Arthur C.
Corcoran Memorial Lecture
Angiogenic Factors in Preeclampsia
From Diagnosis to Therapy
S. Ananth Karumanchi
P reeclampsia is one of the most frequently encountered hyper-
tensive complication of pregnancy that affect ≈5% of preg-
nant women worldwide.1 It is often characterized by new onset
of hypertension and proteinuria, usually during the last trimes-
ter of pregnancy, and is commonly associated with edema and
hyperuricemia. Preeclampsia occurs only in the presence of the
placenta, even when there is no fetus (as in hydatidiform mole)
and usually remits when the placenta is delivered. The placenta
in preeclampsia is often abnormal, with evidence of hypoperfu-
sion and ischemia. The renal biopsy and autopsy studies from
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preeclamptic patients showed renal glomerular endotheliosis, a
unique form of microvascular endothelial injury that is described
as the classic lesion of this disorder.2,3 Besides affecting kidneys,
preeclampsia can affect the liver, hematologic system leading
to hemolysis and disseminated intravascular coagulation, brain
resulting in seizures (eclampsia), renal failure, abruption, fetal
growth restriction and in certain cases fetal and maternal death.
Preeclampsia remains a major cause of maternal and fetal mor-
bidity and mortality worldwide.4 Because of a general lack of
access to advanced pre- and postnatal care, most of these deaths
occur in the developing world.
Preeclampsia is about twice as common in first pregnancies as
in multigravidas. Other predisposing factors include pre-existing
hypertension, chronic renal disease, obesity, diabetes mellitus,
thrombophilias, trisomy 13, and multiple gestations.5,6 It occurs
more frequently in women whose mothers had preeclampsia and
in women whose fathers were products of a preeclamptic preg-
nancy.7 The incidence of preeclampsia is higher in women who
live in high altitudes, suggesting that hypoxia may contribute to
the development of the syndrome.8 In vitro fertilization has also
emerged as an important risk factor for preeclampsia.9 Although
none of these risk factors is fully understood, they have provided
insights into pathogenesis. The exact cause of preeclampsia is
heretofore unknown, but improper implantation and a subse-
quent imbalance of proangiogenic and antiangiogenic circulat-
ing factors are considered to be at the root of this disorder.5,10,11
In this review, we will discuss the pathogenic role of angiogenic
factors in the maternal syndrome and will highlight the role of
novel angiogenic factors in early diagnosis and in the develop-
ment of therapies for preeclampsia.
Biology of Antiangiogenic State in Preeclampsia
Using gene expression profiling, our group identified upreg-
ulated soluble fms-like tyrosine kinase 1 (sFlt1) mRNA in
From the Center for Vascular Biology, Departments of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA.
Correspondence to S. Ananth Karumanchi, Center for Vascular Biology, 99 Brookline Ave, RN 370D, Boston, MA 02215. E-mail sananth@bidmc.
harvard.edu
(Hypertension. 2016;67:1072-1079. DOI: 10.1161/HYPERTENSIONAHA.116.06421.)
© 2016 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.116.06421
1072
preeclamptic placentas.12 sFlt1 protein, a splice variant of the
vascular endothelial growth factor (VEGF) receptor Flt-1 or
vascular endothelial growth factor receptor 1, is a circulating
antiangiogenic protein that inhibits proangiogenic factors—
VEGF and placental growth factor (PlGF) signaling in the
vasculature13 (Figure). sFlt1 is made by synytiotrophoblast
layer of the placenta and secreted into maternal circulation.14
Several isoforms of sFlt1 have been reported; however, the
isoform sFLT-1 e15a seems to be predominant protein that cir-
culates in patients with preeclampsia.15
Circulating sFlt1 levels are greatly increased in women
with established preeclampsia and before onset of clini-
cal symptoms.16–20 Consistent with the action of the soluble
receptor protein to bind ligands, as plasma sFlt1 concentra-
tions rise, the free concentrations of the ligands—VEGF and
PlGF fall in preeclampsia.16,21 Removal of sFlt1 or addition
of exogenous VEGF can reverse the antiangiogenic effects
of preeclamptic plasma, as assessed by in vitro angiogen-
esis assays.12,22 Heterologous expression in rodents produces
a syndrome of hypertension, proteinuria, and glomerular
endotheliosis resembling the human syndrome of preeclamp-
sia.12,23–26 Antagonism of sFlt1 has been shown to ameliorate
preeclampsia phenotype in mouse models.23,27,28 Reduction of
VEGF expression by 50% in the glomeruli using genetically
modified mice leads to proteinuria and glomerular endothelial
damage that resemble preeclampsia.29 Furthermore, VEGF
antagonists, used in patients with cancer, sometimes produce
a preeclampsia-like phenotype including hypertension, glo-
merular endothelial damage, and reversible posterior leucoen-
cephalopathy that is often noted in eclampsia.30–33 These data
support the hypothesis that inhibition of VEGF signaling in
the maternal vasculature by high circulating sFlt1 may lead to
preeclampsia-like signs/symptoms.
The studies on sFlt1 and VEGF in preeclampsia biology
have also led to new insights into basic biology of vascular
and placental homeostasis in health and in disease. The cause
of hypertension by sFlt1 has been described to be because of
decreased endothelial nitric oxide production and increased
endothelin secretion.34,35 However, other factors such as pros-
tacyclins and hydrogen sulfide that are downstream of the
VEGF receptor may also be involved.36,37 The microvascu-
lature of organs affected in preeclampsia such as the glom-
eruli and hepatic sinusoidal vasculature are more permeable
because of the presence of intracellular perforations referred
 Karumanchi   Angiogenic Factors and Preeclampsia   1073

Figure. Soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) causes endothelial dysfunction by antagonizing vascular
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endothelial growth factor (VEGF) and transforming growth factor (TGF)-β1 signaling. There is mounting evidence that VEGF and TGF-β1
are required to maintain endothelial health in several tissues, including the kidney and other vascular beds. During normal pregnancy,
vascular homeostasis is maintained by physiological levels of VEGF and TGF-β1 signaling in the vasculature. In preeclampsia, excess
placental secretion of sFlt1 and sEng (2 endogenous circulating antiangiogenic proteins) inhibits VEGF and TGF-β1 signaling, respectively,
in the vasculature. This results in endothelial cell dysfunction, including decreased prostacyclin, nitric oxide production, and release of
procoagulant proteins. Reprinted from Powe et al5 with permission of the publisher. Copyright © 2012, the American Heart Association, Inc.

to as fenestrations. Although it was previously known that
VEGF induces endothelial fenestrae in culture,38 experimental
data in genetically engineered mice that lack VEGF confirmed
that endothelial fenestral density is regulated by constitutive
expression of VEGF.29 Therefore, it is not surprising that the
microvascular damage in preeclampsia is largely concentrated
in vasculature that constitutively express VEGF and that loss
of endothelial fenestrae in preeclampsia is because of excess
circulating sFlt1. Experimental studies in mice have also
helped clarify that angiogenic imbalance and preeclampsia
may be an important trigger for the clinical syndrome of peri-
partum cardiomyopathy.39
Although placenta is the major source of sFlt1 produc-
tion, immunohistochemistry studies have suggested that
syncytial knots (degenerating syncytiotrophoblast tissue) in
the placenta is the major site of sFlt1 production.40,41 These
syncytial knots easily detach from the syncytiotrophoblast,
resulting in free, multinucleated aggregates (50- to 150-μm
diameter) that are loaded with sFlt1 protein and mRNA, and
are capable of de novo gene transcription and translation.40,42
Other studies using autopsy material have suggested that
shed syncytial knots may contribute to circulating sFlt1 in
preeclampsia.43 Because these synytial microparticles are of
fetal origin, this process of syncytial microparticle shedding
may lead to chimerism, as fetal cells can be retained in the
maternal blood and organs for decades after delivery. The
long-term consequences to the mother exposed to excess
fetal material are unknown.
Soluble endoglin (sEng), another antiangiogenic protein,
that is expressed in the synyctiotrophoblast may also contrib-
ute to preeclampsia.44 The role of this protein in producing
preeclampsia phenotypes was evaluated based on the hypoth-
esis that sEng may impair transforming growth factor-β1
binding to its cell surface receptors and decreasing endothelial
nitric oxide signaling45 (Figure). sEng is placental in origin,
is present in the sera of pregnant women, and is elevated in
preeclamptic individuals and correlates with disease sever-
ity.46,47 Administration of both sFlt1 and sEng using an ade-
noviral expression system in pregnant rats produces a severe
preeclampsia-like animal model with hypertension, protein-
uria, glomerular endotheliosis, thrombocytopenia, and fetal
growth restriction.46 Patients who presented with high levels
of both sEng and sFlt1 had more severe and premature form
of the disease.46–48 Patients with eclampsia, a type of severe
preeclampsia, have also been reported to have very high levels
of sFlt1 and sEng and very low levels of free PlGF.49 However,
more data on the precise mechanisms of how sEng contributes
to preeclampsia are needed.
Numerous epidemiological studies also demonstrate that
alterations in circulating sFlt1 may explain several risk factors
for preeclampsia, such as multiple gestation, trisomy 13, nul-
liparity, and molar pregnancies.5,50–53 These epidemiological
studies further lend support to the hypothesis that alterations
in circulating angiogenic factors plays a causal role in mediat-
ing the maternal syndrome of preeclampsia.
The underlying events that induce placental disease acti-
vating the cascade of placental damage and antiangiogenic
factor production remain unknown.5,54 An array of insults may
contribute to placental damage that is proximally linked to the
production of soluble pathogenic factors. Numerous pathways
have been proposed to have key roles in inducing placental dis-
ease, including deficient heme oxygenase expression, placen-
tal hypoxia, genetic factors, corin deficiency, autoantibodies
against the angiotensin receptor, oxidative stress, inflammation,
altered natural killer cell signaling, deficient catechol-O-methyl
transferase, complement activation, and more recently aber-
rant vasopressin production.11,55–62 Interestingly, several of
these pathways were shown to increase placental production
of the antiangiogenic factors in cell culture or animal models.
However, human studies describing the temporal relationship
 1074  Hypertension  June 2016
between the angiogenic factors and the upstream pathways are
still lacking before one can draw definitive conclusions.
Biomarker Studies in Preeclampsia
Free concentrations of plasma VEGF during pregnancy are
low and often below the detection of most commercially avail-
able diagnostic kits. As a surrogate of VEGF impairment, PlGF
levels during pregnancy has emerged an attractive candidate.
PlGF, a member of the VEGF family, is a proangiogenic protein
that is made abundantly during pregnancy and it binds to Flt1
receptor but not the other VEGF receptors. Because sFlt1 levels
rise, free PlGF levels drop and ratio of sFlt1/PlGF correlates
with preeclampsia phenotypes.48,63 Working with industry part-
ners, we and others have developed highly sensitive, specific,
and robust assays with rapid throughput to quantitate levels of
total sFlt1 and free PlGF in plasma and serum.64–66 Using these
automated assays, we have attempted to answer the following
4 questions: (1) How well do plasma/serum sFlt and PlGF dif-
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ferentiate between disease and no disease? (2) How well do
these biomarkers predict prognosis in patients with suspected
preeclampsia? (3) Do alterations in angiogenic biomarkers
serve as early predictive markers for adverse outcomes related
to preeclampsia? and (4) Can we use the angiogenic biomarkers
as an intermediate outcome to measure response to a specific
treatment?
Several groups have demonstrated that measurement for
sFlt1 and PlGF can be used to differentiate preeclampsia
from other diseases that mimic preeclampsia, such as chronic
hypertension, gestational hypertension, kidney disease, and
gestational thrombocytopenia.67–71 Angiogenic markers have
also been shown to be promising in preeclampsia-related
disorders, such as idiopathic fetal growth restriction and still-
birth.72,73 To demonstrate clinical use of these biomarkers, we
led a large clinical study to evaluate the role of angiogenic
biomarkers in the prediction of preeclampsia-related adverse
outcomes among women evaluated at our institution for sus-
pected preeclampsia.74 We demonstrated that the plasma
sFlt1/PlGF ratio on presentation predicts adverse maternal
and perinatal outcomes (occurring within 2 weeks) in the
preterm setting. This ratio alone performed better than the
standard battery of clinical diagnostic measures, including
blood pressure, proteinuria, uric acid, and other laboratory
assays. Several recent studies have confirmed that levels of
sFlt1 and PlGF in the triage setting can be used as a robust
prognostic test and these levels correlate with the duration of
pregnancy.74–77 In addition, we have also provided evidence
that women with clinically diagnosed preeclampsia, but who
have normal angiogenic profile have no adverse maternal or
fetal outcomes.78 sFlt1 and PlGF testing may be, therefore,
useful in women with symptoms of preeclampsia to identify
those with normal angiogenic profile and a reduced risk of
preeclampsia-related complications, thereby avoiding unnec-
essary intervention. Recently, Zeisler et al79 demonstrated in
a prospective multicenter clinical trial that serum sFlt/PlGF
can be used to rule out preeclampsia among patients with sus-
pected disease with negative predictive value >99%.
Numerous studies evaluated the performance of angiogenic
factors in prediction of preeclampsia alone or in combination
with other markers.80 In particular, first trimester prediction
has been developed using models that incorporated angio-
genic factors, maternal characteristics, biophysical and other
biochemical markers. Poon et al81 evaluated 7797 women with
singleton pregnancies, during gestational weeks 11 to 13. This
study yielded very good results using an algorithm developed
by logistic regression that combined the logs of uterine pulsa-
tility index, mean arterial pressure, PAPP-A (pregnancy asso-
ciated plasma protein A), serum-free PlGF, body mass index,
and presence of nulliparity or previous preeclampsia. At a 5%
false-positive rate, the detection rate for early preeclampsia
was 93.1%. The calculated positive likelihood ratio was 16.5
and negative likelihood ratio was 0.06.82 The same group more
recently confirmed that maternal factors when combined with
PlGF levels and uterine artery pulsatility index can detect
75% of cases of preterm preeclampsia in a study of >35,000
patients.83 Circulating angiogenic factors measured during
early gestation have a high negative predictive value in ruling
out the development of severe adverse maternal and perinatal
outcomes among patients with systemic lupus erythematosus
or antiphospholipid antibody syndrome.84 In a prospective mul-
ticenter study, we demonstrated that among high-risk subjects
with systemic lupus erythematosus or antiphospholipid anti-
body syndrome, the combination of sFlt1 and PlGF was most
predictive of severe adverse pregnancy outcomes when mea-
sured early in pregnancy (16–19 weeks), with risk greatest for
subjects with both PlGF in lowest quartile (<70.3 pg/mL) and
sFlt1 in highest quartile (>1872 pg/mL; odds ratio, 31.1; 95%
confidence interval, 8.0–121.9; positive predictive value, 58%;
negative predictive value, 95%). Severe adverse outcome rate
in this high-risk subgroup was 94% (95% confidence interval,
70%–99.8%), if lupus anticoagulant or history of high blood
pressure is additionally present.84 We have therefore proposed
that among a high-risk population, measurement of angiogenic
profile would allow clinicians to identify subjects with low risk
for severe adverse outcomes and in this group the number of
medical visits could be substantially reduced. Patients at low
risk can be reassured and healthcare costs for their pregnancies
decreased, whereas those at high risk can be managed by spe-
cialists with close monitoring and delivery for severe maternal
or fetal disease. Future studies in other high-risk populations to
evaluate the clinical use of early prediction using angiogenic
biomarkers because it relates to preeclampsia-related adverse
maternal and fetal outcomes are needed.
Angiogenic factor levels have also been used as a surro-
gate marker in clinical trials.85–87 In summary, data from mul-
tiple groups support the hypothesis that angiogenic factors are
useful in risk stratification of women with preeclampsia to
accurately diagnose preeclampsia and predict development of
complications. More studies are needed to evaluate the impact
of clinical decisions based on results of sFlt1 and PlGF testing
on health outcomes, and assess the cost-effectiveness of man-
agement strategies based on sFlt1 and PlGF testing.
Therapeutic Studies
Human and animal studies as outlined above have strongly
suggested that targeting angiogenic pathway may be a viable
strategy to prevent or treat preeclampsia. We summarize 3 dif-
ferent strategies that have been evaluated in either preclinical
or early clinical studies.
 Karumanchi   Angiogenic Factors and Preeclampsia   1075
Therapeutic Apheresis
Removal of toxic circulating factors in preeclampsia has met
with limited success. Plasmapheresis to remove circulating
antibodies and toxic proteins has not prolonged pregnancy in
preterm preeclampsia. Because sFlt1 has a large volume of dis-
tribution and that circulating plasma levels of sFlt1 represent
<20% of the total body sFlt-1 burden,88 we hypothesized that
a selective adsorption column would create a concentration
gradient and augment its removal. We identified dextran sulfate
(a polyanionic derivative of dextran) columns as one potential
strategy for use in preeclampsia as dextran sulfate bound sFlt1
efficiently.85 Dextran sulfate columns bind apolipoprotein B–
containing low-density lipoprotein cholesterol and is Food and
Drug Administration–approved for use as an apheresis strategy
in patients with familial homozygous hypercholesterolemia.
Among pregnant patients with familial homozygous hypercho-
lesterolemia, dextran sulfate apheresis using whole blood has
been used throughout pregnancy without any major complica-
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tions. In a small pilot proof-of-concept study, we demonstrated
that a 30% to 40% reduction in circulating sFlt1 levels using
dextran sulfate apheresis is sufficient to ameliorate preeclamp-
tic signs and symptoms and prolong pregnancy duration by 2 to
4 weeks with no neonatal or maternal morbidity.85 During the
course of the treatment, the extracorporeal adsorption device
only lowered soluble sFlt1 levels by 35% on average, validating
the idea that modest lowering circulating sFlt1 levels is sufficient
to successfully prolong preeclamptic pregnancies. In a follow-up
study, Thadhani et al86 using plasma-specific apheresis strategy
further validated this concept and demonstrated amelioration
of proteinuria and stabilization of blood pressure by reducing
sFlt1 levels on average by 18%. Interestingly, among women
treated once, pregnancy continued for an average of 8 days and,
among women treated multiple times, pregnancy continued on
average for 15 days, which is in contrast to 3 days in untreated
contemporaneous preeclamptic subjects. A more specific apher-
esis cartridge that selectively removes sFlt1 and other toxic pro-
teins such as sEng with antibody affinity columns may be a more
effective strategy with predictable clinical outcomes for patients
and with less side effects.
Recombinant Ligands
In animal models, several groups have tested whether the
naturally occurring ligands for sFlt1, such as VEGF or PlGF,
would be of benefit in ameliorating preeclampsia.23,27,28,89,90
However, no data are available in humans, if this strategy
would be safe. Experimental studies suggest that the hor-
mone relaxin may also be used to ameliorate preeclampsia
by improving vascular compliance and upregulating VEGF
locally.91 Clinical studies to test the safety of human relaxin in
women with preeclampsia is ongoing.92
Small Molecules
Compounds that upregulate proangiogenic factors such as statins
have been used to ameliorate preeclampsia in animal models.24
A clinical trial to test safety of statins in women with established
preeclampsia has been initiated in the United Kingdom and in
the United States.93,94 More recently, hypoxia-inducible factor
inhibitors have also been evaluated in preclinical models. In a
rat model of placental ischemia–induced hypertension, ouabain
acting as hypoxia-inducible factor-1α inhibitor reduced mean
arterial pressure without any adverse effects on pups.95 Several
groups have also demonstrated efficacy in animal models of pre-
eclampsia for sildenafil and endothelin antagonists, both drugs
acting on pathways downstream of the VEGF receptor.96
Long-Term Complications of Preeclampsia
Epidemiological studies have shown an increased risk of
chronic hypertension, cardiovascular disease (CVD), and
chronic kidney disease in women with a history of preeclamp-
sia.97–100 Recently, the American Heart Association has recog-
nized preeclampsia as a novel risk factor for CVD in women.101
It is currently thought that the background metabolic milieu
of women (ie, shared risk factors) confer risk for both pre-
eclampsia and for long-term CVD. Romundstad et al102 have
suggested that at least 50% of the long-term hypertension can
be explained by pre-existing risk factors. However, it is also
possible that seemingly transient vascular injury induced by
preeclampsia, subclinical in nature, predisposes to the develop-
ment of chronic hypertension, and CVD. The absence of hyper-
tension in the siblings of women with preeclampia who might
be expected to be at similar risk of CVD and increased risk
of CVD in women with recurrent preeclampsia supports this
hypothesis.103,104 Data from a recent epidemiological study sug-
gested that increased risk of chronic kidney disease after pre-
eclampsia seems to be explained by the pregnancy exposure per
se and not by familial aggregation of risk factors.105 Recently,
using the sFlt1 overexpression model in mice, we demon-
strated that preeclampsia exposure potentiates the adverse vas-
cular remodeling response to injury later in life.106 The vascular
injury response in mice is enhanced after preeclampsia despite
complete normalization of blood pressure and other cardiovas-
cular parameters after delivery, as in women with preeclamp-
sia. Moreover, examination of uninjured vessels reveals that in
the absence of a vascular injury stimulus, there is no difference
in vascular remodeling after preeclampsia. Experimental pre-
eclampsia in mice has also been shown to induce long-term
changes in the global plasma protein profile (proteome) that
correlate with changes associated with CVD.107 This supports
a new paradigm in which preeclampsia causes changes in vas-
cular physiology that enhance the response to future vascular
damage that may be mediated by pre-existing or new risk fac-
tors to which women are exposed after preeclampsia. A greater
understanding of the mechanism of postpreeclampsia CVD
will improve screening and suggest novel targets for preven-
tion of future CVD in this high-risk population of women.108
Summary
During the past decade, epidemiological, experimental, and
therapeutic studies have provided evidence that altered antian-
giogenic state because of altered circulating sFlt1 and related
proteins, such as PlGF and sEng leads to preeclampsia.109
Recent study suggests that sFlt1 and sEng are largely expressed
in syncytial knots in the placenta and released into maternal
circulation as syncytial microparticles.42 Understanding the
dysregulated antiangiogenic pathway in the syncytium and its
role in mediating maternal vascular disease marks a significant
advance in our efforts to explain the origins of preeclampsia.
Further study on the basic biology of placentation and syncy-
tialization may shed clues on fundamental molecular defect
 1076  Hypertension  June 2016
in preeclampsia. Several clinical studies have demonstrated a
potential role for the use of angiogenic biomarkers for aid in
the diagnosis and prognosis of preterm preeclampsia. We now
need clinical trials demonstrating the use of these biomark-
ers in helping obstetrician’s management decisions, improve
health outcomes or reduce costs to the healthcare system.
Targeted therapies against angiogenic pathway are promis-
ing; however, only time will prove whether they will be effec-
tive. After decades of modest progress, in the past few years,
the field has witnessed remarkable successes with the use of
biomarkers and the development of therapies targeting spe-
cific molecular pathways and have brought hope to numerous
women worldwide. In addition, we speculate that exposure to
antiangiogenic factors during preeclampsia may lead to long-
term changes to the vasculature that can have adverse conse-
quences to maternal health.
Acknowledgments
Downloaded from http://hyper.ahajournals.org/ by guest on February 11, 2018
I thank Dr Ravi Thadhani for help with this article and for providing
valuable insights.
Disclosures
S.A. Karumanchi is a coinventor on patents related to preeclamp-
sia biomarkers that have been out licensed to multiple companies.
S.A. Karumanchi has financial interest in Aggamin LLC and re-
ports serving as a consultant to Siemens Diagnostics, Roche, and
Thermofisher.
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 Angiogenic Factors in Preeclampsia: From Diagnosis to Therapy
S. Ananth Karumanchi

Hypertension. 2016;67:1072-1079; originally published online April 11, 2016;

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doi: 10.1161/HYPERTENSIONAHA.116.06421
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