGF- signaling
designated sFlt1-14 (43, 85). sFlt1-14 is the predomi-
reversible pos
There is mounting evidence that VEGF and TGF- 1 are
nant VEGF inhibitor produced by human nonen-
with human ec
required to maintain endothelial health in several tissues,
dothelial cells and in early studies appears to be the
ed by interfere
including the kidney and perhaps the placenta. During
normal pregnancy, vascular homeostasis is maintained by
majority of the VEGF-neutralizing protein produced
tion (see FIGU
physiological levels of VEGF and TGF- 1 signaling in the
by the placenta in preeclamptic women (85).
levels are elev
vasculature. In preeclampsia, excess placental secretion
VEGF is highly expressed by glomerular podocytes,
(51). The prec
of sFlt1 and sEng (two endogenous circulating anti-
angiogenic proteins) inhibits VEGF and TGF- 1 signal-
and VEGF receptors are present on glomerular
relationship w
ing, respectively, in the vasculature. This results in
endothelial cells (58). Anti-VEGF therapies given to
Placental is
endothelial cell dysfunction, including decreased prosta-
adult animals cause glomerular endothelial damage
whether the sh
cyclin, nitric oxide production, and release of procoagu-
lant proteins. Figure adapted from Ref. 41.
with proteinuria (93). In a podocyte-specific VEGF
to incomplete
152
PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org

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REVIEWS
y in the setting
knockout mouse, heterozygosity for VEGF-A resulted
seen in preeclampsia is a consequence or cause of pla-
(36) as well as
in renal disease characterized by proteinuria and
cental ischemia/ hypoxia. In pregnant primates and
or cancer ther-
glomerular endotheliosis (26). In humans, anti-angio-
other mammals, constriction of uterine blood flow
sible posterior
genesis cancer trials with anti-VEGF antibodies have
(32, 60) has been shown to induce hypertension and
rior reversible
led to proteinuria, hypertension, and loss of glomeru-
proteinuria. However, in these animal models, uterine
is association
lar endothelial fenestrae (25, 116). In experimental
ischemia does not lead to seizures or HELLP syn-
antiangiogenic
glomerulonephritis, VEGF is necessary for glomerular
drome. In addition, in most cases of preeclampsia,
reeclampsia/
capillary repair (61, 70) and may be particularly
there are minimal downstream fetal consequences
on.
important in maintaining the health of fenestrated
expected from placental ischemia, with no evidence of
endothelium (28). Fenestrated endothelium is found
fetal growth restriction or fetal intolerance of labor.
in the renal glomerulus, choroid plexus, and the
Conversely, cases of fetal growth restriction secondary
ce of endoge-
hepatic sinusoids, organs that are disproportionately
to placental insufficiency frequently occur without
in the patho-
affected in preeclampsia. Thus VEGF deficiency,
preeclampsia. In addition, defective trophoblast inva-
ression of sol-
whether induced by anti-VEGF antibodies, gene dele-
sion and inadequate maternal spiral artery remodel-
1), associated
tion, or excess sFlt1, is likely responsible for protein-
ing is common to both IUGR and preeclampsia.
or (PlGF) and
uria and glomerular endotheliosis.
Placental ischemia and hypoxia frequently go hand-
abnormalities
The physiological role of PlGF is less well under-
in-hand. Women with preeclampsia have alterations
thelial cells in
stood than that of VEGF, but PlGF appears to stimulate
in placental hypoxia-inducible factor (HIF) and its tar-
y important in
angiogenesis under conditions of ischemia, inflam-
gets(75). Women residing at high altitudes also have
Downloaded from
ney, liver, and
mation, and wound healing (15) and may contribute
similar alterations in HIF, and the rates of preeclamp-
receptors: Flk
to atherosclerosis (57). PlGF, with structural homology
sia in this population are two- to fourfold higher (72).
variant of the
to VEGF-A, is a potent angiogenic growth factor that is
Common subjects of HIF-1 regulation include many
1, also called
thought to amplify VEGF signaling by displacing VEGF
angiogenic proteins, including Flt-1, VEGFR-2, Tie-1,
ellular ligand-
from the Flt1 receptor and allowing it to bind to the
and Tie-2. Invasive cytotrophoblasts express several
embrane and
more potent KDR receptor instead. During pregnancy,
other angiogenic factors regulated by HIF, including
physiologyonline.physiology.org
ted by prima-
inhibition of both PlGF and VEGF is necessary to pro-
VEGF, PlGF, and VEGFR-1; expression of these
nal circulation
duce preeclampsia-like changes in pregnant rats (63).
proteins by immunolocalization is altered in
ade in mono-
Derangements in other angiogenic factors have also
preeclampsia (115). Transforming growth factor beta-
F and PlGF by
been observed. The other major VEGF receptor, a nat-
3 (TGF-B3), which has been shown to block cytotro-
d preventing
urally occurring soluble form of Flk (VEGFR-2), has
phoblast invasion, is another HIF target. Hypoxia has
eceptors (see
been identified as being produced by the placenta (23),
been shown to upregulate expression and secretion of
but its role in preeclampsia is unknown. Additionally,
soluble Flt1 protein in primary trophoblast cultures
s increased in
maternal serum levels of endostatin, an inhibitor of
from first-trimester placentas (67). Paradoxically, ciga-
th a marked
angiogenesis, are elevated in preeclampsia (37).
rette smoking, an important risk factor for fetal growth
(63). Several
Soluble endoglin (sEng), a truncated form of endoglin,
restriction, is consistently associated with a reduced
on April 10, 2011
e increase in
which binds and antagonizes TGF- (see FIGURE 3), is
risk for preeclampsia (24). Levels of circulating sFlt1
onset of clini-
upregulated in preeclampsia in a pattern similar to that
and sEng are significantly lower in women who smoke
d with disease
of sFlt1. Endoglin is expressed at high levels in the syn-
(51). Circulating pro-angiogenic proteins such as pla-
estations, lev-
cytriotrophobast and invading cytotrophoblasts.
cental growth factor are increased in smokers (51).
may play a role
Levels of endoglin are significantly increased in
Recent in vivo experiments in mice strongly suggest
such pregnan-
preeclamptic placentas (51). Soluble endoglin ampli-
that placental hypoxia contributes to preeclampsia by
vasoconstric-
fies the vascular damage mediated by sFlt1 in pregnant
upreguating soluble anti-angiogenic factors affecting
genous sFLT1,
rats, inducing a severe preeclampsia-like syndrome
the vasculature. In recent work by Kanasaki et al. (40),
pregnant rats
with features of the HELLP syndrome (96).
pregnant mice deficient in catechol-O-methyltrans-
preeclampsia,
Overexpression of sFlt1 and sEng in rodents was also
ferase (COMT) also showed a preeclampsia-like
nd glomerular
found to induce focal vasospasm, hypertension, and
phenotype resulting from an absence of 2-methoxy-
Flt1 have been
increased vascular permeability that was associated
oestradiol (2-ME), a natural metabolite of estradiol
variant that is
with brain edema, producing images reminiscent of
that is elevated during the third trimester of normal
the predomi-
reversible posterior leukoencephalopathy associated
human pregnancy. The addition of 2-ME can improve
uman nonen-
with human eclampsia (59). This effect may be mediat-
all preeclampsia-like features without toxicity in the
ears to be the
ed by interference with nitric oxide-mediated vasodila-
Comt(–/–) pregnant mice. In addition, 2-ME has been
tein produced
tion (see FIGURE 3). As with sFlt1, circulating sEng
shown to suppress placental hypoxia, hypoxia-
(85).
levels are elevated weeks before preeclampsia onset
inducible factor-1alpha expression, and sFlt1
lar podocytes,
(51). The precise role of sEng in preeclampsia and its
elevation. The levels of COMT and 2-ME are also sig-
n glomerular
relationship with sFlt1 are currently being explored.
nificantly lower in women with severe preeclampsia.
apies given to
Placental ischemia/hypoxia. It is not understood
More work is needed to better assess the role of this
helial damage
whether the shallow cytotrophoblast invasion leading
pathway in human disease.
specific VEGF
to incomplete remodeling of the uterine spiral arteries
In summary, the role of trophoblast invasion is
PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org
153

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REVIEWS
clearly critical to successfully supporting a pregnancy,
Studies have identified agonistic (AT1) receptor
(KIRs) present
but overt placental ischemia and hypoxia may not be
autoantibodies in women with preeclampsia (99).
NK-cell signal
the causative factor in preeclampsia but rather an
These AT1 receptor autoantibodies, like angiotensin II
secretion of cy
important secondary event.
itself, could lead to the production of tissue factor by
ate the abnorm
Renin-angiotensin-aldosterone. In addition to
endothelial cells. Xia et al. found that AT1 receptor
Normal pre
altered angiogenic balance and failed cytotrophoblast
autoantibodies decreased invasiveness of immortal-
systemic infla
invasion, the renin-angiotensin-aldosterone axis is
ized human trophoblasts in an in vitro invasion
exaggerated in
also perturbed in preeclampsia. In normal pregnancy,
assay(109). Studies from Zhou et al. indicate that AT1
increased cir
renin, aldosterosterone, and angiotensin are
receptor autoantibodies recovered from the circula-
phoblast debr
increased. These hormones are suppressed relative to
tion of women with preeclampsia can replicate the key
with preeclam
normal pregnancy in preeclampsia. Women with
features of preeclampsia in pregnant mice and
of syncytriotro
preeclampsia have increased vascular responsiveness
increase both sFlt1 and sEng in pregnant mice (112).
cytokeratin fra
to angiotensin II and other vasoconstrictive agents.
The effects of these antibodies can be blocked with
cause for incre
Angiotensin II is a well recognized octapeptide medi-
losartan, a pharmacological AT1 receptor antagonist,
Endothelial
ator of elevated blood pressure that signals arterial
or by an antibody-neutralizing peptide (30). However,
been attribut
vasoconstriction after binding to the angiotensin II
AT1 receptor autoantibodies do not give explanation
excess produ
type 1 (AT1) receptor. Angiotensin II hypersensitivity
for the suppression of aldosterone production noted
species (77). A
in preeclampsia may also be due to heterodimeriza-
in preeclampsia (42). Present not only during preg-
produced by
tion of AT1 receptors with bradykinin receptors (1).
nancy, AT1 receptor autoantibodies appear to be
Downloaded from
(NO) synthe
increased as well in malignant renovascular hyperten-
methyl-ester)
sion and vascular rejection (30). These autoantibodies
hypertension
may account for the increased angiotensin II sensitiv-
(110). In preec
ity for preeclampsia. In summary, AT1-AA may be one
of enzymatic
of several insults that can contribute to the placental
high oxidative
damage that is proximally linked to the production of
physiologyonline.physiology.org
tic placentas (
anti-angiogenic factors (see FIGURE 4).
tion (89, 104)
Immunological intolerance and inflamma-
(101), and pro
tion/oxidative stress. Immune maladaption remains
(101). There h
an intriguing explanation about the pathogenesis of
looking for be
preeclampsia. Normal placentation requires the
a small study,
development of immune tolerance between the fetus
was also found
and the mother. Preeclampsia occurs more often in
Unfortunately
first pregnancies, after a change in paternity (94), or
plementation
with long interpregnancy interval (95). In addition,
has not been s
women using barrier contraceptive methods that
in nulliparous
on April 10, 2011
reduce maternal exposure to sperm have increased
and other adv
incidence of preeclampsia (46). Women who con-
mary, althou
ceived via intracytoplasmic sperm injection (ICSI) in
preeclampsia,
which sperm was surgically obtained from the male
test specific an
had a threefold increased risk of preeclampsia com-
secretion of to
pared with ICSI cases where sperm was obtained by
mote vascular
ejaculation (102). These observations suggest that
Genetics. A
preeclampsia may involve an abnormal maternal
occur in wome
immune response to novel paternally derived fetal
of preeclamps
antigens. Women with untreated HIV have a very low
woman’s risk
incidence of preeclampsia, but the incidence returns
(16). If a wom
to normal in HIV-positive women who are on anti-
already father
retroviral therapy (108).
ent woman, h
Natural killer (NK) cells at the maternal/fetal inter-
almost double
face are also thought to play an important role in the
paternal (thus
pathogenesis of preeclampsia. They are thought to be
position and s
important in modulating immune tolerance required
that requires
for normal placental development as well as the
gene in both
induction of angiogenic factors and vascular remodel-
hypothesized
FIGURE 4. Summary of the pathogenesis of preeclampsia
ing (33). Recent genetic studies have suggested that
has been exte
Immune factors (such as AT1-AA), oxidative stress, NK cell abnormalities, and other fac-
the susceptibility to preeclampsia may be influenced
ings about its
tors may cause placental dysfunction, which in turn leads to the release of anti-angio-
by polymorphic human leukocyte antigen C (HLA-C)
Still others bel
genic factors (such as sFlt1 and sEng) and other inflammatory mediators to induce
hypertension, proteinuria, and other complications of preeclampsia.
ligands and the killer immunoglobulin receptors
influence from
154
PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org

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REVIEWS
AT1) receptor
(KIRs) present on NK cells (35). Alterations in decidual
candidate genes that have been studied include pro-
lampsia (99).
NK-cell signaling with subsequent disturbance in the
thrombin, lipoprotein lipase, superoxide dismutase,
angiotensin II
secretion of cytokine and angiogenic factors may medi-
nitric oxide synthetase, and apolipoprotein E (107).
ssue factor by
ate the abnormal placentation noted in preeclampsia.
Currently in progress in Great Britain is a large study
AT1 receptor
Normal pregnancy, a condition with an enhanced
called The Genetics of Preeclampsia Collaborative
of immortal-
systemic inflammatory response, becomes markedly
(GOPEC) study that is collecting genomic information
vitro invasion
exaggerated in preeclampsia (77). There is evidence of
from 1,000 women with preeclampsia, along with the
icate that AT1
increased circulating fetal DNA and synctiotro-
proband’s parents, child, and partner to explore both
m the circula-
phoblast debris in the maternal circulation in women
maternal and fetal contributions to preeclampsia risk.
plicate the key
with preeclampsia (38, 78, 83). This debris, consisting
From an evolutionary perspective, Flt1 variants may
nt mice and
of syncytriotrophoblast membrane microparticles and
confer increased fetal fitness in sub-Saharan Africa
nt mice (112).
cytokeratin fragments, is proinflammatory and a likely
from placental malaria and may be under natural
blocked with
cause for increased oxidative stress.
selection in a malaria endemic area (66).
or antagonist,
Endothelial dysfunction in preeclampsia has also
Clinical implications
(30). However,
been attributed to placental oxidative stress, the
ve explanation
excess production of damaging reactive oxygen
Although there is not yet any definitive therapeutic or
duction noted
species (77). A key animal model of preeclampsia is
preventative strategy for preeclampsia, clinical experi-
during preg-
produced by infusion of an inhibitor of nitric oxide
ence suggests that early detection, monitoring, and sup-
appear to be
(NO) synthesis called
Downloaded from
L-NAME (L-nitroarginine
portive care are beneficial to the patient and the fetus.
ular hyperten-
methyl-ester), into pregnant rats, which produces
Reliable prediction of preeclampsia would allow closer
utoantibodies
hypertension, proteinuria, and thrombocytopenia
prenatal monitoring and timely intervention with
sin II sensitiv-
(110). In preeclampsia, there is decreased production
steroids to enhance fetal lung maturity, magnesium for
AA may be one
of enzymatic antioxidants (100, 103, 117). Markers of
seizure prophylaxis, anti-hypertensive medications and
the placental
high oxidative stress are also detectable in preeclamp-
bedrest, and expeditious delivery as necessary.
production of
tic placentas (77), with increased superoxide genera-
Furthermore, a robust biomarker for preeclampsia
physiologyonline.physiology.org
tion (89, 104), placental levels of lipid peroxidation
would provide a clear endpoint to simplify human stud-
d inflamma-
(101), and production and secretion of isoprostanes
ies of novel therapies and preventative strategies for
ption remains
(101). There have been a few human clinical trials
preeclampsia. However, no screening test has yet proven
athogenesis of
looking for benefit of antioxidants in preeclampsia. In
accurate enough for widespread clinical use (19).
requires the
a small study, treatment with the antioxidant lycopene
Because alterations in circulating levels of angio-
ween the fetus
was also found to reduce the risk of preeclampsia (86).
genic factors occur weeks before the clinical onset of
more often in
Unfortunately, in randomized controlled studies, sup-
preeclampsia, they represent promising biomarkers for
ernity (94), or
plementation with vitamin C and E during pregnancy
screening and/or diagnosis. Significant elevations in
. In addition,
has not been shown to reduce the risk of preeclampsia
maternal sFlt1 and sEng are observed from mid-gesta-
methods that
in nulliparous women, intrauterine growth restriction,
tion onward (73, 105) and appear to rise 5–8 wk before
on April 10, 2011
ave increased
and other adverse fetal outcomes (13, 74, 81). In sum-
onset of disease (34, 51). The ratio of sFlt1 and sEng to
en who con-
mary, although oxidative stress is present in
PlGF is a better marker for the diagnosis/prognosis of
ction (ICSI) in
preeclampsia, more work will be needed to design and
preeclampsia than any measure alone (51).
rom the male
test specific antioxidants that ameliorate the placental
Retrospective studies demonstrating the feasibility of a
lampsia com-
secretion of toxemic factors but at the same time pro-
urine screening test (PlGF) followed by a confirmatory
s obtained by
mote vascular endothelial health.
blood test for circulating angiogenic proteins (sFlt1 and
suggest that
Genetics. Although most cases of preeclampsia
PlGF) for the prediction of preeclampsia are promising
mal maternal
occur in women without a family history, the presence
(53). Placental protein 13 (PP13) has been reported to
derived fetal
of preeclampsia in a first-degree relative increases a
be a robust first trimester biomarker for predicting
ave a very low
woman’s risk of severe preeclampsia two- to fourfold
preeclampsia. The biological role of PP13 and its rela-
dence returns
(16). If a woman becomes pregnant by a man who has
tionship with angiogenic factors remain unknown (31).
o are on anti-
already fathered a preeclamptic pregnancy in a differ-
Other than delivery of the placenta, there is no
ent woman, her risk of developing preeclampsia is
known cure. After delivery, symptoms typically resolve
nal/fetal inter-
almost doubled (55). These studies implicate a strong
within 48–72 h. Potential novel pharmacological treat-
ant role in the
paternal (thus fetal) component to the genetic predis-
ment strategies may include restoration of normal
thought to be
position and support a single-gene inheritance model
angiogenic balance in the maternal circulation. One
ance required
that requires homozygosity for the same recessive
example would be VEGF-121. VEGF-121 was shown to
s well as the
gene in both mother and fetus (56). Others have
diminish hypertension and proteinuria and prevent
cular remodel-
hypothesized a role for genomic imprinting. STOX1
extensive renal pathology in a rat model of sFlt-1-
uggested that
has been extensively studied, with inconsistent find-
induced preeclampsia, without apparent harm to the
be influenced
ings about its association with preeclampsia (11, 45).
fetus (54). Any intervention that could delay delivery
en C (HLA-C)
Still others believe that preeclampsia is polygenic with
and prolong fetal gestation could have a tremendous
lin receptors
influence from multiple susceptibility genes. Other
impact on neonatal morbidity and mortality. Studies
PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org
155

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