Kidney International, Vol. 67 (2005), pp.

21012113

PERSPECTIVES IN RENAL MEDICINE

Preeclampsia: A renal perspective

S. ANANTH KARUMANCHI, SHARON E. MAYNARD, ISAAC E. STILLMAN, FRANKLIN H. EPSTEIN,
and VIKAS P. SUKHATME
Renal Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston,
Massachusetts; Department of Obstetrics & Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School,
Boston, Massachusetts; and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston,
Massachusetts

Preeclampsia: A renal perspective. Preeclampsia is a syndrome

that affects 5% of all pregnancies, producing substantial maternal and perinatal morbidity and mortality. The aim of this review
is to summarize our current understanding of the pathogenesis
of preeclampsia with special emphasis on the recent discovery
that circulating anti-angiogenic proteins of placental origin may
play an important role in the pathogenesis of proteinuria and
hypertension of preeclampsia.

Preeclampsia, the syndrome of hypertension and proteinuria that heralds the seizures of eclampsia, remains
one of the great mysteries in the field of obstetrics.
Although our understanding of the pathophysiology
of preeclampsia has increased over the past 50 years,
it is quite incomplete, and management remains supportive: close observation, treatment with antihypertensive agents and magnesium sulfate, and if progressive
signs and symptoms occur, urgent delivery of the fetus.
Preeclampsia is still one of the leading causes of maternal
and neonatal mortality in the world.
Preeclampsia is characterized by a constellation of
signs and symptoms, including the new onset of hypertension and proteinuria during the last trimester of
pregnancy, usually associated with edema and hyperuricemia [1, 2]. It occurs only in the presence of the
placenta, even when there is no fetus (as in hydatidiform mole) and remits dramatically postpartum [3]. The
placenta in preeclampsia is usually abnormal, with evidence of hypoperfusion and ischemia. Although these
placental changes are neither universal nor specific for
preeclampsia, there appears to be a correlation between
Key words: pregnancy, HELLP syndrome, angiogenesis, pseudovasculogenesis, VEGF, PlGF, soluble Flt-1, soluble VEGFR-1, proteinuria,
edema.
Received for publication February 9, 2004
and in revised for April 23, 2004
Updated on November 23, 2004
Accepted on January 12, 2005


C

2005 by the International Society of Nephrology

the severity of the disease and the extent of placental abnormalities. The clinical findings of severe preeclampsia
are unified by the presence of systemic endothelial dysfunction and microangiopathy, in which the target organ
may be the brain (seizures or eclampsia), the liver [the
hemolysis, elevated liver function tests, and low platelet
count (HELLP) syndrome], or the kidney (glomerular
endotheliosis and proteinuria). Severe preeclampsia is
also associated with small for gestational age (SGA) fetuses. Because of the strong clinical and experimental evidence of early placental involvement and dysfunction of
the maternal endothelium, it is currently believed that
preeclampsia has its origin in disordered vascular development of the placenta, which in turn leads to widespread
maternal vascular endothelial effects [4, 5] (Fig. 1). This
review will discuss mechanisms underlying the clinical
manifestations of preeclampsia. In addition, we will describe evidence suggesting that placental secretion of an
antiangiogenic protein may contribute to the endothelial
dysfunction of preeclampsia.

RISK FACTORS FOR THE DEVELOPMENT OF

PREECLAMPSIA
The risk factors for the development of preeclampsia
are listed in Table 1 [1, 57]. Preeclampsia is more
common not only in first pregnancies, but also in multigravidas who have a new partner, suggesting that prior
exposure to paternal antigens may be protective [8, 9].
However, recent evidence from a large Norwegian birth
registry suggests that prolonged interpregnancy interval,
rather than primipaternity, accounts for this increase in
risk [10], though why this occurs is unclear. Although
preeclampsia is traditionally not considered to be a
genetic disease, it is clear that genetic factors contribute
to the susceptibility to preeclampsia [6]. A family history
(mother, sister, or both) of preeclampsia is associated
with a fourfold increased risk for preeclampsia [6]. Other
epidemiologic studies suggest that paternal genetic
contributions to the zygotic genotype in addition to
2101

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Karumanchi et al: Preeclampsia and angiogenic factors

Table 1. Risk factors for the development of preeclampsia

Family history of preeclampsia
Nulliparity
Multiple gestation
Molar pregnancies
Older maternal age
Obesity
Preexisting hypertension
Chronic renal disease
Diabetes mellitus
Thrombotic vascular disease

maternal genes may contribute susceptibility to

preeclampsia [11]. Polymorphisms of genes involved in
the regulation of blood pressure or coagulation, such as
renin, angiotensinogen (T235), endothelial nitric oxide
synthase (eNOS), prothrombin, factor V Leiden, and
methyltetrahydrofolate (MTHFR), though promising in
early studies [1215], have not been confirmed in larger
studies [1620]. Genome-wide scanning of Icelandic
families revealed a significant locus on chromosome 2p13
[logarithm of the odds (LOD) score 4.70] [21]. More
recently, the 2p locus was confirmed in a study of patients
from New Zealand and Australia [22]. Finally, a Dutch
study reported linkage of HELLP syndrome, but not
preeclampsia, with a locus on 12q, suggesting that genetic
factors important in HELLP (hemolysis, elevated liver
function tests, low platelets) syndrome may be distinct
from those in preeclampsia [23]. Women with trisomy 13
fetuses have a higher incidence of preeclampsia, regardless of parity, suggesting that a gene on chromosome 13
may be important in preeclampsia [24]. An activating
mineralocorticoid receptor mutation was described in a
rare group of patients who have only pregnancy-induced
hypertension without proteinuria [25]. The incidence of
preeclampsia is also higher in women who live at high
altitudes and in the third world, suggesting that hypoxia
and/or hitherto unknown environmental factors may
also contribute to the development of preeclampsia [26,
27].
CLINICAL MANIFESTATIONS AND THEIR
PATHOPHYSIOLOGIC UNDERPINNINGS
Hypertension
While in normal pregnancy peripheral vascular resistance and blood pressure are decreased, in preeclampsia these changes are reversed. Increased peripheral
vascular resistance, rather than increased cardiac output,
is the chief cause of hypertension [28]. Sympathetic activation is noted in preeclampsia as it is in other forms
of hypertension, a conclusion supported by electrical
recordings of sympathetic nerve impulses [29] and by
reports of increased concentrations of circulating catecholamines [30]. Sympathetic activation may be respon-

sible for the increase in cardiac output noted by some in

the early stages of preeclampsia [31]. Preeclampsia is also
notable for an exaggerated response to angiotensin II,
catecholamines, and other hypertensive stimuli when
compared to normal pregnant controls [32, 33]. One
group has reported that this response may precede the
onset of overt hypertension by weeks to months [34]
(a finding disputed by others [35]), reminiscent of the
exaggerated response to vasoconstrictors described in
normotensive relatives of patients with essential hypertension [36].
Although total plasma volume has been reported to
be low in preeclampsia [37], there may be increased
effective circulating volume as evidenced by suppressed renin and aldosterone [38, 39] and elevated brain
natriuretic hormone [40] relative to normal pregnancy.
These findings are reminiscent of the fall in plasma volume and rise in blood pressure produced by infusion
of vascoconstrictors suggesting that peripheral vasoconstriction, especially of small venules, shifts blood to the
arteries and central veins while elevating capillary pressure [41]. Blood pressure rises, and renin and aldosterone
levels fall as a secondary phenomenon.
Generalized vascular constriction is universally
present in preeclampsia, at least compared to the physiologic vasodilation of normal pregnancy [28]. There is
substantial evidence that this may be due to endothelial
dysfunction. A myriad of markers for endothelial activation and dysfunction, including endothelin, cellular
fibronectin, plasminogen activator inhibitor-1 (PAI-1),
and von Willebrands factor, are altered in preeclampsia.
Women with preeclampsia have enhanced responsiveness to vasopressors as compared with normal pregnant
women. Women with a history of preeclampsia exihibit
evidence of impaired endothelial-dependent vasorelaxation as measured by brachial artery flowmediated
dilatation up to 3 years after delivery, implying these
changes in the maternal endothelium may be more than
transient [42, 43]. Alterations of endothelial function
have been noted in preeclamptic vessels examined in
vitro, supporting the hypothesis that endothelial dysfunction may underlie the hypertension of preeclampsia
[4, 5]. The increased incidence of preeclampsia in women
with chronic diseases such as diabetes and hypertension
also suggests some factor in the maternal milieu may also
lend susceptibility to preeclampsia. In addition to increased vascular reactivity, the vasoconstriction appears
to be mediated at least in part by alterations in local
concentrations of several vasoactive molecules, including
the vasoconstrictors norepinephrine, endothelin, and
perhaps thromboxane, and the vasodilators prostacyclin
and perhaps nitric oxide.
Prostaglandin I 2 (PGI 2 ) (prostacyclin), a circulating vasodilator produced primarily by the endothelial and smooth muscle layers of blood vessels, is

Karumanchi et al: Preeclampsia and angiogenic factors

Genetic
factors

Environmental
factors

2103

Other

Placental
dysfunction

Circulating
factor(s)

Vascular endothe lial dysfunction

Hypertension

Glomerular
endotheliosis
proteinuria edema
renal insufficiency

Headache
Cerebral edema
Seizures

LFTs
HELLP syndrome

Fig. 1. Placental dysfunction and endothelial

dysfunction in the pathogenesis of preeclampsia. Placental dysfunction, triggered by poorly
understood mechanisms, which may include
genetic, immunologic, and environmental factors, plays an early and primary role in the
development of preeclampsia. The diseased
placenta in turn secretes a factor(s) into
the maternal circulation, causing systemic
endothelial cell dysfunction. Most of the
manifestations of preeclampsia, including
hypertension, proteinuria (glomerular endotheliosis), seizures (cerebral edema and/or
vasospasm), and the hemolysis, elevated
liver function tests, and low platelet count
(HELLP) syndrome can be attributed to vascular and endothelial effects.
Fig. 2. Glomerular endotheliosis. (A) Normal human glomerulus (hematoxylin and
eosin stain). (B) Human preeclamptic
glomerulus (hematoxylin and eosin stain). A
33-year-old woman with twin gestation and
severe preeclampsia at 26 weeks gestation
with urine protein/creatinine ratio of 26 at
the time of biopsy. (C) Electron microscopy
of glomerulus of the above patient described
in (B). Note occlusion of capillary lumen cytoplasm and expansion of the subendothelial
space with some electron-dense material.
Podocyte cytoplasms show protein resorption
droplets and relatively intact foot processes
(original magnification 1500). (D) Control
rat glomerulus (hematoxylin and eosin
stain). Note normal cellularity and open
capillary loops. (E) Soluble Flt-1treated rat
(hematoxylin and eosin stain). Note occlusion
of capillary loops by swollen cytoplasm with
minimal increase in cellularity. (F) Electron
microscopy of sFlt-1treated rat. Note occlusion of capillary loops by swollen cytoplasm
with relative preservation of podocyte foot
processes (original magnification 2500). All
light micrographs taken at identical original
magnification of 40).

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Karumanchi et al: Preeclampsia and angiogenic factors

increased in normal pregnancy [44]. In preeclampsia,

prostacyclin production is lower than in normal pregnancy well before the onset of hypertension and proteinuria [45, 46]. Endothelial cells incubated with serum from
women with preeclampsia (vs. serum from normotensive
pregnant women) produce less prostacyclin in vitro, suggesting the presence of a circulating factor suppressing
prostacyclin synthesis [47]. Prostacyclin concentrations
are normal in pregnant women with chronic hypertension but without preeclampsia [48], providing further
circumstantial evidence that decreased prostacyclin is a
contributing cause of preeclampsia rather than a consequence of hypertension.
Thromboxane A 2 (TXA 2 ) is a potent vasoconstrictor synthesized by endothelial cells, activated platelets,
macrophages, and other organs. Urinary excretion of
TXA 2 metabolites has been reported to be increased in
preeclampsia by some [49] but not all investigators [46,
50]. TXA 2 production appears to parallel the severity of
preeclampsia, being higher in patients with coagulopathy
and pronounced platelet activation [50]. Some attempts
to prevent preeclampsia in high risk patients by inhibiting
platelet thromboxane synthesis using aspirin were successful but others found no benefit, either in low risk or
high risk populations [51, 52].
There is some evidence that nitric oxide, a vascular
smooth muscle relaxant synthesized by vascular endothelium, may also mediate the generalized vasodilation of
normal pregnancy [53, 54]. In rodent experiments, nitric oxide inhibition during pregnancy induces hypertension [5557] and proteinuria [58] and reverses the
norepinephrine and angiotensin II resistance characteristic of pregnancy [59, 60]. Thus, damage to vascular endothelium with decreased nitric oxide production might
contribute to vascular constriction in preeclampsia. Although some human studies have reported decreased
nitric oxide production in preeclampsia [6163], others
report nitric oxide production to be unchanged [64, 65]
or even increased [66, 67]. Unfortunately, studies of nitric oxide production are difficult due to its extremely
short circulating half-life and other challenges to its
measurement.
Endothelin-1, a potent vasoconstrictor that can be released by vascular endothelial cells in response to injury [68], has also been implicated in the hypertension of
preeclampsia. Reports of plasma endothelin concentrations in preeclampsia have been mixed, with most [6971]
but not all [50] investigators reporting a modest increase
in circulating concentrations. The release of endothelin
by cultured endothelial cells is enhanced by exposure
to plasma from preeclamptic patients, as compared with
plasma from women with normal pregnancies [72]. Limited animal data suggest that hypertension induced by
endothelin-1 administration during pregnancy produces
proteinuria [73].

Renal dysfunction, proteinuria, and renal pathology

In normal pregnancy, glomerular filtration rate (GFR)
as measured by inulin clearance and renal plasma flow
(para-aminohippurate clearance) increases by 40% to
60% during the first trimester [74, 75], resulting in a fall in
serum markers of renal clearance, including blood urea
nitrogen (BUN), creatinine, and uric acid. In preeclampsia, both GFR and renal plasma flow decrease by 30%
to 40% compared with normal pregnancy of the same
duration [76, 77]. Rarely, prolonged renal hypoperfusion
with resulting acute tubular necrosis can occur in severe
preeclampsia. It is important to note that in preeclampsia, BUN and creatinine often remain in the normal range
for nonpregnant women despite a significant decrease in
GFR from the high level of normal pregnancy.
Proteinuria may rarely precede hypertension but usually accompanies or follows it. After pregnancy is terminated, proteinuria commonly disappears within 3 to 8
weeks, but occasionally persists for months. The quantity
of protein excreted in the urine varies widely from less
than a gram to 8 to 10 g per day. The urinary sediment is
usually bland; red blood cells and cellular casts are rare.
Preeclampsia is the leading cause of nephrotic syndrome
during pregnancy. Recent data suggest that a loss of both
size and charge selectivity of the glomerular barrier contribute to the development of albuminuria [77].
Preeclampsia is associated with a characteristic
glomerular lesion, glomerular capillary endotheliosis (Fig. 2A to C) [7880]. By light microscopy, the
glomeruli are enlarged and the glomerular capillary lumen is bloodless due to endothelial and mesangial cell
swelling and hypertrophy. While these changes may be
focally present in other conditions (such as abruptio placentae), only in preeclampsia is endotheliosis so prominent and widespread. Glomerular cellularity is at most
slightly increased. Mesangial interposition may occur in
severe cases or in the healing stages. Glomerular visceral epithelial cells (podocytes) usually appear swollen
with periodic acid-Schiff (PAS)-positive hyaline droplets.
Immunofluorescence may reveal deposition of fibrin
or fibrinogen derivatives particularly in biopsies done
within 2 weeks postpartum [81]. Electron microscopy
is important to confirm endotheliosis and the loss of
endothelial fenenstrae. Remarkably, despite heavy proteinuria the podocyte foot processes are relatively preserved [82]. Glomerular subendothelial and occasional
mesangial electron-dense deposits can be seen. These
likely relate to fibrin or related breakdown products. Mild
glomerular endotheliosis has been noted in up to 50%
of patients with pregnancy-induced hypertension without proteinuria [83], suggesting that pregnancy-induced
hypertension may in some cases reflect an earlier or
milder form of the same syndrome. Glomerular enlargement and endothelial swelling usually disappear within
8 weeks of delivery, coinciding with resolution of the

Karumanchi et al: Preeclampsia and angiogenic factors

hypertension and proteinuria. Focal segmental glomerulosclerosis (FSGS) can accompany the generalized
glomerular endotheliosis of preeclampsia in 50% or more
of cases [84, 85].
Edema
Although the presence of edema is not necessary for
the diagnosis, sudden weight gain, with edema of the
feet, hands, and face, is a common presenting symptom in preeclampsia [32]. Salt loads are excreted more
slowly than in normal pregnancy [86, 87]. The edema of
preeclampsia is unlike that in congestive heart failure,
hepatic cirrhosis, and nephrotic syndrome, where low
effective circulating volume leads to high plasma renin
and aldosterone concentrations and secondary renal
sodium retention (underfill edema) [88]. Instead, renin
and aldosterone concentrations are suppressed relative
to normal pregnancy [39]. The edema of preeclampsia
thus resembles the overfill edema of acute glomerulonephritis or of acute ischemic renal failure in which
GFR is decreased out of proportion to the drop in renal
plasma flow and in which glomerular-tubular imbalance
has been invoked as a cause of salt retention.
Decreased GFR, increased capillary permeability, and
hypoalbuminemia may contribute to the edema formation. Albumin-bound Evans blue dye disappears
more quickly from the intravascular space in preeclamptic women compared with normal pregnant women,
suggesting endothelial permeability is increased [89].
However, this phenomenon is also seen in non-pregnant
patients with heart failure and the nephrotic syndrome
[90, 91]. Hypoalbuminemia is common and may contribute to edema. However, correction of hypoalbuminemia with albumin infusions in preeclampsia patients
usually does not produce a diuresis, suggesting that the
hypoalbuminemia alone is not responsible for the edema
[92].
Hyperuricemia
The association between preeclampsia and elevated
serum uric acid was first noted more than 80 years
ago [93]. Serum uric acid levels are usually elevated in
preeclampsia, and the degree of uric acid elevation has
been correlated with the severity of proteinuria [94], renal
pathologic changes [83], maternal morbidity [95], and fetal demise [96]. Often, the elevation of uric acid precedes
the onset of proteinuria and fall in GFR [97]. Although
it has been proposed that uric acid generation may be increased in preeclampsia as a result of tissue ischemia [98],
most evidence suggests that decreased renal clearance is
the more important mechanism [99]. Similar decreases in
uric acid clearance have been noted by infusions of vasoconstrictors in humans [100]. It has recently been sug-

2105

gested that hyperuricemia may also directly contribute

to vascular damage and hypertension [101, 102].
Coagulopathy and HELLP syndrome
Preeclampsia is sometimes complicated by consumptive coagulopathy and thrombotic microangiopathy culminating in the HELLP syndrome. HELLP syndrome
develops in approximately 10% to 20% of women with
severe preeclampsia. The tendency of blood to coagulate
is increased in normal pregnancy at least in part because
of changes in the circulating concentrations of coagulant
factors. In the indolent microangiopathy of preeclampsia, it is mainly the factors that are synthesized in the
vascular endothelium that are abnormal. These include
prostacyclins (PGI 2 ), von Willebrand factor, thrombomodulin, cellular fibronectin, and PAI-1 [103106]. Even
in the absence of overt coagulopathy, serum and urine fibrin degradation products are increased, implicating subclinical activation of the coagulation cascade.
These changes are not simply epiphenomena in response to hypertension. Plasma concentrations of cellular fibronectin may be increased weeks before the onset
of hypertension [107]. Exposure of cultured endothelial
cells to serum from women with preeclampsia triggers
increased cellular filbronectin [108, 109] and thrombomodulin [110] release compared with serum from normotensive pregnant women, again suggesting that a
factor in preeclamptic serum is directly activating
endothelial cells. It is interesting to note that other
endothelial disorders, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, vasculitis,
and disseminated intravascular coagulation can produce
similar alterations in markers of endothelial activation
[111113]. There is also evidence that platelet activation
is present in preeclampsia as a consequence of endothelial damage. Markers of platelet activation such as beta
thromboglobulin have been found to be elevated prior to
the onset of clinical disease [114]. Furthermore, adhesion
molecules such as soluble P-selectin, soluble E-selectin,
and soluble vascular cell adhesion molecule-1 (VCAM-1)
that reflect endothelial, platelet, and leukocyte activation
have also been reported to be elevated in preeclampsia
[115]. The severe thrombocytopenia that is occasionally
seen is likely due to consumption during intravascular
coagulation.
Neurologic abnormalities
Preeclampsia is occasionally complicated by the development of seizures (eclampsia). Other neurologic symptoms include headache, blurred vision, and temporary
loss of vision. The neurologic changes in eclampsia and
preeclampsia have been attributed to cerebral edema and
vasoconstriction. Brain edema by magnetic resonance

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Karumanchi et al: Preeclampsia and angiogenic factors

(MR) imaging and abnormalities in circulating endothelial markers correlate closely with the occurrence of
eclampsia, suggesting that endothelial damage and disruption of the blood-brain barrier may be an underlying
mechanism [116]. The cerebral edema of eclampsia involves predominantly the posterior portions of the white
matter, and has been referred to as reversible posterior leukoencephalopathy syndrome (RPLS) [117]. Interestingly, patients with thrombotic thrombocytopenic
purpura (TTP), another disorder with microangiopathy
also have features of RPLS on MR imaging examinations [118], as do some patients with hypertensive encephalopathy.
ABNORMAL PLACENTATION IN
PREECLAMPSIA
It was 1939, when E.W. Page first proposed that
placenta plays a central role in preeclampsia [3]. Placentas from severe preeclamptic pregnancies classically
have numerous infarcts, sclerotic narrowing of arteries and arterioles, and fibrin deposition and thrombosis.
Physiologic studies have confirmed that uteroplacental
blood flow is diminished and uterine vascular resistance is
increased in preeclamptic women. In addition, placental
ischemia induced by mechanical constriction of the uterine arteries or aorta produces hypertension, proteinuria,
and, variably, glomerular endotheliosis, in a variety of
species [119121]. Placental ischemia may be contributed
to by a decrease in placental production of nitric oxide
[122]. However, placental ischemia alone, as in intrauterine growth restriction, does not appear to be sufficient
to produce preeclampsia. Thus, although uteroplacental
ischemia is an important trigger of preeclampsia, the response to this ischemiaeither at the placental or the
maternal systemic levelmust be variable.
Evidence suggests that placental ischemia in
preeclampsia occurs as a result of defective placental vascular remodeling. Early in normal placental
development, cytotrophoblast cells, fetal in origin, attach
to the uterine deciduas via anchoring villi (see Fig. 3).
Floating villi, containing fetal vessels which participate in
nutrient exchange, are bathed in maternal blood which
fills the intravillous space via uterine spiral arteries.
During placental vasculogenesis, a small percentage of
cytotrophoblasts in the anchoring villi break through
the syncytium and migrate into the endometrium.
These extravillous trophoblasts invade the uterine
spiral arteries of the myometrium, a process that peaks
at about 12 weeks gestation. By 18 to 20 weeks, the
endometrial and superficial myometrial segments of
the spiral arteries are lined by cells of cytotrophoblast
origin, with transformation of these vessels from small
resistance vessels to flaccid, high-caliber capacitance
vessels [123, 124]. This dramatic transformation allows

the increase in placental blood flow needed to sustain

the fetus through the pregnancy.
The characteristic pathologic placental lesion in severe
preeclampsia is diminished endovascular invasion by cytotrophoblasts and failure of uterine spiral arteriolar remodeling [123, 125]. Cytotrophoblast invasion is limited
to the proximal decidua, and the myometrial segments
of the spiral arteries remain narrow and undilated [126],
resulting in uterine hypoperfusion. Zhou et al [127, 128]
have shown that invasive cytotrophoblasts down-regulate
the expression of adhesion molecules characteristic of
their epithelial cell origin and adopt a cell-surface adhesion phenotype typical of endothelial cells, a process
referred to as pseudovasculogenesis. They hypothesized
and confirmed that in preeclampsia, cytotrophoblast cells
fail to undergo this switching of cell-surface integrins
and adhesion molecules [129]. This work suggests that
cytotrophoblast differentiation is abnormal in severe
preeclampsia, and may be an early defect that eventually
leads to placental ischemia. Others have demonstrated
that hypoxia-inducible factor-1 (HIF-1) is up-regulated in
preeclampsia and have suggested that HIF-1 target genes
such as transforming growth factor-beta 3 (TGF-b3) may
block the cytotrophoblast invasion [130132]. More recently, heparin-binding epidermal growth factor (EGF)like growth factor (HB-EGF) has been demonstrated to
be decreased in preeclamptic cytotrophoblasts; however,
its role in cytotrophoblast differentiation and invasion is
unclear [133]. Interestingly, uteroplacental ischemia produced in monkeys by aortic constriction late in gestation
does not produce the defective placental cytotrophoblast
invasion seen in preeclampsia, though it is associated with
proteinuria and hypertension [134].

THE PLACENTAL FACTOR IN PREECLAMPSIA

All of the clinical manifestations of preeclampsia can
be attributed to endothelial cell dysfunction leading to
end-organ damage and hypoperfusion. Based on this
observation, it has been suggested that there may be
a circulating factor, likely placental in origin, which
affects systemic endothelial endothelial cell function
and leads to the clinical syndrome of preeclampsia [4,
135]. Intense investigation has focused on the search
for a placental factor which might induce the maternal
syndrome. Although many candidate factors, including
tumor necrosis factor-a (TNF-a), interleukin (IL)-6,
IL-1a, IL-1b, Fas ligand, neurokinin B, and asymmetric
dimethy L-arginine (ADMA) have been suggested, none
so far has been proven to be etiologic [1, 2, 5, 136, 137].
Recent data suggest that increased syncytiotrophoblast
shedding as a consequence of placental apoptosis may
contribute to endothelial dysfunction [138140]; however, there is no in vivo evidence so far that circulating

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Karumanchi et al: Preeclampsia and angiogenic factors

Placenta Anchoring villus

cytotrophoblast
column
Cytotrophoblast
stem cells

Decidua

Myometrium

Cytotrophoblast
Tunica media
smooth muscle

Syncytiotrophoblast
Maternal blood

Bloo

d flow

Spiral
artery

Floating villus
Cytotrophoblast Endovascular
cytotrophoblast
Placenta Anchoring villus
cytotrophobast
column
Cytotrophoblast
stem cells

Decidua

Myometrium

Cytotrophoblast
Maternal
endothelial cells
Syncytiotrophoblast
Maternal blood
Fetal blood
vessel

Less
blood
flow

Maternal
endothelial
cells

Tunica media
vascular smooth
muscle layer

Spiral artery

Cytotrophoblast

Floating villus

Fig. 3. Abnormal placentation in preeclampsia. Exchange of oxygen, nutrients, and waste

products between the fetus and the mother
depends on adequate placental perfusion by
maternal vessels. In normal placental development, invasive cytotrophoblasts of fetal
origin invade the maternal spiral arteries,
transforming 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 differentiate from an epithelial phenotype to an endothelial phenotype, a process
referred to as pseudovasculogenesis (upper
panel). In preeclampsia, cytotrophoblasts fail
to adopt an invasive endothelial phenotype.
Instead, invasion of the spiral arteries is shallow and they remain small caliber, resistance
vessels (lower panel). This may result in the
placental ischemia.

Anticoagulant and
vasodilatory factors

VEGF

PIGF

Healthy endothelial cell

FLT-1
Healthy
placenta

Blood vessel

sFLT-1
Procoagulant and
vasoconstricting factors

Dysfunctional endothelial cell

Blood vessel
Preeclampsia
placenta

Fig. 4. Soluble Flt-1 (sFlt-1) causes endothelial dysfunction by antagonizing vascular endothelial growth factor (VEGF) and placental growth
factor (PlGF). There is mounting evidence that VEGF, and possibly PlGF, are required to maintain endothelial health in several tissues including
the kidney and perhaps the placenta. In normal pregnancy, the placenta produces modest concentrations of VEGF, PlGF, and soluble Flt-1. In
preeclampsia, excess placental soluble Flt-1 binds circulating VEGF and PlGF and prevents their interaction with endothelial cell-surface receptors.
This results in endothelial cell dysfunction, including decreased prostacyclin, nitric oxide production and release of procoagulant proteins such as
von Willebrand factor, endothelin, cellular fibronectin, and thrombomodulin.

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Karumanchi et al: Preeclampsia and angiogenic factors

placental debris induces preeclampsia-like features. Recently, preeclampsia-like features were noted in p57kip2 (a
cell-cycle inhibitor) knockout mice, however, the mechanisms responsible for this phenotype are unclear [141].
Some [142], but not all [143], investigators have found
markers of oxidative stress to be elevated in women
with preeclampsia, suggesting that generation of reactive
oxygen-free radicals may contribute to endothelial dysfunction [2]. Decreased intake of the antioxidant vitamin
C and low circulating ascorbic acid concentrations are
associated with an increased risk of preeclampsia [144].
A small randomized controlled trial found that antioxidant therapy decreased the incidence of preeclampsia,
suggesting that oxidative stress may be a cause, rather
than a consequence, of the syndrome [145]. Additional
studies are needed to test this hypothesis.
As noted earlier, increased sensitivity to the vasopressor effects of angiotensin is a well-established feature
of preeclampsia. Two recent advances have illuminated
possible mechanisms for this phenomenon. AbdAlla
et al [146] reported increased angiotensin-1/bradykinin
B2 receptor heterodimers in women with preeclampsia,
and showed that such heterodimers can result in enhanced angiotensin II responsiveness [146]. In a similar
vein, Wallukat et al [147] noted increased concentrations
of agonistic antibodies to the angiotensin II type 1 (AT1) receptor in women with preeclampsia. These autoantibodies may induce the production of reactive oxygen
species and block cytotrophoblast invasion in vitro [148,
149], thus accounting for several of the clinical features of
preeclampsia. Further work is needed to establish if these
alterations are etiologic or epiphenomenona that might
be encountered in other examples of microangiopathy.
Recently, gene expression profiling has been used to
search for candidate factors produced by the placenta in
preeclampsia. Using this approach, we found that placental sFlt-1 mRNA (soluble fms-like tyrosine kinase-1) is
up-regulated in preeclampsia [150]. sFlt-1 is a splice variant of the vascular endothelial growth factor (VEGF))
receptor Flt-1, lacking the transmembrane and cytoplasmic domains. sFlt is made in large amounts by the
placenta and is released into the maternal circulation
[151153]. sFlt-1 acts as a potent VEGF and placental growth factor (PlGF) antagonist by binding these
molecules in the circulation [154]. Circulating sFlt-1 concentrations are increased in women with established
preeclampsia [150, 155157]. Consistent with the antagonistic effect of sFlt-1, free (or unbound) VEGF and
free (or unbound) PlGF concentrations are decreased in
preeclamptic women at disease presentation and even
before the onset of clinical symptoms [150, 158, 159] (see
Fig. 4). When administered to pregnant and nonpregnant
rats, sFlt-1 produces a syndrome of hypertension, proteinuria, and glomerular endotheliosis that mimics the
human syndrome of preeclampsia (Fig. 2D to F) [150].

Recently, our laboratory as well as others have observed

that there is a marked rise in circulating sFlt-1 concentration beginning about 5 to 6 weeks before the onset of
clinical preeclampsia, accompanied by decreases in the
circulating free PlGF and VEGF [160, 161]. Moreover,
alterations in these circulating angiogenic proteins correlated with disease severity, earlier onset of preeclampsia,
and the birth of an infant small for gestational age. Finally,
we have also recently reported that decreased urinary
concentrations of free PlGF during midgestation predict the subsequent development of clinical preeclampsia
[162]. These data lend further support to the hypothesis that circulating sFlt-1 may have a pathogenic role in
preeclampsia.
The possibility that antagonism of VEGF and PlGF
might play a role in preeclampsia has sound physiologic
underpinnings (Fig. 4). In addition to being a potent
promoter of angiogenesis, VEGF is known to induce
nitric oxide and vasodilatory prostacyclins in endothelial cells, decreasing vascular tone and blood pressure
[163]. There is evidence from animal models that VEGF
is important in maintaining glomerular endothelial cell
health and healing [164, 165], and its absence induces proteinuria and glomerular endotheliosis [166, 167]. In antiangiogenic oncology trials, antagonism of VEGF using
neutralizing antibodies and VEGF receptor inhibitors
can produce headaches, hypertension, proteinuria, and
coagulopathy in human subjects [168170]. Furthermore,
exogenous VEGF and PlGF can reverse the antiangiogenic properties of preeclamptic serum, as assessed by in
vitro angiogenesis assays [150]. Thus, the antiangiogenic
effects of sFlt-1 may account for many of the manifestations of preeclampsia, including the unique glomerular effects. Some tissues targeted in preeclampsia (i.e.,
renal glomeruli, hepatic sinusoids) have fenestrated endothelia, which are necessary for physiologic diffusion of
water and solutes. It has been shown that VEGF, which
is expressed constitutively in these organs, is necessary
to induce and maintain the health of the fenestrated endothelium [167, 171]. Thus, it is intuitive that tissues with
fenestrated endothelium, especially the renal glomerulus, might be particularly susceptible to damage by sFlt1mediated VEGF blockade.
How placental dysfunction is related to placental sFlt1 production, and why placental perfusion is deranged
in preeclampsia remains unknown. Recent data using
in vitro primary cytotrophoblast cultures suggest that
placental hypoxia may play an important role in upregulating sFlt-1 production [172]. It remains to be shown
if sFlt-1 can induce other features of preeclampsia such
as the HELLP syndrome or if additional synergistic factors are needed. Additionally, the Flt-1 locus at 13q12 has
not been localized within the genomic region identified
by genetic linkage studies for preeclampsia. However, if
the Flt-1 locus contributed to preeclampsia, one could

Karumanchi et al: Preeclampsia and angiogenic factors

hypothesize that patients who carry trisomy 13 fetuses

should have a 50% increased risk of preeclampsia. Two
case-control studies done several years ago did in fact
demonstrate higher incidence of preeclampsia in mothers who carry trisomy 13 fetuses as compared to other trisomies or control pregnant patients [24, 173]. Although
sFlt-1 levels were not measured in the patients with trisomy 13, these data are consistent with the hypothesis that
elevated production of sFlt-1 may lead to preeclampsia.
IMPACT OF PREECLAMPSIA ON LONG-TERM
MATERNAL HEALTH
Women with hypertensive disorders of pregnancy have
an increased long-term incidence of dyslipidemias, insulin
resistance, and cardiovascular diseases [174176]. Sibai,
el-Nazer, and Gonzalez-Ruiz [177] reported an 18-fold increase in the incidence of chronic salt-sensitive hypertension in women with a history of preeclampsia. It has been
speculated that this late-onset hypertension may play a
role in the eightfold increase in cardiovascular mortality
that is also observed in these patients [176]. However, it is
difficult to determine causality, because many of the risk
factors for preeclampsia (such as diabetes mellitus, hypertension, and renal insufficiency) predispose to hypertension and cardiovascular disease as well. It has also been
suggested that subtle renal injury caused by preeclampsia
can eventually lead to the development of chronic hypertension [178, 179]. It is tempting to speculate that the longterm cardiovascular complications noted in some patients
who have had preeclampsia may be due to a chronic antiangiogenic state resulting from polymorphisms in genes
such as sFlt-1. Additionally, patients with preeclampsia
are said to have a decreased long-term incidence of malignancy [180], a provocative observation disputed by some
[181], that may suggest that the antiangiogenic state of
preeclampsia may reflect a permanent state of the maternal milieu.
CONCLUSION
Preeclampsia is a systemic disorder characterized by
widespread endothelial dysfunction. Substantial animal
and human experimental evidence fulfilling Kochs postulates [182] supports the hypothesis that placental sFlt1,
an antiangiogenic protein, may be etiologic. Several important questions remain to be explored, and many of
these can now be approached experimentally. Why do
certain conditions (see Table 1) predispose to preeclampsia? Are there additional synergistic factors which might
induce/predispose to HELLP syndrome? What is the relationship of sFlt-1 with other postulated mediators of
the maternal syndrome such as hyperuricemia, ADMA,
or antibodies to angiotensin II AT-1 receptor? What
governs regulation of sFlt1 transcription and splicing,

2109

and why is it abnormal in preeclampsia? Is placental ischemia a cause or a consequence of excessive placental sFlt1? Large genetic trials such as GOPEC (Genetics
of Preeclampsia) [6], ongoing proteomic/genomic studies of tissue and blood specimens from patients with
preeclampsia, and further characterization of the sFlt-1
induced animal model of preeclampsia may help to answer these questions.
The implications of these advances on our clinical
management of preeclampsia may be profound. Large,
prospective studies are needed to describe in detail
the changes in sFlt1, VEGF, and PlGF that precede
preeclampsia onset; measurement of these factors in
pregnant women may prove to be useful diagnostically. Pharmacologic intervention aimed at restoring
sFlt1/PlGF/VEGF balance may prevent or modify the
course of preeclampsia. Safely prolonging pregnancy
by only a few weeks could substantially reduce maternal and neonatal morbidity and mortality resulting
from preeclampsia, the worlds most common glomerular
disease.
ACKNOWLEDGMENTS
We would like to thank Ben Sachs and Kee-Hak Lim of the Department of Obstetrics and Gynecology at the Beth Israel Deaconess
Medical Center (BIDMC) and Marshall Lindheimer of the University of Chicago for helpful discussions and strong support. This work
was supported by NIH grants (DK02825, DK64255, and DK65997),
the American Society of Nephrology Carl W. Gottschalk award, and
BIDMC seed funds to S.A.K. S.A.K, S.E.M, and V.P.S are listed as coinventors in a patent filed by BIDMC for the use of angiogenesis-related
proteins for the diagnosis and treatment of preeclampsia. Therapeutic
claims of the patent have been licensed by BIDMC to Scios, Inc, CA.
Reprint requests to S. Ananth Karumanchi, M.D., Beth Israel Deaconess Medical Center, Renal Division, 330 Brookline Avenue, Dana
517, Boston, MA 02215.
E-mail: sananth@bidmc.harvard.edu

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