Compendium on the Pathophysiology and

Treatment of Hypertension
Preeclampsia
Pathophysiology, Challenges, and Perspectives
Sarosh Rana, Elizabeth Lemoine, Joey Granger, S. Ananth Karumanchi

Abstract: Hypertensive disorders of pregnancy—chronic hypertension, gestational hypertension, and preeclampsia—

are uniquely challenging as the pathology and its therapeutic management simultaneously affect mother and
fetus, sometimes putting their well-being at odds with each other. Preeclampsia, in particular, is one of the most
feared complications of pregnancy. Often presenting as new-onset hypertension and proteinuria during the third
trimester, preeclampsia can progress rapidly to serious complications, including death of both mother and fetus.
While the cause of preeclampsia is still debated, clinical and pathological studies suggest that the placenta is central
to the pathogenesis of this syndrome. In this review, we will discuss the current evidence for the role of abnormal
placentation and the role of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine
kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia. We will discuss angiogenic biomarker
assays for disease-risk stratification and for the development of therapeutic strategies targeting the angiogenic
pathway. Finally, we will review the substantial long-term cardiovascular and metabolic risks to mothers and
children associated with gestational hypertensive disorders, in particular, preterm preeclampsia, and the need for
an increased focus on interventional studies during the asymptomatic phase to delay the onset of cardiovascular
disease in women.   (Circ Res. 2019;124:1094-1112. DOI: 10.1161/CIRCRESAHA.118.313276.)
Key Words: biomarkers ◼ blood pressure ◼ cardiovascular disease ◼ preeclampsia ◼ pregnancy

H ypertensive disorders are a common complication of

pregnancy that put women and their fetuses at dispro-
important risk factor for peripartum morbidity in the United
States.6 Hypertensive disorders of pregnancy and in particu-
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portionate risk for further complications, as well as life-long
sequelae. Ranging in severity, hypertensive disorders of preg-
nancy include chronic hypertension—systolic blood pressure
(BP) ≥140 mm Hg or diastolic BP ≥90 mm Hg that predates
the onset of pregnancy; gestational hypertension—hyperten-
sion diagnosed after 20 weeks gestation without concurrent
proteinuria; preeclampsia-eclampsia—classically, new-onset
hypertension with new-onset proteinuria; and chronic hyper-
tension with superimposed preeclampsia—chronic hyperten-
sion with new-onset proteinuria or other signs/symptoms of
preeclampsia after 20 weeks or chronic proteinuria with new-
onset hypertension.1 With the greatest morbidity and mortality,
preeclampsia affects 5% to 7% of all pregnant women but is
responsible for over 70 000 maternal deaths and 500 000 fetal
deaths worldwide every year. In the United States, it is a leading
cause of maternal death, severe maternal morbidity, maternal
intensive care admissions, cesarean section, and prematurity.2–4
Delivery can resolve most signs and symptoms; however,
preeclampsia can persist after delivery and, in some cases,
can develop de novo in the postpartum period.1,5 De novo
or persistent postpartum preeclampsia has emerged as an
lar preterm preeclampsia is also associated with substantial
risk for cardiovascular disease (CVD) and cerebrovascular
disease in the long-term.7,8
Epidemiology and Clinical Definition
of Preeclampsia
Risk Factors for Preeclampsia
Risk factors for the development of preeclampsia have been
studied extensively (Table 1). Major risk factors include a
history of preeclampsia, chronic hypertension, pregesta-
tional diabetes mellitus, antiphospholipid syndrome, and o-
besity, among others.9 Other risk factors include advanced
maternal age, nulliparity, history of chronic kidney disease,
and use of assisted reproductive technologies. Relatively
rare risk factors are a family history of preeclampsia and
mother carrying a trisomy 13 fetus.10,11 Genetic susceptibil-
ity to preeclampsia has been extensively studied.12,13 A 2017
genome-wide association study analysis of neonates from
4380 cases of preeclampsia and 310 238 controls found a
genome-wide susceptibility locus (rs4769613; P=5.4×10−11)
near the FLT1 (FMS-like tyrosine kinase 1) gene, the protein

From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago, IL (S.R.); Harvard Medical School,
Boston, MA (E.L.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.G.); Departments of Medicine, Obstetrics and
Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (S.A.K.); and Department of Medicine, Cedars-Sinai
Medical Center, Los Angeles, CA (E.L., S.A.K.).
Correspondence to S. Ananth Karumanchi, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90004. Email sananth.
karumanchi@csmc.edu
© 2019 American Heart Association, Inc.
Circulation Research is available at https://www.ahajournals.org/journal/res DOI: 10.1161/CIRCRESAHA.118.313276

1094
 Rana et al   Preeclampsia and Vascular Disease   1095
Nonstandard Abbreviations and Acronyms
ACOG American College of Obstetrics and Gynecology
Arrb1 β-arrestin-1
ASPRE aspirin for evidence-based preeclampsia preven-
tion trial
AT1-AA Angiotensin II type 1 receptor autoantibodies
AT1-B2 Angiotensin II type 1 receptor and Bradykinin B2
receptor complex
BP blood pressure
COMT catechol-O-methyl transferase
CVD cardiovascular disease
DV decidual vasculopathy
ER endoplasmic reticulum
ET-1 endothelin-1
FLT1 fms-like tyrosine kinase
HELLP syndrome Hemolysis Elevated Liver enzymes Low Platelets
syndrome
HIF hypoxia-inducible factors
HO heme oxygenase
hsFLT1 human soluble FMS-like tyrosine kinase 1
KIR killer cell Ig-like receptors
IL interleukin
MHC major histocompatibility complex
PAPP-A pregnancy-associated plasma protein A
PGC-1a proangiogenic transcriptional cofactor- 1alpha
PlGF placental growth factor
PPCM peripartum cardiomyopathy
PPV positive predictive value
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RNAi RNA interference technology
ROS reactive oxygen species
RR relative risk
RUPP reduction in uterine perfusion pressure rodent model
sENG soluble endoglin
sFLT1 soluble fms-like tyrosine kinase 1
SGA small for gestational age
StAmP Statins to ameliorate early onset preeclampsia trial
STRIDER Sildenafil for severe fetal growth restriction trial
TF transcription factor
TGF-β1 transforming growth factor β1
Th1/Th2 T helper type 1/type 2 cells
TNF Tumor necrosis factor
uNK uterine natural killer cell
UPR unfolded protein response
VEGF vascular endothelial growth factor
product of which is a well-established pathogenetic fac-
tor in preeclampsia.14 rs4769613 has a higher frequency in
late-onset preeclampsia, exerts effects only in the fetal—not
maternal—genome, and has no difference in transmission
of disease association with parental sex inheritance, mak-
ing the effects of imprinting unlikely. However, maternal
genetic susceptibility may play a role as well. A multieth-
nic maternal preeclampsia genome-wide association study
discovered a genome-wide susceptibility locus at rs9478812
(P=5.90×10−7), an intronic region of protein PLEKHGI im-
plicated in BP regulation.15
Table 1.  Risk Factors for Preeclampsia
Major Risk Factors
  Prior preeclampsia (RR, 8.4; 95% CI, 7.1–9.9)
  Chronic hypertension (RR, 5.1; 95% CI, 4.0–6.5)
  Pregestational diabetes mellitus (RR, 3.7; 95% CI, 3.1–4.3)
  Multiple gestation (RR, 2.9; 95% CI, 2.6–3.1)
  Prepregnancy BMI >30 (RR, 2.8; 95% CI, 2.6–3.1)
  Antiphospholipid syndrome (RR, 2.8; 95% CI, 1.8–4.3)
Other risk factors
  Systemic lupus erythematosus (RR, 2.5; 95% CI, 1.0–6.3)
  History of stillbirth (RR, 2.4; 95% CI, 1.7–3.4)
  Prepregnancy BMI >25 (RR, 2.1; 95% CI, 2.0–2.2)
  Nulliparity (RR, 2.1; 95% CI, 1.9–2.4)
  Prior placental abruption (RR, 2.0; 95% CI, 1.4–2.7)
  Assisted reproductive technology (RR, 1.8; 95% CI, 1.6–2.1)
  Chronic kidney disease (RR, 1.8; 95% CI, 1.5–2.1)
  Advanced maternal age >35 (RR, 1.2; 95% CI, 1.1–1.3)
  Genetic susceptibility (mother, father)
Rare risk factors
  Family history of preeclampsia
  Trisomy 13 fetus
Relative Risk provided from meta-analyses by Ray et al.9 BMI indicates body
mass index; and RR, relative risk.
Clinical Definition of Preeclampsia
Classically, the American College of Obstetrics and
Gynecology (ACOG) defines preeclampsia as the presence
of hypertension and proteinuria occurring after 20 weeks of
gestation in a previously normotensive patient. However, a
significant proportion of women develop systemic manifesta-
tions of preeclampsia—such as low platelets or elevated liver
enzymes—before the hallmark of proteinuria is detectable,16,17
resulting in delayed diagnoses. The evolving understanding
of preeclampsia as a heterogeneous hypertensive disorder of
pregnancy led to ACOG’s hypertension 2013 task force to re-
vise the definition of preeclampsia to include the presence of
severe features with or without proteinuria and to exclude de-
gree of proteinuria as a criterion of severe features (Table 2).1
These criteria were confirmed more recently in an update of
the ACOG’s practice guidelines.18
Pathogenesis of Preeclampsia
A placental disease, preeclampsia progresses in 2 stages: (1) ab-
normal placentation early in the first trimester followed by (2) a
“maternal syndrome in the later second and third trimesters char-
acterized by an excess of antiangiogenic factors19,20 (Figure 1).
While the mechanism of abnormal placentation is controversial,
animal models have demonstrated that uteroplacental ischemia
drives the hypertensive, multi-organ failure response observed
in the maternal preeclamptic syndrome21 (stage 2). A number of
theories have been proposed for the placental dysfunction ob-
served in stage 1, including oxidative stress, abnormal natural
killer cells (NKs) at the maternal-fetal interface, and genetic and
 1096  Circulation Research  March 29, 2019
Table 2.  Clinical Definition of Preeclampsia1
Preeclampsia
  Elevated blood pressure
Systolic ≥140 mm Hg or diastolic ≥90 mm Hg, 2 occasions, 4 h apart
   observed in preeclampsia.30,31 Decidual vasculopathy (DV) is a
in previously normotensive woman
  AND Proteinuria
  ≥300 mg/24 hour urine collection
  or protein/creatinine ≥0.3
   or dipstick reading =1+
  OR severe features*
Severe features
 Systolic blood pressure ≥160 mm Hg or diastolic ≥110 mm Hg, 2
occasions, 4 h apart on bedrest
  Thrombocytopenia (<100 000 μL)
 Liver function tests 2× normal or severe persistent right upper quadrant
or epigastric pain
 Serum creatinine concentration >1.1 mg/dL or doubling of creatinine in
the absence of other renal disease
  Pulmonary edema
  New-onset cerebral or visual symptoms
environmental factors, though none have conclusive evidence in
humans. However, substantive evidence supports the idea that
the diseased placenta leads to release of soluble toxic factors in
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the maternal circulation that result in inflammation, endothelial
dysfunction, and maternal systemic disease.19,20,22
Stage 1: Abnormal Placentation, Trophoblast
Invasion, and the Maternal-Fetal Interface
During normal placental implantation, cytotrophoblasts mi-
grate into the maternal uterine spiral arteries, forming vascular
sinuses at the fetal-maternal interface to provide nutrition to
the fetus. In normal pregnancy, this invasion progresses deeply
into the spiral artery to the level of the myometrium,23,24 which
leads to extensive remodeling of the maternal spiral arterioles
into high capacitance, high flow vessels.23 In placentas destined
to develop preeclampsia, cytotrophoblasts fail to transform
from the proliferative epithelial subtype to the invasive en-
dothelial subtype which causes incomplete remodeling of the
spiral artery.25 Inadequate spiral arteriolar remodeling leads to
narrow maternal vessels, and relative placental ischemia.26 The
narrow spiral arteries are prone to atherosis—characterized by
the presence of lipid-laden macrophages within the lumen, fi-
brinoid necrosis of the arterial wall, and a mononuclear peri-
vascular infiltrate,27 leading to further compromise in placental
flow. In humans, placental ischemia can be noninvasively iden-
tified using uterine artery Doppler studies. During normal
pregnancy, uterine artery Doppler studies have confirmed ro-
bust systolic and diastolic uterine arterial flows; in contrast,
women with preeclampsia have significant impairment of di-
astolic flow with a characteristic notch in the waveform that
antedates clinical signs and symptoms of preeclampsia.28,29
These findings suggest that an abnormality in the trophoblasts
themselves may result in shallow placentation and inadequate
transformation of the spiral arteries, leading to placental ische-
mia and the maternal syndrome of preeclampsia.25
Atherosclerotic changes in maternal radial arteries that
supply the decidua—as opposed to the spiral arteries—are also
lesion common to disorders of placental insufficiency, includ-
ing intrauterine growth restriction and preeclampsia, and com-
bines (1) acute atherotic lesions with (2) medial hypertrophy
and perivascular lymphocytes (Figure 2). Within preeclampsia
phenotypes, the presence of DV is associated with worse clin-
ical outcome, higher diastolic BP, worse renal function, and
perinatal fetal death.32 Histologically, normal third-trimester
decidual vessels are characterized by flat endothelium and a
loss of medial smooth muscle, while preeclamptic decidua
show signs of loose, edematous endothelium, hypertrophy of
the vessel media, and loss of smooth muscle modifications (as
seen in atherosclerosis), characterizing DV.30 Correlated with
clinical diagnosis, DV has the highest association with pree-
clampsia with small for gestational age (SGA) and a lesser but
significant association with SGA with doppler abnormalities,
suggesting a pathogenetic similarity between SGA with dop-
pler abnormalities and preeclampsia with SGA at the level of
the decidua.30 Overall, there is significant evidence that decid-
ual vessels demonstrate secondary atherosclerotic changes in
preeclampsia. Further studies are needed to determine if these
changes are representative of the maternal systemic endothe-
lial damage secondary to pathological changes such as hyper-
tension or if DV contributes to the pathogenesis of stage 1.30
In addition to uteroplacental insufficiency, epidemiological
studies suggest that poor uterine decidualization—the stromal
transformation of uterine endometrium to prepare for implan-
tation—may affect the development of preeclampsia. Global
transcriptional profiling of chorionic villus samples points to in-
sufficient or defective decidualization in pregnancies that were
later complicated by severe preeclampsia.33 Endometrial stromal
cells from nonpregnant donors with a history of severe preeclamp-
sia fail to decidualize in vitro and are transcriptionally inert, sug-
gesting baseline genetic abnormalities or genetic modifications.34
Finally, global transcriptional profiling of decidual tissue from
the women with preeclampsia also revealed defects in gene ex-
pression. These cells failed to redecidualize in culture, and their
conditioned medium failed to support cytotrophoblast invasion,
suggesting that decidual cells may be an important contributor
to downregulated cytotrophoblast invasion in preeclampsia.34
The in vitro studies are confirmed ex vivo in histological stud-
ies of preeclampsia showing shallow placentation.31 Given the
mounting evidence of fetal and maternal abnormalities in pre-
eclampsia, defective placentation might be the result of com-
binations of factors that affect both trophoblast and decidua.35,36
Hypoxia and Trophoblast Invasion
Upregulation of hypoxia-inducible transcription factors (TFs)
and hypoxia-related gene signatures in the placenta suggest
that hypoxia is central to the pathogenesis of preeclampsia.37
In the early phases of implantation, the gestational sac exists
in a low oxygen tension environment, favoring trophoblast
proliferation. Before the invasion, the proliferating tropho-
blasts anchor the blastocyst to maternal tissues and plug the
tips of the spiral arteries within the decidua.38 Eventually these
 Rana et al   Preeclampsia and Vascular Disease   1097

Figure 1. Schematic of the pathogenesis of preeclampsia. Genetic factors, immunologic factors, other maternal factors cause placental dysfunction which
in turn leads to the release of antiangiogenic factors (such as sFLT1 [soluble fms-like tyrosine kinase 1] and sENG [soluble endoglin]) and other inflammatory
mediators to induce preeclampsia.
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trophoblastic-spiral artery plugs collapse, forming an intervil- maternal-fetal interface oxygen tension48,49 and may be useful
lous space. The newly formed sinuses allow for the arrival of for mapping areas of placental pathology and insufficiency.50
maternal blood, increasing oxygen tension, generating oxi-
dative stress, and promoting trophoblast differentiation from Oxidative Stress
a proliferative to an invasive phenotype that will invade and While low oxygen tension followed by maternal blood flow
remodel the spiral arteries.39 HIF (Hypoxia-inducible factors)- oxygenation results in normal placentation, intermittent hy-
1α and -2α, markers of cellular oxygen deprivation, are ex- poxia and reoxygenation caused by poor spiral artery invasion
pressed at high levels in proliferative trophoblasts and in the may cause oxidative stress. At the molecular level, preeclamp-
placentas of women with preeclampsia.40 Overexpression tic placentas show an imbalance of reactive oxygen species
of HIF-1α in pregnant mice is associated with hypertension,
proteinuria, and fetal growth restriction in mice41 and may
result in failure of trophoblastic differentiation from the pro-
liferative to the invasive phenotype.42 Furthermore, inhibition
of HIF-1α by 2-methoxyestradiol, a metabolite of estradiol
that destabilizes HIF-1α, suppresses the production of sFLT1
(soluble fms-like tyrosine kinase 1), a potent antiangiogenic
factor known to contribute to the maternal syndrome.43 HIF-
1α expression is regulated by many factors in addition to hy-
poxia, therefore, isolating the dysregulated signal upstream is
challenging.23,44 Magnetic resonance imaging has been used
to assess the placental perfusion fraction—an estimate of the
fraction of perfused tissue by volume—as a marker of uterine
flow or placental function.45–47 In a Swedish study of 35 women
with singleton pregnancies (13 with preeclampsia), Sohlberg
et al47 found a smaller placental perfusion fraction associated
with fetal growth restriction, as well as abnormalities in mater-
nal and fetal vessel doppler flow, neonatal weight, and plasma Figure 2. Decidual vasculopathy. Placental bed of the uterus with
decidual vasculopathy in the third trimester. Vessels show chronic injury
markers, including higher levels of sFLT1. Novel blood ox-
with endothelial fragmentation and detachment (arrow) and fibrinoid
ygen level-dependent magnetic resonance imaging responses necrosis (**) of the vessel wall. Scale bar is 100 μm. Reprinted from Hecht
promise new, noninvasive, in vivo techniques for assessing et al30 with permission. Copyright ©2016, Elsevier.
 1098  Circulation Research  March 29, 2019
(ROS)-generating enzymes and antioxidants. In the ex vivo
preeclamptic trophoblast, ROS-producing enzyme expres-
sion and activity are increased51 and inhibit the Wnt/β-catenin
signaling pathway that promotes trophoblast invasiveness.52
Oxidative stress may also promote the transcription of an-
tiangiogenic factors such as sFLT1.53 In humans, placental
antioxidant mechanisms are impaired in patients with pree-
clampsia, as shown by their decreased expression of super-
oxide dismutase and glutathione peroxidase compared with
women with normal pregnancies.54 However, treatment with
the antioxidants Vitamin E and Vitamin C did not alter disease
in women with preeclampsia, suggesting that ROS may be
less integral to the pathway of the human syndrome.55,56
ROS may derive from mitochondrial stress. Zsengellér et
al57 demonstrated decreased activity of the mitochondrial elec-
tron transport chain (ETC) enzyme cytochrome C oxidase in
the syncytiotrophoblast cells of preeclamptic placentas, which
correlated with increased placental sFLT1 expression. Based
on evidence that hydrogen sulfide donors inhibit HIF-1α,58
Covarrubias et al59 demonstrated that AP39, a mitochondrial-
targeting hydrogen sulfide donor, pretreatment could decrease
sFLT1 expression in human syncytiotrophoblasts and increase
cytochrome C oxidase activity in a dose-dependent fashion in
normal and preeclamptic placentas, preventing the release of
ROS and the subsequent stabilization of HIF-1α.60 Recently
published studies with mitochondrial antioxidants in animal
models of preeclampsia have also been promising.61
Another possible source of oxidative stress is endoplasmic
reticulum stress caused by ischemia-reperfusion injury.62,63
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Endoplasmic reticulum stress has been observed in the de-
cidua and placentas of patients with fetal growth restriction
and preeclampsia and triggers decidual cell and cytotropho-
blast apoptosis through the activation of the UPR (unfolded
protein response).64,65 PERK (PKR-like endoplasmic reticulm
kinase), a transmembrane kinase that decreases the transla-
tional burden of the endoplasmic reticulum and upregulates
proapoptotic TFs, has emerged as the leading signaling path-
way implicated in preeclampsia.64,65 Interestingly, a recent
study suggests that synergy between ATF4 (activating tran-
scription factor 4), a TF downstream of PERK, and ATF6, a
TF regulator of misfolded proteins in endoplasmic reticulum
homeostasis,65,66 negatively regulate the transcription of PlGF
(placental growth factor), an proangiogenic factor central to
the pathogenesis of preeclampsia.67
Heme Oxygenase and Other Enzyme Abnormalities
There is growing evidence that heme oxygenase (HO), the
heme degradation catalyst, has an important role in the vas-
cular function of the mother and the fetus, as well as in pla-
cental development and function.68–70 Three isoforms of HO
have been characterized,68,71 with HO-2 playing a role in spi-
ral artery invasion72 and HO-1 highly expressed in noninvasive
trophoblastic phenotypes.73 Treatment of the reduced uterine
perfusion pressure (RUPP) rodent model with CoPP (cobalt
protoporphyrin), an inducer of HO-1, decreased BP and result-
ed in a proangiogenic shift in the VEGF (vascular endothelial
growth factor)/sFLT1 ratio in the placenta.74 These preclinical
studies have fueled interest in manipulating the expression of
HO-1 as a potential therapeutic intervention for preeclampsia.
Another influence on trophoblastic invasion and spiral ar-
tery remodeling may come from corin, a transmembrane en-
zyme that locally activates atrial natriuretic peptide through
zymogen modification. Corin acts primarily in heart tissue,
however, Cui et al75 found significantly decreased uterine-lo-
calized corin mRNA and protein levels as well as several corin
gene mutations in preeclamptic patients. The group then creat-
ed a knockout corin rodent model as well as transgenic crosses
that retained isolated cardiac corin activity. Both phenotypes
mimicked the hallmarks of preeclampsia, independently of
preexisting hypertension or cardiac-derived atrial natriuretic
peptide. However, in human studies, the evidence is mixed,
as systemic levels of corin and its target—atrial natriuretic
peptide—are upregulated during preeclampsia76,77 not down-
regulated as would be expected based on the animal studies.
In earlier studies, women with hypertensive disorders of
pregnancy were found to have lower levels of placental cate-
chol-O-methyl transferase (COMT) enzyme,78 while women
with normal gestations were found to have increasing concen-
trations of 2-methoxyestradiol, the COMT breakdown prod-
uct of estradiol.79 Based on these observations, Kanasaki et
al43 characterized a COMT knockout rodent model that repro-
duced the hallmarks of preeclampsia. However, COMT altera-
tions are not a feature of severe early-onset preeclampsia in
humans.80 Given that COMT is decreased in many hyperten-
sive disorders of pregnancy,78 more evidence is required to im-
plicate COMT in the pathogenesis of preeclampsia rather than
a risk factor for all gestational hypertensive disorders.
NK Cells and Impaired Placentation
The uterine NK (uNK) is well characterized in decidualization
physiology81 and may play a role in the abnormal placenta-
tion observed in preeclampsia. Unlike peripheral NKs, uNK
is not cytotoxic.82,83 Rather, in the decidua, uNK cells regu-
late the depth of placentation, spiral artery remodeling, and
trophoblastic invasion.84,85 As the main immunologic player
interacting at the allogenic maternal-fetal cell interface,81
uNKs recognize self-major histocompatibility complexes
(MHCs) derived from the maternal contribution and nonself-
allogenic MHCs from the paternal genotype. Specifically,
uNK express KIR (killer cell Ig-like receptors),86 while fe-
tal invasive extravillous trophoblasts express the main KIR
ligand, polymorphic HLA-C (human leukocyte antigen-C)
MHCs.87 Because of independent segregation of maternal
KIR and HLA loci86 and the paternal contribution to extravil-
lous trophoblast HLA-C, every pregnancy results in a unique
combination of KIR (maternal) and HLA-C (fetal) which may
affect the success of placentation.83 Mouse models selected
for nonmatched maternal uNK and paternal MHC molecules
in otherwise genetically identical parents have demonstrated
that allogenicity may promote decidual artery dilation, spiral
artery remodeling, more efficient placentas, and larger fetal
weights.88 In other words, inhibition of the uNK response by
MHC-self recognition may lead to defective artery remodel-
ing.89 Furthermore, certain maternal KIR haplotypes (uNK)
appear protective against preeclampsia while others confer
risk.83,90–92 However, the presence of the risk-associated haplo-
type is insufficient for disease, suggesting an additional envi-
ronmental or genetic hit.
 Rana et al   Preeclampsia and Vascular Disease   1099
Stage 2: Pathogenesis of the Maternal Syndrome
Imbalance in Circulating Angiogenic Factors
More than a decade ago, several groups identified elevated
levels of the antiangiogenic protein sFLT1 in placentas col-
lected from women with a clinical diagnosis of preeclamp-
sia.93,94 sFLT1 is a soluble protein that exerts antiangiogenic
effects by binding to and inhibiting the biological activity of
proangiogenic proteins VEGF and PlGF95 (Figure 3). VEGF
is important for the maintenance of endothelial cell function,
especially in fenestrated endothelium, which is found in the
brain, liver, and glomeruli, the primary organs affected by pre-
eclampsia.96 A member of the VEGF family, PlGF is impor-
tant in angiogenesis and selectively binds to VEGFR1/sFLT1
not VEGFR2.97 Several findings implicated sFLT1 in the path-
ogenesis of preeclampsia: sFLT1 protein levels were high in
maternal plasma or serum94,98; sFLT1 mRNA expression was
high in preeclamptic placentas99; and injecting exogenous
sFLT1 into rodents led to hypertension, proteinuria, glomer-
ular endotheliosis (a hallmark of preeclampsia seen in renal
biopsy), as well as several other preeclamptic features94,100;
treatment of cancer patients with anti-VEGF drugs results in
hypertension and proteinuria101,102; depletion of sFLT1 in pre-
eclamptic plasma using antibodies reverses the antiangiogenic
phenotype in cell culture studies93; lowering sFLT1 or antago-
nizing sFLT1 in animal models of preeclampsia improves
clinical symptoms103–105 and, spontaneous resolution of clin-
ical signs and symptoms of preeclampsia, when sFLT1 levels
are lowered by 50% or more by treatment of the underlying
placental conditions such as fetal hydrops or removal of dis-
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eased placenta in multiple pregnancies.106,107 In addition to the
elevated sFLT1 levels, circulating levels of free PlGF were re-
duced in women with preeclampsia, suggesting an imbalance
of antiangiogenic and proangiogenic proteins.94,108
The availability of robust immunoassays for angiogenic
factors led to a number of clinical studies measuring the anti-
angiogenic/proangiogenic markers in large cohorts of human
pregnancies showing that sFLT1 levels are high and free PlGF
is low at the time of clinical diagnosis of preeclampsia as well
as several weeks before the diagnosis.108,109 Angiogenic factor
abnormalities in the plasma correlated with severity of presen-
tation, predicting disease, and adverse outcomes.110,111 Early
studies called into question the utility of angiogenic factors
in prediction of preeclampsia.112 However, a recent multisite,
blinded randomized trial for the use of aspirin for prevention
of preeclampsia used several physiological and biochemical
parameters, including PlGF, with a detection rate of 90% at
a fixed false positive rate of 5% for preeclampsia, suggesting
that the markers may be used algorithmically for early diagno-
sis.113 Such a strategy for prediction of the syndrome in early
pregnancy would identify women who are at risk for develop-
ing the disease and who may benefit from preventative inter-
ventions such as aspirin. Early diagnosis would also reduce
anxiety and unnecessary interventions in women at otherwise
low risk of developing preeclampsia.
Another antiangiogenic protein that has also been exten-
sively studied in preeclampsia is soluble endoglin (sENG), an
endogenous TGF-β1 (transforming growth factor β1) inhibi-
tor114 (Figure 3). sENG is elevated in the sera of preeclamptic
women 2 months before the onset of clinical signs of pree-
clampsia, correlates with disease severity, and falls after
delivery.109,115 In pregnant rats, it appears to potentiate the
vascular effects of sFLT1 to induce a severe preeclampsia-
like state, including the development of thrombocytopenia
and fetal growth restriction,116,117 and, in combination with
sFLT1, appears to induce cerebral edema resembling the re-
versible posterior leukoencephalopathy seen in patients with
eclampsia.118,119
Inflammatory Cytokines and Immune Cell Alterations
It is well-established that preeclampsia is a proinflammatory
state, but the culpable cells have yet to be fully elucidated.
Syncytial knots120,121 are allogenic nano to microvesicles shed
from apoptotic or activated trophoblasts121 that have been
identified in the lungs120,122 and plasma of normal pregnan-
cies and in increased amounts in preeclampsia.122–124 Rich in
sFLT1 and endoglin,125,126 syncytiotrophoblast microvesicles
and exosomes may instigate an inflammatory response. In
vitro, syncytiotrophoblast microvesicles activate cultured pe-
ripheral blood mononuclear cells, causing a release of pro-
inflammatory cytokines124,127 that is even more robust when
exposed to peripheral blood mononuclear cells from preg-
nant patients.127 However, in vitro data are not consistent, as
microvesicles induced by an alternative mechanism are not
proinflammatory.128,129
IL (Interleukin)-10—a cytokine that induces the differen-
tiation of the T cell into the Th (T helper type)2 phenotype—
stands out in the literature as an important mitigator of the
maternal syndrome by neutralizing proinflammatory cyto-
kines, AT1-AA (angiotensin II receptor 1 autoantibodies),
placental ROS, and ET-1 (endothelin-1).130 Many cell types
in preeclamptic patients demonstrate a dysregulation in the
balance of IL-10 and proinflammatory cytokines,131–133 includ-
ing uterine and circulating NKs134 and peripheral blood mon-
onuclear cells. Studies of peripheral blood mononuclear cells
of preeclamptic women had reduced IL-10 secretion,135–138
which may lead to failure of T-cell differentiation. Commonly
referred to as Th2 polarization, normal pregnancy is charac-
terized by a shift in T-cell phenotype towards Th2 relative to
Th1.139,140 Multiple studies have reported an aberrant shift to-
wards the Th1 phenotype in preeclampsia, resulting in insuffi-
cient trophoblast invasion.141 Furthermore, a preeclamptic-like
syndrome can be induced in normal pregnant rats with transfer
of CD4+ cells obtained from RUPP models.122
Preeclampsia is also associated with elevated comple-
ment levels142,143 and with genetic mutations in C3.144 In an-
imal models, complement inhibition restores spiral artery
capacitance145 and decreases sFLT1 production,146 and a C1q
knockout mouse model mimics preeclamptic features.147,148
However, complement dysregulation is most severe in the
form of severe preeclampsia called hemolysis elevated liver
enzymes low platelets (HELLP) syndrome. HELLP syndrome
has been shown to share a genetic mutation with149 and has a
similar presentation to atypical hemolytic uremic syndrome,
a disease thought to be caused by uncontrolled complement
activation.150–152 Interestingly, many of the same complement
pathway mutations found in hemolytic uremic syndrome are
also associated with preeclampsia.142,150 Further evidence to
 1100  Circulation Research  March 29, 2019

Figure 3. sFLT1 (soluble fms-like tyrosine kinase 1) and sENG (soluble endoglin) causes endothelial dysfunction by antagonizing VEGF (vascular
endothelial growth factor) and TGF (transforming growth factor)-β1 signaling. There is mounting evidence that VEGF and TGF-β1 are required to
maintain endothelial health in several tissues including the kidney and perhaps the placenta. 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 al114 with permission. Copyright ©2011, the
American Heart Association.

the pathogenic link between atypical hemolytic uremic syn- patients, implicating B lymphocytes as an immune player.170
drome and HELLP, a patient presenting with early-onset se- These findings suggest that anti-AT1-AA made by a subpopu-
vere preeclampsia and HELLP was able to delay delivery by lation of CD19+CD5+ in response to placental ischemia and
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17 days after treatment with Eculizumab,153 an Food and Drug
Administration-approved C5 inhibitor used to treat atypical
hemolytic uremic syndrome 154,155 including in pregnancy.156
The use of Eculizumab as an effective treatment for a severe
form of preeclampsia is promising, however, HELLP is di-
agnostically difficult to distinguish from atypical hemolytic
uremic syndrome,157 likely because of the overlap in comple-
ment pathology.
Renin-Angiotensin Pathway
There is evidence for alterations in the renin-angiotensin-
aldosterone system in the pathogenesis of preeclampsia.158
Several studies show enhanced angiotensin II sensitivity dur-
ing and before the onset of preeclampsia despite reduced cir-
culating renin and angiotensin II during preeclampsia when
compared with normal pregnancy.159,160 One potential mechan-
ism for the increased angiotensin II sensitivity is the presence
of circulating autoantibodies to AT1 in the sera of preeclamp-
tic women.161,162 In preclinical studies, autoantibodies to AT1
reproduce many of the hallmark characteristics of preeclamp-
sia: vasoconstriction through activation of ET-1163; endothelial
cell necrosis and apoptosis in human umbilical vein endothe-
lial cells164; stimulation of tissue factor production contribut-
ing to hypercoagulation165; reduction of trophoblast invasion
in human cell culture models166; and increased production of
ROS in culture models.167 Produced in response to placen-
tal ischemia and systemic inflammation,168 anti-AT1-AA can
also stimulate placental production of antiangiogenic factors
sFLT1 and sENG.169 Finally, CD19+CD5+ cells, as well as
anti-AT1-AA activity, are elevated in the sera of preeclamptic
systemic inflammation may contribute to the hypertension and
production of antiangiogenic factors that characterize the ma-
ternal syndrome.
Recent preclinical studies on the hypersensitivity of the
AT1 receptor when complexed with the bradykinin B2 re-
ceptor provide compelling evidence for another model for
the activation of the renin-angiotensin-aldosterone system in
the setting of downregulated renin.171 Using a new transgenic
mouse model with maternal, systemically upregulated smooth
muscle AT1-B2 complexes, the group was able to replicate
the preeclampsia syndrome, with pregnant animals develop-
ing hypertension, proteinuria, low platelets, increased sFLT1,
AT1-AA, and ET-1, smaller litter sizes, intrauterine growth
restriction, lower renin levels, and a decreased placental lab-
yrinth layer. Furthermore, when heteromerized with B2, ATI
seems independently sensitive to angiotensin II and mechano-
stimulation, which, the authors suggest, may evolve with an
increase in fetal-placental mass regardless of renin activity.
The preeclamptic-like transgenic mice were then rescued with
lentiviral administration of an inactivation-resistant variant of
Arrb1 (β-arrestin-1), G-protein coupled receptor-associated
protein that desensitizes the AT1 receptor leading to signal
dampening. In ex vivo studies of human placentas, the group
found significantly elevated levels of inactivated (phosphory-
lated) levels of Arrb1 in preeclamptic placentas compared
with normotensive placentas, as well as increased AT1-B2
complex formation on the vessels of the basal plate of a pre-
eclamptic placenta. Though the AT1-B2 model does appear
to replicate the maternal syndrome well, only a small num-
ber of human placentas were analyzed as part of this study.
 Rana et al   Preeclampsia and Vascular Disease   1101
Additional human studies are required to assess applicability
of this model to the biology of preeclampsia.
Elevated levels of an oxidized form of angiotensinogen
that is more readily cleaved by renin have also been impli-
cated in the pathogenesis of the hypertension observed in pre-
eclampsia.172 However, robust assays to measure this modified
form of angiotensinogen in the blood are needed to charac-
terize a role for oxidized angiotensinogen in preeclampsia.
Finally, in animal models, elevated levels of circulating sFLT1
were sufficient to induce angiotensin II sensitivity by inter-
fering with endothelial nitric oxide production.173
Sympathetic Nervous System
While a major emphasis of study in the pathogenesis of pre-
eclampsia has been on the link between placental factors and
maternal endothelial dysfunction, several studies have im-
plicated the sympathetic nervous system in the pathogenesis
of preeclampsia.174,175 Schobel et al174 observed that muscle
sympathetic nerve activity is elevated in women with pree-
clampsia over normal pregnant and hypertensive, nonpregnant
control women. Women with preeclampsia also have reduced
baroreflex sensitivity and greater antihypertensive responses
to nonselective adrenergic receptor blockade.176,177 Studies
using experimental animal models supports that sympathetic
nerve activity is increased in preeclampsia. Placental isch-
emia-induced hypertension in the RUPP rat model is associ-
ated with a hypertensive shift in baroreceptor control on renal
sympathetic nerve activity, 178 and a recent study found that
adrenergic receptor blockade markedly attenuates placental
ischemia-induced hypertension.179 Collectively, studies from
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humans and animal models suggest that an intact sympathetic
nervous system may be important in eliciting the full hyper-
tensive response to factors released in response to placental
ischemia.
Lessons From Animal Models
One of the many challenges of the study of preeclampsia is
its reproducibility in animal models. Spontaneous preeclamp-
sia is unique to human gestation. Therefore, animal models
approximate rather than replicate the disease, predominantly
through evidence of systolic hypertension, renal endothelio-
sis, proteinuria, and, at times, fetal growth restriction and pro-
duction of antiangiogenic factors.180 The RUPP rodent model,
produced by clipping the abdominal aorta and the main uter-
ine arteries of pregnant Sprague-Dawley rats,181 is most com-
monly used and presents with elevated mean arterial pressure,
greater vascular reactivity to α-adrenergic agonists181 and in-
creased production of AT1-AA, ROS, and sFLT1 and sENG
as observed in preeclamptic women.182 Other animals, includ-
ing pregnant rabbits, rhesus monkeys, and baboons, have also
been used to model preeclampsia by inducing uteroplacental
insufficiency.182 To replicate the placenta as the inherently
pathogenic organ rather than as secondary to uterine ische-
mia, Kumasawa et al104 implanted mice with transgenic blas-
tocysts with trophectodermal layers expressing human sFLT1
via lentiviral vectors. Human sFLT1 levels increased in the
maternal serum as gestation progressed, with corresponding
development of the hallmarks of preeclampsia. However, the
rodents did not develop the full spectrum of severe features as
in humans. Genetic rodent models, such as the BPH/5 model,
have been used as well. Mildly hypertensive at baseline, the
BPH/5 model demonstrates elevated mean arterial pressure,
proteinuria, and progressive glomerular damage in late gesta-
tion and delivers significantly smaller litters than controls.183
The previously discussed COMT knockout rodent model sim-
ilarly presents with systolic hypertension, elevated sFLT1, and
proteinuria that decline after parturition, however, there is no
evidence of systemic vascular damage or fetal growth restric-
tion, suggesting that this model approximates gestational hy-
pertension or mild preeclampsia.43 The C1q knockout mouse
model relies on the observation of the complement factor C1q
at the decidual endothelium-trophoblast interface184 and was
found to have small litters, intrauterine growth restriction, el-
evated BP, proteinuria, elevated levels of sFLT1, and evidence
of endothelial dysfunction.147,148 Systemic delivery of argi-
nine vasopressin was also sufficient to induce preeclampsia-
like state in pregnant mice, but lack of placental hypoxia and
sFLT1 upregulation in this model suggest that it may be more
relevant for term preeclampsia that is often characterized by
modest levels of antiangiogenic biomarkers.185 Older rodent
models manipulate the renin-angiotensin system (placental
renin and maternal angiotensinogen) to model pregnancy-in-
duced hypertension,186 however, the relevance of this model to
human disease is questionable as humans with preeclampsia
are characterized by suppressed renin and angiotensin II when
compared with normal pregnancy.
Primarily designed on the observation that placental is-
chemia induces systemic hypertension, the described animal
models have been useful for characterizing the molecular en-
vironment of uteroplacental hypoperfusion as well as a variety
of cytokines and proteins released into the maternal circula-
tion. Animal models can be used to extend correlation data
observed in humans into cause and effect relationships, as has
been seen in sFLT1 and sENG manipulation in RUPP mod-
els, and are critical tools for assessing toxicity and efficacy
in novel therapeutics. Of course, animal models are imperfect
for this human-specific disease, as they fail to demonstrate
thrombocytopenia, HELLP syndrome, eclamptic seizures,
and other signs and symptoms that define the severe features
of preeclampsia in humans. Perhaps, the imperfect overlap
in presentation stems from the fact that the primary driver
of preeclampsia, insufficient trophoblast invasion and failure
of spiral artery remodeling, does not occur naturally in other
species and has yet to be modeled accurately. In fact, rodent
trophoblasts minimally invade the spiral arteries, as decidu-
alization occurs after implantation,187 and therefore, may be
an inherently insufficient model species. Furthermore, human
gestation is significantly longer than in rodents, and exposes
pregnant women to much larger doses of circulating toxins,
such as sFLT1, possibly leading to severe features. In fact,
when sFLT1 and sENG levels are concurrently pushed to
exaggerated levels, severe features do occur in animal mod-
els.108–110,113 Despite their limitations, experimental studies in
animal models allow investigators to test directly whether
certain factors found in women with preeclampsia can in-
deed lead to hypertension and other manifestations of the
syndrome. Further investigation is necessary with models that
better approximate human gestation physiology and length to
isolate the primary pathogenic factors.
 1102  Circulation Research  March 29, 2019
Maternal Contribution to Disease
Epidemiological studies suggest that several prepregnancy
maternal characteristics increase risk for preeclampsia.188
Interest is growing around obesity and diabetes mellitus as
risk factors (relative risk [RR], ≈3.5 each)189 in light of data
suggesting Metformin, the biguanide first-line therapy for
type 2 diabetes mellitus, may decrease sFLT1.190 In a recent
meta-analysis of 15 randomized controlled trials reporting
the incidence of hypertensive disorders of pregnancy with
Metformin use, Kalafat et al191 found a reduced risk of hyper-
tensive disorders of pregnancy (RR, 0.56; 95% CI, 0.37–0.85)
but a nonsignificantly reduced risk of preeclampsia (RR, 0.74;
95% CI, 0.09–6.28). However, authors admit the low quality
of the evidence and the clinical heterogeneity of the included
studies, limiting conclusions. Prepregnancy vascular dysfunc-
tion, such as in women with chronic hypertension, not only
jeopardizes placental perfusion but may also enhance the pla-
cental response to ischemia as well as the vascular response
to antiangiogenic factors such as sFLT1. Therefore, baseline
host characteristics may put women at risk of preeclampsia,
even at physiological elevations of antiangiogenic factors
and cytokines. A history of acute kidney injury before preg-
nancy, despite apparent full recovery, is also associated with
increased risk of pregnancy complications.192 Interestingly, a
shorter interval between the AKI episode and the pregnancy
were associated with higher risks of preeclampsia. This sug-
gests that subclinical renal dysfunction may interfere with the
hemodynamic adaptation of normal pregnancy, which in turn
may lead to impaired placental perfusion and preeclampsia.192
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Translation of Preeclampsia
Biology in the Clinic
Biomarkers for Diagnosis, Prediction,
and Prognosis
The ACOG committee opinion issued in 2015 and reaffirmed
in 2017 does not recommend screening to predict preeclamp-
sia beyond obtaining an appropriate medical history.18,193
Because of the lack of adequate screening methods and the
severe sequelae of the disease, all women suspected of pree-
clampsia undergo resource intensive testing, often requiring
several-day hospitalizations for further investigation. Other
methods of screening have been investigated, including a me-
tabolomic pathways and combined metabolomic-proteomic
data approaches.194–197 A 2017 head to head comparison of the
Fetal Medicine Foundation algorithm-based screening method
(a combination of maternal factors, mean arterial pressure,
uterine-artery pulsatility index, and PlGF) demonstrated su-
periority to the screening methods currently recommended
by National Institute for Health and Care Excellence and
ACOG.198 Using a similar screening algorithm with the addi-
tion of maternal serum PAPP-A (pregnancy-associated plasma
protein-A), the ASPRE trial (aspirin for evidence-based pre-
eclampsia prevention) screened women in the first trimester
to identify those at high risk for preeclampsia.199 High-risk
women were then randomized to receive 150 mg of aspirin
or placebo daily until 36 weeks gestation. Daily low-dose as-
pirin use in high-risk women was associated with a signifi-
cantly lower incidence of preterm preeclampsia than placebo,
and detection rate of preterm preeclampsia was 76.7%
(138/180)—43.1% for term preeclampsia—with a false pos-
itive rate of 9.1%. These results suggest that early screening
with plasma biomarkers and imaging studies allows for early
intervention and possible prevention of disease.
Perhaps most promising among screening methods is the
use during the third trimester of combined biomarkers—such
as sFLT1, sEng, and PlGF—with high sensitivity and spec-
ificity for early diagnosis and prognosis of preeclampsia.200
Substantial evidence already demonstrates encouraging test
characteristics of biomarker assays in this population.201,202 In
a study of over 600 women undergoing initial evaluation of
preeclampsia, an sFLT1/PlGF ratio of ≥85 correlated with di-
agnosis of preeclampsia and predicted adverse outcomes and
delivery within 2 weeks among women presenting <34 weeks
gestation. Furthermore, the biomarker ratio performed better
than all other currently available tests for prediction of pree-
clampsia.110 A follow-up study of 402 patients presenting with
preterm singleton pregnancies by the same group showed that
an sFLT1/PlGF ratio >85 had a PPV of 59% in all patients and
74% among patients presenting <34 weeks for developing pre-
eclampsia with severe features within 2 weeks.203 Patients with
preeclampsia with normal angiogenic profile have fewer ad-
verse outcomes suggesting that the angiogenic form of pree-
clampsia is clinically more important.111 Other groups have
shown similar results. In a multicenter study of women with
suspected preeclampsia, authors showed a reverse association
of free PlGF with gestational age at delivery.204 In a recent mul-
tisite study of angiogenic factors, authors concluded that an
sFLT1/PlGF ratio of ≤38 had an negative predictive value of
99.9% for ruling out preeclampsia within 1 week.205 A follow-up
study from the same cohort showed an negative predictive value
of 95% within 4 weeks.206 Overall, serum or plasma angiogenic
factors appear to be a reliable risk-stratification method among
women with suspected preeclampsia, especially for  preterm
preeclampsia, allowing for appropriate management.
Recent studies have also suggested that by reducing false
positive rates of diagnosis and consequent unnecessary hospi-
talizations, risk stratification with biomarkers is economical.
Assays using these plasma biomarkers are available for clini-
cal use in Europe, Canada, Africa, and Asia, and their clinical
success has led to the incorporation of angiogenic factors in
the definition of preeclampsia in the British National Institute
for Health and Care Excellence and national German guide-
lines.207 Finally, a study in Mozambique showed that meas-
urement of PlGF is feasible in resource poor environments.
The authors concluded that low PlGF in women with sus-
pected preeclampsia was associated with increased transfers
to higher levels of care and increased maternal and perinatal
risks.208 Looking forward, biomarker assays are a cost-effec-
tive and reliable screening method that could be lifesaving,
even in areas of limited expertise and resources.
Though not part of any formal diagnostic criteria, hyper-
uricemia is classically a biomarker indicating progression of
gestational or chronic hypertension to preeclampsia and of
risk for fetal and maternal complications such as SGA.209–212
However, in all-comers, uric acid levels do not predict devel-
opment of preeclampsia.213–215 Evidence about the contribu-
tion of uric acid to the pathogenesis of preeclampsia is mixed,
 Rana et al   Preeclampsia and Vascular Disease   1103
though general consensus suggests that levels are elevated
secondary to renal injury and decreased excretion.216
Treatment and Management of Preeclampsia
Current management of preeclampsia in the developed world
includes preconception counseling, perinatal BP control and
monitoring, prenatal aspirin therapy in high-risk women, be-
tamethasone for patients <34 weeks, parenteral magnesium
sulfate, and careful follow-up of postpartum BPs.1 Timely
delivery of the fetus and placenta remains the only definitive
treatment. Even among patients who did not show antena-
tal signs of preeclampsia, surveillance continues postpartum
because of the rising incidence of postpartum preeclampsia.
Preeclampsia without severe features can be managed expect-
antly with twice-weekly maternal and fetal monitoring until
37 weeks in the absence of labor, rupture of membranes, vag-
inal bleeding, or abnormal antepartum testing.1,18 In women
with preeclampsia with severe features at <34 weeks, expect-
ant management can be attempted based on strict inclusion
criteria and with appropriate resources. In these patients, care-
ful attention should be given to worsening maternal and fetal
well-being and delivery is indicated at any time with deterio-
ration of maternal and fetal status. ACOG currently does not
recommend pharmacological treatment of mild to moderate
range hypertension (systolic <160 mm Hg or diastolic <110
mm Hg) in the setting of preeclampsia,1 as it does not appear
to attenuate risk of disease progression and may increase the
risk of fetal growth restriction.217 In a multinational random-
ized trial for control of BPs enrolling women with chronic and
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gestational hypertension, authors found lower prevalence of
severe hypertension (≥160/110 mm Hg) among patients with
tight control of BPs during pregnancy (40.6% versus 27.5%).
There was no difference in development of preeclampsia and
perinatal outcomes were similar.218 A large randomized trial is
underway in the United States to evaluate treatment of mod-
erate hypertension during pregnancy (URL: http://www.clini-
caltrials.gov. Unique identifier: NCT02299414). Treatment of
severe hypertension requires pharmacological therapy with la-
betalol, nifedipine, or methyldopa,1 however, recent evidence
from animal studies suggest that amlodipine may be superior
to nifedipine because of its inducing effects on Arrb1 and sub-
sequent downregulation of the AT1-B2 receptor complex,171
though more clinical evidence is needed. Though current clin-
ical management is limited, innovative medical therapies are
on the horizon.
Small molecules have had variable success in treating hy-
pertensive disorders of pregnancy. Early studies, including the
1998 National Institutes of Health trial, did not show improved
outcomes in women at high risk of preeclampsia when treated
with low dose (60 mg) of aspirin compared with placebo.219
However, with improved risk-stratification methods, Rolnik et
al199 demonstrated a lower incidence of preterm preeclampsia
in high-risk women treated with 150 mg of aspiring compared
with placebo. Aspirin is now recommended for the prevention
of preeclampsia in high-risk women.1
Sildenafil, a phosphodiesterase type 5 inhibitor, was ini-
tially thought to be a promising way to reduce placental is-
chemia given its ability to potentiate the actions of nitric
oxide, causing uterine vasodilation. However, in the 2018
Maternal STRIDER trial (Sildenafil for Severe Fetal Growth
Restriction), sildenafil did not prolong pregnancy or improve
pregnancy outcomes compared with placebo in women with
severe intrauterine growth restriction in the late second to
third trimester.220 A 2017 randomized controlled trial of sil-
denafil therapy in fetal growth restriction did not show any
benefit in attenuating disease compared with placebo221 and
was prematurely halted when 11 neonates in the sildenafil arm
died secondary to pulmonary disease.222 However, other small
molecules that effect nitric oxide production are still under
investigation. For example, statins continue to show promise
in animal models and in human ex vivo tissue samples.223–225
Likely because of its stimulatory effects on HO and improved
vascular function,224 pravastatin improves fetal and mater-
nal outcomes in patients with antiphospholipid syndrome226
and mitigates disease in patients with severe features225 and
with evidence of placental vascular pathology.227 StAmP trial
(Statins to Ameliorate Early Onset Preeclampsia), a dou-
ble-blind, multicenter, randomized controlled trial looking at
the effects of Pravastatin on serum biomarkers in preeclamp-
sia, has completed recruitment and is now in the data-analysis
phase (ISRCTN 23410175). Metformin, an insulin sensitizer
and the first-line treatment of type 2 diabetes mellitus, is as-
sociated with reduced incidence of hypertensive disorders in
pregnancy,191 as well as decreased levels of circulating sFLT1
and sENG in vitro.228 Metformin has been shown to be safe in
pregnancy, with no significant difference in neonatal outcomes
when compared with insulin in the treatment of gestational di-
abetes mellitus,229 making Metformin an attractive and readily
available therapy. Finally, ouabain, a cardiac glycoside, has
been shown to inhibit sFLT1 mRNA and protein expression
through the HIF-1α/heat-shock protein 27 pathway in human
cytotrophoblasts and explant cultures as well as in rat mod-
els without any fetal adverse effects.230 Further investigation
is necessary to further characterize ouabain as a therapeutic.
Most small molecules target the prevention of preeclamp-
sia in high-risk women, however, no therapy currently exists
for the treatment of preeclampsia to delay preterm delivery.
Adapting apheresis technology safely and commonly used
in pregnant women with familial hypercholesterolemia,231
Thadhani et al232 used a negatively charged dextran sulfate cel-
lulose column to remove positively charged sFLT1 from the
serum of 3 women with preterm (<32 weeks) preeclampsia,
resulting in dose-dependent delays in delivery. To minimize
the side effect profile—namely, transient hypotension—and
improve the efficiency of removal, the same group repeated
the pilot study with an apheresis device that incorporated
plasma separation for sFLT1 removal.233 Eleven women with
very preterm preeclampsia were treated with dextran sulfate
column apheresis with a mean reduction in sFLT1 of 18% per
treatment and an average of 8 days (range 2–11) of extended
gestation with a single treatment and an average of 15 days
(range 11–21) extended gestation with multiple treatments,
compared with an average of 3 to 4 days in controls. There
were no additional adverse events in neonates treated with
apheresis compared with normal and preeclamptic controls
born comparably preterm. Direct therapies for the treatment
of preeclampsia would revolutionize the management of this
highly morbid disease, and the results from these pilot studies
 1104  Circulation Research  March 29, 2019
show immense promise, with refinement of the specificity of
the apheretic column for known preeclamptic markers.
Other promising therapies for preeclampsia include recom-
binant human PlGF and RNA interference technology-based
methods. A ligand specific to VEGFR1/Flt1, recombinant
human PlGF has the potential to scavenge excess circulating
sFLT1 without the additional side effects of vascular permea-
bility and edema associated with VEGFR2. Baboon and rodent
studies have shown promising results, lowering BP, proteinu-
ria, and sFLT1 mRNA.234,235 However, the treatment may be
limited given that only a small percentage of total body sFLT1
is circulating236 and, therefore, amenable to ligand interaction.
RNA interference technology provides a cheaper alternative
to recombinant therapies. Silencing sequences of RNA spe-
cific to all 3 isoforms of circulating sFLT1 mRNA have been
shown to decrease sFLT1, BP, and proteinuria in pregnant ba-
boon models with a single dose.237 However, given the limi-
tations of animal models of preeclampsia and the regulatory
implications of developing oligonucleotide therapies, signifi-
cant further study is required before clinical trials.
Preeclampsia and CVD
Short-Term Cardiovascular Complications in the
Postpartum Period
Postpartum hypertension (defined as hypertension >48 hours
or more after delivery) occurring either de novo or in the set-
ting of preeclampsia has emerged as an important risk fac-
tor for significant morbidity in women in the United States.238
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While the pathogenesis of this syndrome is still being elucidat-
ed, clinical studies have suggested that postpartum hyperten-
sion may share similar plasma angiogenic profiles as women
with antepartum preeclampsia and, therefore, may represent a
group of women with subclinical preeclampsia or unresolved
preeclampsia.5 In the peripartum period, preeclampsia is as-
sociated with an increased risk of peripartum cardiomyopa-
thy (PPCM) that can progress to chronic heart failure, cardiac
transplantation, or death.239,240 Given that VEGF pathway in-
hibitors in oncology patients also induce cardiomyopathy,241
elevated levels of antiangiogenic factors may play a role in
the development of PPCM. Using a PGC (proangiogenic tran-
scriptional cofactor)-1α knockout mouse model and human
serum studies, Patten et al240 showed that repeatedly elevated
levels of sFLT1 and prolactin cleavage fragments were syn-
ergistically associated with PPCM and that both angiogenic
factor imbalance and prolactin fragmentation are regulated
by PGC-1α. Authors proposed a 2-hit hypothesis for the de-
velopment of PPCM: (1) an increase in antiangiogenic fac-
tors such as sFLT1 that causes cardiac dysfunction as seen
in preeclampsia and (2) an independent decrease in defenses
against antiangiogenic factors in the heart as seen in low levels
of cardiac PGC-1α expression. Thus, inhibition or removal of
sFLT1 could attenuate PPCM in preeclamptic women with an
environmental or genetic predisposition to disease.
In the short-term, neonates may also present with
vascular effects secondary to the elevated levels of anti-
angiogenic factors. Though hypertension and proteinuria
observed in the mother are not observed in the fetus, ele-
vated levels of sFLT1 have been observed in the amniotic
fluid in women with preeclampsia.242 Epidemiological stud-
ies have shown an increased incidence of bronchopulmona-
ry dysplasia243,244 and decreased incidence of retinopathy of
prematurity (adjusted odds ratio 0.65; 95% CI, 0.49–0.86
for early preterm),245 2 diseases of prematurity associated
with neoangiogenesis. Intraamniotic injections of sFlt1 in
rat models disrupt pulmonary angiogenesis and increase
the incidence of bronchopulmonary dysplasia,244 while ad-
ministration of anti-sFLT1 monoclonal antibody increases
alveolar counts and pulmonary vessel density in the pre-
mature pups of preeclampsia rat models.246 Together, these
epidemiological and animal studies imply that sFLT1 af-
fects fetal angiogenesis at mucous membranes exposed to
amniotic fluid.
Preeclampsia and Long-Term CVD
There is accumulating evidence that preeclampsia-eclampsia
predisposes to long-term cardiovascular risk247,248 including
risk of hypertension, peripheral arterial disease (RR, 1.87;
0.94–3.73), coronary artery disease (overall CVD RR: 2.3;
1.95–2.78), cerebrovascular disease (RR, 2.03; 1.54–2.67),
congestive heart failure, vascular dementia (hazard ratio, 3.46;
1.97–6.10), and death (RR, 2.29; 1.73–3.04).248–250 Potential
explanations for the association between preeclampsia and
CVD are debated. It has been proposed that endothelial dam-
age caused by preeclampsia persists beyond postpartum re-
covery, increasing the risk of CVD,247 and that the risk of
future CVD increases with multiple episodes of preeclamp-
sia.248 Alternatively, an unfavorable cardiovascular risk profile
characterized by higher levels of glucose, cholesterol, hyper-
tension, and abdominal obesity may contribute to the develop-
ment of preeclampsia and later, CVD.249
The odds of a fatal outcome from CVD have been shown
to be greater than odds of diagnosis (odds ratio =2.89; 95%
CI, 1.71–4.89 and odds ratio =2.01; 95% CI, 1.68–2.41; re-
spectively)250 in preeclampsia, suggesting that women may
die from the sequelae of CVD without first being diagnosed.
Furthermore, meta-regression reveals a graded relationship
between the severity of preeclampsia-eclampsia and the risk
of cardiac disease (mild: RR 2.00, 1.83–2.19; moderate: RR
2.99, 2.51–3.58; and severe: RR 5.36, 3.96–7.27; P<0.0001),
implicating a dose-response to the severity of preeclamp-
sia.249 Studies are underway to find biomarkers and subclin-
ical echocardiographic measures, such as global longitudinal
strain,251–253 to provide early risk assessment and stratification
in women with preeclampsia.
The question remains if there is an opportunity for inter-
vention in asymptomatic women with a history of preeclamp-
sia. A study of 2 tertiary medical centers in the Netherlands254
found that a total of 42% of women with a history of pre-
eclampsia had significant CVD risk factors compared with
14.3% among women with a history of an uncomplicated
pregnancy. In the United States, a 2018 study using the
Nurses’ Health Study II suggested that hypertensive disorders
of pregnancy were associated with 10-year CVD risk overall,
independent of established CVD risk factors. Globally there is
increasing evidence that a history of preeclampsia should be
considered in CVD risk stratification.7
 Rana et al   Preeclampsia and Vascular Disease   1105
Preeclampsia is also associated with 4.7-fold risk for subse-
quent end-stage renal disease.255 Based on sibling studies, Vikse
et al256 reported that familial aggregation of risk factors could not
explain the increased end-stage renal disease risk and, therefore,
concluded that preeclampsia per se may lead to long-term kid-
ney damage. Women with preeclampsia are also at a 4-fold risk
of stroke257 and 3-fold risk of vascular dementia later in life.258
Additional studies are needed to elucidate the pathogenesis of
these long-term complications in women with preeclampsia.
Decades of literature observe a relationship between life-
long CVD risk and growth restriction in utero, such as seen
in the fetuses of preeclamptic pregnancies. First described
by Barker and Osmond,259 the so-called Barker Hypothesis
suggests that lack of early nutrition, growth restriction, and
the uterine environment increase susceptibility to other risks
for CVD. Indeed, children born to women with preeclamp-
sia have an increased risk of CVD.260 Neonates may also be
at risk for pulmonary hypertension into their teenage years
and beyond.261 Pulmonary amniotic sFLT1 exposure leading
to decreased pulmonary angiogenesis has been proposed as
a mechanism for this long-term lung injury,246 though the se-
quelae of prematurity or systemic sFLT1 exposure246 cannot
be excluded. Current research seeks to further characterize
CVD in children born to preeclamptic mothers.262
Conclusions
Preeclampsia is a leading cause of maternal morbidity and
mortality worldwide, whose only definitive treatment—de-
livery of the fetus and placenta—carries significant morbidity
Downloaded from http://ahajournals.org by on April 15, 2019
and mortality for the neonate. Though the mortality of pre-
eclampsia-eclampsia has decreased significantly in the United
States because of increased antenatal surveillance and early
interventions, the postpartum and lifelong sequelae of pree-
clampsia have risen in number and significance. Whether the
risk predates and confounds preeclampsia or is a result thereof,
we now know that women with a history of preeclampsia are
at increased risk for CVD250,263 and dementia258 later in life,
including acutely fatal myocardial infarction without the pro-
gressive, forewarning symptoms of the acute coronary syn-
drome.263 An increased focus on interventional studies during
the postpartum, asymptomatic phase is imperative to mini-
mize the risk of CVD and its potentially fatal complications.
Improved risk stratification and therapeutics are other areas
of opportunity with several innovations on the horizon. While
ongoing work in placental oxidative stress and the maternal
immune response demonstrate intriguing insights, perhaps
the most promising area under investigation is the maternal
angiogenic factor imbalance and its effects on vascular func-
tion. Ongoing development of methods of risk stratification
using ratios of proangiogenic factors—such as PlGF—and an-
tiangiogenic factors—such as sFLT1 and sENG—have high
detection rates for preterm preeclampsia when incorporated
into algorithms with other predictive elements264 and have
shown high negative predictive value as an isolated assay.
Removal of antiangiogenic proteins through plasma apheresis
significantly prolongs gestation compared with controls and
attenuates the symptoms of preeclampsia,232,233 and recombi-
nant human PlGF and siRNA have shown promising results
in animal models,234,235,237 suggesting possible therapeutic
alternatives to preterm delivery. Most importantly, risk-strat-
ification methods using antiangiogenic factors have already
proven to be safe, efficient, cost-effective, and economical,
making them possibilities for improving care in countries that
carry the highest mortality from preeclampsia.
Disclosures
S. Rana reports serving as a consultant for Roche Diagnostics and
Thermofisher and has received research funding from Roche and
Siemens. Dr Karumanchi is colisted as coinventors on patents re-
lated to preeclampsia biomarkers and therapies that are held at
Beth Israel Deaconess Medical Center. He has a financial inter-
est in Aggamin LLC and also reports serving as a consultant to
Thermofisher.He has received research funding from Siemens. The
other authors report no conflicts.
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