Am J Physiol Regul Integr Comp Physiol 309: R1326 –R1343, 2015.

Review First published October 7, 2015; doi:10.1152/ajpregu.00178.2015.

Increased risk for the development of preeclampsia in obese pregnancies:

weighing in on the mechanisms
Frank T. Spradley, Ana C. Palei, and Joey P. Granger
Department of Physiology and Biophysics, Cardiovascular-Renal Research Center, Women’s Health Research Center, The
University of Mississippi Medical Center, Jackson, Mississippi
Submitted 30 April 2015; accepted in final form 28 September 2015

Spradley FT, Palei AC, Granger JP. Increased risk for the development of
preeclampsia in obese pregnancies: weighing in on the mechanisms. Am J Physiol
Regul Integr Comp Physiol 309: R1326 –R1343, 2015. First published October 7,
2015; doi:10.1152/ajpregu.00178.2015.—Preeclampsia (PE) is a pregnancy-spe-
cific disorder typically presenting as new-onset hypertension and proteinuria. While

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numerous epidemiological studies have demonstrated that obesity increases the risk
of PE, the mechanisms have yet to be fully elucidated. Growing evidence from
animal and human studies implicate placental ischemia in the etiology of this
maternal syndrome. It is thought that placental ischemia is brought about by
dysfunctional cytotrophoblast migration and invasion into the uterus and subse-
quent lack of spiral arteriole widening and placental perfusion. Placental ischemia/
hypoxia stimulates the release of soluble placental factors into the maternal
circulation where they cause endothelial dysfunction, particularly in the kidney, to
elicit the clinical manifestations of PE. The most recognized of these factors are the
anti-angiogenic sFlt-1 and pro-inflammatory TNF-␣ and AT1-AA, which promote
endothelial dysfunction by reducing levels of the provasodilator nitric oxide and
stimulating production of the potent vasoconstrictor endothelin-1 and reactive
oxygen species. We hypothesize that obesity-related metabolic factors increase the
risk for developing PE by impacting various stages in the pathogenesis of PE,
namely, 1) cytotrophoblast migration and placental ischemia; 2) release of soluble
placental factors into the maternal circulation; and 3) maternal endothelial and
vascular dysfunction. This review will summarize the current experimental evi-
dence supporting the concept that obesity and metabolic factors like lipids, insulin,
glucose, and leptin affect placental function and increase the risk for developing
hypertension in pregnancy by reducing placental perfusion; enhancing placental
release of soluble factors; and by increasing the sensitivity of the maternal
vasculature to placental ischemia-induced soluble factors.
body mass index; inflammation; placental ischemia; pregnancy; RUPP; sFlt-1

PE IS A PREGNANCY-SPECIFIC DISORDER typically identified by
new-onset hypertension in the second half of pregnancy. Al-
though often accompanied by new-onset proteinuria, PE can be
associated with many other signs and symptoms including
headaches, visual disturbances, epigastric pain, and the devel-
opment of edema (4, 192). Globally, this disease affects over 8
million pregnancies per year and is estimated to account for
40 – 60% of maternal deaths in developing countries (125). In
the United States, there was a 25% increase in the rate of PE
between the years 1987–2004 (189). This significant increase
highlights the importance of understanding how risk factors
like obesity play a role in the pathogenesis of this maternal
syndrome. Obesity is defined as a body mass index (BMI) of
greater than or equal to 30 kg/m2. Greater than one-half of
pregnant women are overweight or obese (48), and more than
two-thirds of reproductive-aged women in the United States
Address for reprint requests and other correspondence: J.P. Granger, Car-
diovascular-Renal Research Center, Dept. of Physiology and Biophysics,
Univ. of Mississippi Medical Center, Jackson, MS 39216 (e-mail:
jgranger@umc.edu).
R1326 0363-6119/15 Copyright © 2015 the American Physiological Society
are overweight or obese (49). Although mounting epidemio-
logical evidence supports obesity as a major risk factor for PE,
the mechanisms linking these two morbidities are unclear. In
this review, we use epidemiological and experimental studies
to propose potential mechanisms linking obesity and the de-
velopment of PE. We also highlight the importance of utilizing
animal models to investigate the relative importance of meta-
bolic factors in the pathophysiology of PE.
We will discuss numerous studies that reinforce that obesity
increases the risk for the development of PE. However, less is
known regarding the specific mechanisms whereby obesity
poses this risk. Mounting evidence supports that the pathogen-
esis of PE encompasses a two-stage process. The first stage is
thought to involve improper placental development as a result
of dysfunctional proliferation, migration, and invasion of fetus-
derived cytotrophoblast cells into the uterus (170). Ultimately,
this leads to inappropriate uterine spiral arteriole widening,
decreased placental blood flow, and placental hypoxia. A
number of experiments using the RUPP (reduced uterine per-
fusion pressure) model of placental ischemia in pregnant rats,
mice, and baboons have clearly demonstrated that placental
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LINKING OBESITY TO PREECLAMPSIA RISK
ischemia is a strong stimulus for the release of soluble placen-
tal factors into the maternal circulation, which facilitate the
second stage in the pathogenesis of PE: maternal endothelial
and vascular dysfunction. Table 1 lists the similarities between
the RUPP rat model and the clinical pathologies in preeclamp-
tic women. These placental ischemia-associated factors include
the anti-angiogenic soluble fms-like tyrosine kinase 1 (sFlt-1)
and pro-inflammatory factors like tumor necrosis factor
(TNF)-␣ and agonistic autoantibodies to the angiotensin II type
1 receptor (AT1-AA). Similarly, each one of these factors is
increased in preeclamptic women. A direct role for each of
these factors in increasing blood pressure during pregnancy
was demonstrated by studies showing that infusion of each of
these factors into normal pregnant rats increases blood pres-
sure. This was accompanied by endothelial dysfunction driven
by reductions in the pro-vasodilatory molecule nitric oxide
(NO) and production of the pro-vasoconstrictor peptide endo-
thelin (ET)-1 in endothelial cells. In the kidney, vascular
dysfunction leads to altered renal hemodynamics and reduced
renal excretory function. The kidney is important in the long-
term control of blood pressure and endothelial dysfunction in
the kidney manifests as hypertension and proteinuria (31).
Because this cascade of events is thought to play an important
role in the pathogenesis of PE, it is likely that obesity-related
metabolic factors may increase the risk of developing PE by
impinging on these pathophysiological processes. Therefore, in
this review, we propose that obesity impacts the various stages
thought to encompass the pathogenesis of PE by: 1) acting on
the placenta causing cytotrophoblast dysfunction and placental
ischemia; 2) enhancing ischemia/hypoxia-induced release of
soluble placental factors; and 3) by increasing the sensitivity by
which placental ischemia-factors are able to promote endothe-
lial dysfunction and hypertension.
Epidemiological Evidence Supporting That Obesity Increases
the Risk for the Development of PE
One of the early observations indicating that obese pregnan-
cies are at greater risk for PE was reported in 1969 by Tracy
and Miller (181). This study was published before the wide-
spread use of BMI to classify body weight status. In their
Table 1. Similarities in cardiovascular outcomes; circulating
placental ischemia factors; and fetal consequences compared
between human preeclampsia and the RUPP rat model of
preeclampsia
Parameter Human RUPP
Hypertension ⫹ ⫹
Proteinuria ⫾ ⫾
Renal vasoconstriction ⫹ ⫹
1TPR/2CO ⫹ ⫹
Endothelial dysfunction ⫹ ⫹
1sFlt-1/2VEGF ⫹ ⫹
1Proinflammatory factors (TNF-␣, AT1-AA) ⫹ ⫹
Placental insufficiency (Fetal/placental weight) ⫹ ⫹
Intrauterine growth restriction ⫾ ⫹
RUPP, reduced uterine perfusion pressure; TPR, total peripheral resistance;
CO, cardiac output; sFlt-1, soluble fms-like tyrosine kinase 1; VEGF, vascular
endothelial growth factor; TNF-␣, tumor necrosis factor-␣; AT1-AA, agonistic
autoantibodies to the angiotensin II type 1 receptor. Plus sign (⫹) denotes the
presence, whereas ⫾ indicates that the symptom is not always present in
preeclamptic women and RUPP rats.
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
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R1327
16.0
Late-onset pre-eclampsia
14.0 Early-onset pre-eclampsia 0.4
Rates of pre-eclampsia (%)
12.0
0.4
10.0 0.4
8.0 0.3
13.0
6.0
10.5
9.1
4.0 0.1 7.4
2.0
3.2
0.0
Normal weight Class l obesity Class ll obesity Class lll obesity Super obesity
Fig. 1. Rates of preeclampsia (PE) increase with increasing body mass index
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(BMI). From Mbah AK et al. (110).
cohort of 48 women weighing greater than 250 pounds at any
point during their pregnancies, there was found a staggering
31% prevalence of PE. In fact, PE was the number one
obstetric complication found in their sample population. Sim-
ilar statistics have been reported in more recent studies de-
signed to compare obese and normal weight pregnant women.
Indeed, Roberts and colleagues (15) showed that prepregnancy
obesity attributes a 30% risk for PE in pregnant women with a
BMI ⬎ 35 compared with lean pregnant counterparts. Further-
more, another study reported that prepregnancy obesity confers
a three- to fourfold elevated risk for PE in triple gestations
(152). The significance of BMI status as a predictor for PE is
emphasized by an almost linear-response effect of BMI on the
incidence of PE: incidence has been shown to be 7% in those
gravidas with class I obesity (BMI ⫽ 30 –34.9), 9% with class
II (BMI ⫽ 35–39.9), 11% with class III obesity (BMI ⫽
40 – 49.9), 13% in super-obese women (BMI ⫽ 50), whereas
normal weight gravidas (BMI ⫽ 18.5–24.9) had a 3% chance
of developing PE (110) (Fig. 1). The differences in the percent
risk for PE within the same BMI class in these reports may be
due to environmental exposure differences; the type of study
(prospective vs. retrospective); and/or inclusion criteria for
study volunteers. The vast majority of studies have demon-
strated a detrimental impact of obesity on the rates of PE where
this association between prepregnancy obesity and PE has been
found in several countries across the world. In the United
Kingdom, for example, nulliparous, morbidly obese women
with a BMI ⬎ 40 determined at 10 wk of gestation were found
to have a 30% chance of developing PE (13). This strong
positive correlation between obesity and the prevalence of PE
has also been observed in Americans (110), New Zealanders
(103), and Canadians (43).
Data illustrated in Fig. 1 suggest that obesity adds risk to the
development of both early-onset and late-onset PE [odds ratios
(OR) ⫽ 2.94; 95% confidence intervals (CI) ⫽ 2.87–3.01].
This risk was stronger for late PE (OR ⫽ 2.97; 95% CI ⫽
2.90 –3.04) than early PE (OR ⫽ 2.22; 95% CI ⫽ 2.06 –2.40)
(110). It has been proposed that the etiology of early and late
PE is different, being abnormal placentation implicated in the
development of early-onset PE, whereas an abnormal maternal
metabolic milieu at conception has been linked to late-onset PE
(144). It is likely that an abnormal metabolic environment is
tied to increased secretion of factors by adipose tissue, which
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R1328 LINKING OBESITY TO PREECLAMPSIA RISK
is not only a triglyceride-storing depot, but an endocrine organ
that synthesizes and secretes a variety of hormones and inflam-
matory factors (182). Because increased body fat is associated
with elevated circulating cytokine levels, obese women are
more likely to begin pregnancy in a subclinical inflammatory
state than normal weight women. Studies have shown that BMI
is positively correlated with neutrophil infiltration into blood
vessels, vascular inflammation, and blood pressure in women
(159). On top of this, clinical studies have pointed to a positive
relationship between BMI and activation of inflammatory path-
ways within the placenta (154), suggesting that metabolic
factors exaggerate placental ischemia-induced release of in-
flammatory factors. Thus a harmful prepregnant pro-inflamma-
tory status is most likely accompanied by baseline vascular
dysfunction resulting in a lowered threshold and increased
sensitivity to the combined ability of obesity-related metabolic
factors and soluble placental ischemic inflammatory factors to
elicit maternal endothelial dysfunction and hypertension. This
represents a potential mechanism whereby obesity increases
the risk for the development of late-onset PE.
These above reports highlight that it is important to under-
stand how prepregnancy and increased early pregnancy BMI
predisposes obese women to the development of PE. Some
studies have also assessed whether gestational weight gain
poses additional risk for this maternal disorder. The Avon
Longitudinal Study of Parents and Children conducted at the
University of Bristol confirmed that increased prepregnancy
weight is associated with increased PE risk. These investiga-
tors went on to also show that, after adjustment for prepreg-
nancy weight, weight gain of 200 g/wk in early pregnancy
before 18 wk of gestation was independently associated with
increased blood pressure during mid (18 –29 wk) and very late
(⬎36 wk) but not late (29 –36 wk) pregnancy. However, it was
found that if this amount of weight gain was reached during
each of these gestational periods, there was an increase in
blood pressure within that respective period (101). Studies
such as this lead to recommendations by the Institute of
Medicine (IOM) that women gain between 6.8 and 11.3 kg
during pregnancy. In a study examining cohorts of women in
Missouri having gestational weight gain of either ⬍6.8, 6.8 –
11.3, or ⬎11.3 kg, it was found that, compared with women
with normal gestational weight gain, those with lower weight
gain had reduced risk, whereas those with the highest weight
gain were at greater risk for PE (94). Future studies, especially
in experimental animal models, should tease out the relative
importance of prepregnancy body weight versus gestational
weight gain in promoting and exaggerating the mechanisms
that promote PE. This could be accomplished in experimental
animals having high-fat diet or genetic obesity in combination
with adipose tissue transplant studies to increase fat content at
different time points through pregnancy.
With concern to fetal growth, a discrepant feature between
PE and obesity is that while PE is regularly accompanied by
intrauterine growth restriction, obesity is often associated with
macrosomia (201). However, different reports have found that
maternal obesity may also increase the risk for low birth weight
and intrauterine growth-restricted babies (135, 139, 141, 150).
Additionally, epidemiological studies have shown that gesta-
tional weight gain is independently associated with birth
weight and can contribute to the impact of obesity on fetal
growth (39, 40, 46, 51, 105) in a way that limiting gestational
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
weight gain in obese women reduces the odds of having a baby
with high birth weight. Furthermore, using a high-fat diet-
induced obesity model, Hayes et al. (64) observed that fetuses
of obese pregnant animals are lighter than fetuses of lean
counterparts. Interestingly, we have reported that individual
metabolic factors lead to distinct adverse fetal outcomes:
whereas euglycemic hyperinsulinemic pregnant rats presented
fetuses with increased body weight (128), hyperleptinemic
pregnant rats exhibited fetuses with decreased body weight
compared with normal pregnant controls (126). In vivo and in
vitro studies have demonstrated that obesity-related metabolic
factors can alter the placental transport of nutrients and then
lead to abnormal fetal growth (185). Therefore, it is possible
that the development of adverse fetal outcomes in obese
pregnancies might depend on the specific metabolic profile and
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the amount of weight gained during gestation.
Effects of Obesity on the Placental Function and Perfusion
The placenta is a pregnancy-specific organ of which its
existence foremost depends on its own ability to remodel blood
vessels in the uterine wall to meet its metabolic needs. For this
purpose, fetus-derived cytotrophoblasts are tasked with invad-
ing the uterine spiral arteries where they differentiate into an
endothelial cell-like phenotype while incorporating and repop-
ulating both the tunica intima and tunica media. This results in
transformation of the spiral arteries from high-resistance, low-
flow blood vessels into high capacitance conduits. In normal
pregnancy, sufficient remodeling occurs to meet the metabolic
demands of the growing uteroplacental-fetal unit. In contrast,
PE is associated with abnormal migration and invasion and
reductions in spiral artery remodeling and placental perfusion
(17, 184).
Reduced cytotrophoblast-mediated remodeling of spiral ar-
teries represents an attractive mechanism whereby obesity
could potentially increase the risk for the development of PE.
It has been shown that reduced serum levels of the angiogenic
factor placental growth factor (PlGF), which is an important
factor in the proliferative nature of trophoblast cells, is better at
predicting the development of PE in obese pregnant women
compared with underweight/lean counterparts when assessed
early in the second trimester (5, 56). This corroborates obser-
vations that obese women have reduced fetoplacental vascu-
larity characterized by villi having large diameters and low
numbers of capillaries (42). In addition, there is evidence
showing that the degree of muscularity in the uteroplacental
vasculature of obese women is greater than nonobese controls
(147).
Therefore, it is reasonable to hypothesize in some cases that
obesity may promote placental ischemia. This hypothesis is
also supported by indirect evidence. It has been shown that
there is a reduction in the fetus/placenta weight ratio (a marker
of placental efficiency) with increased maternal BMI, which is
in stark contrast to the 40-fold increase in this value seen from
6 wk of gestation to term in normal pregnancy (9, 187). Indeed,
reductions in placental efficiency are linked to compensatory
increases in placental growth and hypertrophy (7, 112). Hig-
gins et al. (67) found that obesity is associated with placental
hypertrophy along with reduced cell turnover, which are both
characteristics of a fetal hypoxic insult (37, 85). These findings
suggest that obesity-related metabolic factors may attenuate

LINKING OBESITY TO PREECLAMPSIA RISK
cytotrophoblast-mediated spiral artery remodeling thereby
contributing to the development of placental ischemia-induced
hypertension.
Experimental evidence supports that high-fat diet (HFD)-
induced obesity adversely affects placental perfusion. Strong
findings by Frias et al. (52) showed that 4 years of HFD (32%
calories from fat) in pregnant monkeys increased maternal
body weight and reduced placental perfusion measured in the
third trimester. They calculated placental volume blood flow
(cQUV) to estimate the blood flow on the fetal side of the
placenta. The authors indicated that cQUV is reduced in preg-
nancies accompanied by intrauterine grow restriction. Interest-
ingly, their HFD-fed monkeys segregated into those that had
statistically significant increases in body weight (HFD sensi-
tive) and those that did not (HFD resistant) compared with their
control diet (14% calories from fat) counterparts. The HFD-
resistant group had reduced uterine artery volume blood flow
that was even greater in the HFD-sensitive group with placen-
tal volume blood flow being reduced only in the latter (Fig. 2).
These data indicate that obesity per se is deleterious to pla-
cental perfusion. To begin probing the mechanisms responsible
for the reduced placental perfusion, these authors found that
circulating levels of the obesity-related metabolic factors leptin
and insulin were significantly increased only in the HFD-
sensitive group, and this was accompanied by higher placental
protein levels of the pro-inflammatory factors toll-like receptor
(TLR)-4, monocyte chemoattractant protein (MCP-1), and in-
terleukin-1␤. Blood pressure was not examined in this study in
monkeys (52). However, it was found in rats maintained on a
HFD from 3 to 19 wk of age that there were not only increases
in body weight, serum leptin levels, and a immunohistochem-
ical marker of placental hypoxia (carbonic anhydrase) but also
elevated systolic blood pressure as measured by tail-cuff pleth-
ysmography on gestational day 15 (52, 64). These animal
studies provide credence to the hypothesis that obesity-related
A B
*
15
1 4
cQutv (mL/min/kg)
Body Weight (kg)
10
5
0 0
Control HFD R HFD S
C D
* placental volume blood flow. *P ⬍ 0.05 vs. control
100
Plasma Leptin (ng/mL)
Plasma Insulin (ng/mL)
80
60
40
20
0 0
Control HFD R HFD S
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
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R1329
metabolic factors and inflammation can induce placental isch-
emia or decrease the threshold whereby placental ischemia
leads to hypertension in pregnancy.
While human and experimental studies in animals suggest
that diet-induced obesity may affect placental function and
perfusion, the pathophysiological mechanisms whereby meta-
bolic factors alter the proliferation, migration, and invasion of
cytrotrophoblast cells and uteroplacental vascular remodeling
and these influences on placental ischemia have yet to be fully
elucidated. Although the pathophysiological mechanisms re-
sponsible for the abnormal placental trophoblast invasion and
vascular remodeling in PE are unclear, a number of factors
have been recently implicated in placentation including the
Notch signaling pathway. This pathway consists of the Notch
receptors numbered 1– 4 and the Notch ligands Jagged 1–2 and
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Delta 1 and 3– 4. The formation of Notch receptor-ligand
complexes on adjacent cells or even by acting in an autocrine
fashion is important in orchestrating cell movements (138).
Indeed, Dr. Susan Fisher’s group demonstrated that Notch 2 is
crucial for proper migration and integration of cytotrophoblasts
into the spiral arteries of mice. They showed that mice lacking
Notch 2 in trophoblast cells had significant reductions in
uteroplacental vascular diameters (76). Blood pressure was not
examined in her study. However, it has been shown in human
placental tissue collected from hypertensive pregnancies and
intrauterine growth restricted pregnancies that there is reduced
Notch 1 (target p21), Notch 2, Notch 4, and reduced Jagged 1
and Jagged 2 (29, 155). These data support a connection
between reduced Notch signaling and the pathogenesis of PE.
At this time there is only indirect evidence supporting that
obesity disrupts Notch signaling in cytotrophoblast cells. It has
been shown that adipose tissue multipotent stem cells isolated
from morbidly obese individuals express reduced levels of Hey
proteins, which are downstream targets of Notch signaling
(151). Furthermore, circulating levels of Delta(DLK)1, which
3
2
*
1
Fig. 2. High-fat diet (HFD) increases maternal
body weight (A) and reduces placental volume
Control HFD R HFD S blood flow (B), which is accompanied by increased
plasma leptin (C) and insulin (D) levels in the third
trimester of pregnancy in baboons. Control, control
diet; R, HFD resistant; S, HFD sensitive; cQutv,
80
*
and HFD R. From Frias AE et al. (52).
60
40
20
Control HFD R HFD S
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R1330 LINKING OBESITY TO PREECLAMPSIA RISK

binds and stimulates apoptosis of Notch 2 expressing cells, are
increased in obese humans (23, 197). While these data provide
some evidence that obesity may attenuate Notch signaling,
cytotrophoblast migration, and uteroplacental vascular mor-
phogenesis, more research needs to evaluate how metabolic
factors impact the Notch signaling pathway.
The mechanisms whereby obesity may cause disruption of
cytotrophoblast migration and placental uterovascular morpho-
genesis are unclear but may be associated with the metabolic
disturbances that occur in obesity such as hyperlipidemia,
hyperinsulinemia, or hyperleptinemia. These factors are known
to be elevated in plasma of obese pregnant women and in many
cases even higher in women with PE. Indeed, total serum
cholesterol levels in the first and second trimesters predict the
onset of PE (38). Cekmen et al. (21) showed increases in
enzyme (82). The major cleavage product of this enzyme is
ET-1. Trophoblast cells express ET precursors and receptors
(163). Fiore et al. (47) showed that exaggerated levels of ET-1
trigger placental villi to produce reactive oxygen species,
which promote trophoblast apoptosis (47, 116). Placentas from
preeclamptic pregnancies have increased placental oxidative
stress and ET-1 binding (8, 22). These data are interesting in
light of the findings that mice with HFD-induced obesity and
insulin resistance have placental oxidative stress and reduc-
tions in trophoblast numbers (96).
As a caveat, the studies showing that increased insulin levels
over the course of pregnancy increases blood pressure in rats
were confounded by the effect of insulin-induced hypoglyce-
mia. However, we have recently shown that increasing insulin
levels toward the end of pregnancy (from gestational days

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low-density lipoprotein (LDL) cholesterol and its transport
protein apolipoprotein B along with reductions in high-density
lipoprotein (HDL) cholesterol in PE over normal pregnancy.
Mechanistically, LDL, in particular its oxidized form, can
reduce extravillous cytotrophoblast migration and promotes
trophoblast apoptosis (95, 131). Oxidized cholesterols, termed
14 –19) while maintaining euglycemia also raises blood pres-
sure in rats (128) (Fig. 3). These data highlight that hyperin-
sulinemia could be a major player in the mechanisms whereby
obesity increases the risk for PE.
A 180

Plasma Glucose (mg/dL)

oxysterols, inhibit first trimester trophoblast cell function and
decrease glial cell missing-1 (GCM-1) (6). GCM-1 is impor-
tant for fusion of syncytiotrophoblasts and the formation of the 120
maternal-fetal interface (97). In addition, hypertriglyceridemia
increases the risk for PE (70, 186). Genetic manipulations that
increase triglycerides by knocking out apolipoprotein E in mice
60
promote hypertension and proteinuria by the end of pregnancy
(104). Placentas from these animals have increased levels of
apoptotic markers including BAX, bcl-1, and caspase-3, and
electron microscopy illustrated increased trophoblast apopto- 0
Pregnant Pregnant + Insulin
sis. Free fatty acid levels are increased in obesity and are
elevated in PE (44, 45). Furthermore, free fatty acids can
activate the nuclear receptor peroxisome proliferator-activated B 20

*
Serum Insulin (μU/mL)

receptor-␥ (PPAR-␥), whose expression is increased in placen-

tas from preeclamptic pregnancies and signal to inhibit the 15
invasiveness of trophoblast cells (69, 175). However, normal
pregnant rats treated with a PPAR-␥ antagonist from gesta-
10
tional days 11–15 developed increased blood pressure, protein-
uria, endothelial dysfunction, reduced fetal weight, and placen-
tal abnormalities. In addition, reduced plasma VEGF and 5
increased plasma and placental sFlt-1 were observed following
administration of the PPAR-␥ antagonist (111). Conversely,
0
treatment of RUPP rats with a PPAR-␥ agonist ameliorated Pregnant Pregnant + Insulin
hypertension, improved vascular function, and reduced mi-
croalbumin-to-creatinine ratios. Therefore, the role of PPAR-␥ C
in mediating trophoblastic invasion and other features of PE 125
Mean Arterial Pressure

requires further investigation.

A hallmark of many forms of obesity is insulin resistance 115
*
and hyperinsulinemia. A higher rate of hyperinsulinemia oc-
(mmHg)

curs in preeclamptic versus normal pregnancy in humans

105
(107). Experimental evidence directly linking hyperinsulin-
emia to the development of hypertension in pregnancy was
demonstrated in pregnant rats where chronic infusion of insulin 95
beginning 1 week before pregnancy and then continued
throughout gestation raised insulin levels and increased blood
85
pressure when measured at the end of pregnancy (136). Sub- Pregnant Pregnant + Insulin
sequent studies in this model showed that insulin reduced PlGF
Fig. 3. Euglycemic (A) hyperinsulinemia (B) elicits hypertension (C) in
and arrested trophoblast invasion in the uterus (168). Intrigu- Sprague-Dawley pregnant rats. Insulin was infused at 1.5 mU·kg⫺1·day⫺1
ingly, it was noted that the trophoblasts in placentas from the from gestational day 14 –19 while rats were provided with 20% glucose in
hyperinsulinemic rats expressed greater endothelin converting drinking water. *P ⬍ 0.05 vs. pregnant. From Palei AC et al. (128).

AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org


LINKING OBESITY TO PREECLAMPSIA RISK
Leptin is an adipokine whose levels rise in parallel with
increasing adiposity and has been shown to mediate obesity-
induced hypertension (160). Obese preeclamptic women have
the greatest circulating leptin levels compared with lean pre-
eclamptic women and lean and obese normotensive pregnant
women (65, 115). Furthermore, leptin levels are greater in
severely preeclamptic women compared with women whose
pregnancies are solely complicated by chronic hypertension,
which suggests that leptin is a link between obesity and PE
(180). Indeed, studies have shown that leptin reduces cytotro-
phoblast proliferation (98) and reduces PlGF production from
BeWo cells (202). Trophoblastic cells do express leptin recep-
tors (199). Furthermore, leptin has been shown to activate the
transcription factor hypoxia inducible factor (HIF)-1␣ in breast
cancer cells (61). Because cytotrophoblast proliferation occurs
early in pregnancy, before migration and invasion of these cells
into the uterus (54), these data suggest that hyperleptinemia
may play a role in obesity-induced placental ischemia and PE.
Although it has been consistently found that placental isch-
emia/hypoxia induces hypertension in pregnant experimental
models, the mechanisms whereby placental dysfunction elicits
maternal hypertension in humans seem to be much more
complicated. It has been shown that early development of
placental dysfunction may not always be the consequence of
chronic ischemia/hypoxia. There are studies with findings
ranging from data showing that placentas from women with PE
have elevated expression of the hypoxia marker HIF-1␣ to data
that there are increased oxygen tensions in PE placentas.
Although these data may conflict one another at first glance,
there are events that may occur within the placenta during the
development of PE that may unify such opposing data. This
includes ischemia-reperfusion (IR) injury. For example, it
seems that low oxygen tension is considered to be in the
physiological range for placental tissue and allows for proper
trophoblast proliferation in early pregnancy. In a review by
Huppertz et al. (77), it was detailed that during the first
trimester, the embryo develops at low oxygen tension below 20
mmHg. This is before maternal blood flow is established
through the uterine spiral arteries and into the intervillous
spaces bathing the fetal villous structures where nutrient and
oxygen exchange take place (77). If there were to be an early
escape of maternal blood from spiral arteries, this could lead to
premature increases oxygen levels in the vicinity of the devel-
oping trophoblast cells. It has been demonstrated that abnormal
spiral artery remodeling is associated with increased, not re-
duced, oxygen levels in placentas from pregnancies compli-
cated by hypertension (with and without proteinuria) or intra-
uterine growth restriction (79 – 81, 164). Thus this sequence of
events seems similar to what is seen with IR insults (72–75).
First, it is known that IR injury induces increased expression of
the transcription factor HIF-1␣ in tissues such as liver (32).
HIF-1␣ levels are greater in placental tissue from preeclamptic
versus normal pregnant women (140). Second, it is established
in tissues such as the heart, liver, and brain that bouts of
ischemia reduce oxygen consumption (133, 179, 196), which
would seemingly result in heightened levels of oxygen and
oxidative stress during reperfusion. In vitro IR injury increases
oxidative stress in the term human placenta in villous endo-
thelial, trophoblast, and stromal cells (71). Regarding tropho-
blast function, oxidative stress produced by xanthine oxidase
elicits apoptosis in isolated extravillous trophoblast cells,
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
Review
R1331
which are those that are derived from proliferating trophoblast
cells (118). There is increased apoptosis of first trimester
extravillous trophoblasts from pregnancies at higher risk for
developing PE with elevated uterine artery resistance (198). It
is important to direct our understanding of how obesity and its
accompanying metabolic factors affect early placental devel-
opment and that high oxygen tensions may in fact be delete-
rious to placental development and function. Indeed, it has
been shown in vitro that high glucose levels reduce prolifera-
tion of a first trimester trophoblast cell line only at high oxygen
tensions (53). Immunohistochemical data from term villous
tissue from obese patients have decreased villous proliferation
(67). Therefore, the development of a model of placental IR
injury may mimic more closely the development of PE in
humans, and we predict this injury would be exacerbated in the
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face of obesity.
Effects of Obesity on the Release of Soluble Placental
Factors
Angiogenic imbalance. The cascade of events linking pla-
cental ischemia to maternal hypertension has been a subject of
intense focus in our laboratory and others. While both placental
and circulating levels of VEGF and PlGF are reduced in
preeclamptic women, the levels of the VEGF/PlGF receptor
sFlt-1 are elevated (27, 102, 143, 161, 193). By using the
RUPP model, we have shown that placental ischemia/hypoxia
elicits the release of sFlt-1 (58). The latter is thought to occur
largely via activation of the transcription factor HIF-1␣ (176).
Sequestration of circulating VEGF and PlGF by sFlt-1 inhibits
their proangiogenic and provasodilatory actions. Supplemen-
tation of VEGF significantly attenuates placental ischemia-
induced hypertension (59). Confirmation that sFlt-1 is capable
of elevating blood pressure during PE is evidenced from
infusion studies whereby increasing sFlt-1 levels to mimic
those found in preeclamptic women promotes the development
of hypertension in pregnant rats (120).
There are fewer investigations examining sFlt-1 levels in
obese pregnancies. For instance, Masuyama et al. (108) re-
ported that sFlt-1 levels in an obese hypertensive pregnancy
were greater than those in obese normotensive pregnancy in
early and late pregnancy. Supportive of this increase in sFlt-1
is the finding that obese preeclamptic women have lower levels
of PlGF, which typically rise during healthy pregnancy, than
nonobese preeclamptic women (108). There are several lines of
evidence suggesting that this may be due to the actions of
obesity-related metabolic factors. Indeed, leptin and insulin,
which are elevated in obesity and PE, both reduce PlGF release
from BeWo human trophoblastic cells (202). Furthermore, we
have collected data using an obese pregnant rat model having
increased body weight and fat mass at gestational day 19,
namely melanocortin-4 receptor heterozygous (MC4R⫹/⫺)
pregnant rats, suggesting that they have baseline levels (with-
out surgically induced placenta ischemia) of sFlt-1 that are
slightly elevated in the circulation; significantly increased in
adipose tissue; but not altered in placental tissue levels (Fig. 4)
(171). These animals also had slight elevations in leptin and
blood pressure. Intriguingly, we have data using ex vivo
placental explant experiments suggesting that sFlt-1 release is
greater under hypoxic conditions in obese pregnant MC4R⫹/⫺
versus control MC4R⫹/⫹ pregnant rats (Fig. 5), which suggests
Review
R1332 LINKING OBESITY TO PREECLAMPSIA RISK

A 400
Circulating (2). This may result in dilution of these soluble placental
factors in the maternal circulation. Also, the extracellular
matrix of adipose tissue expresses heparin sulfate proteogly-
sFlt-1 (pg/mL)

300
cans (106), which may lead to tissue retention of the sFlt-1
produced and sequestration of sFlt-1 from the circulation, in
200 addition to increased local action of sFlt-1 in pregnant women
with greater adipose mass. Therefore, it may not be that sFlt-1
production is reduced, but that there are confounding factors
100
(e.g., increased plasma volume and tissue retention) clouding
these measurements in obese pregnancies if their levels have
0 not reached the steady state between placental metabolic pro-
MC4R+/+ MC4R+/- duction and renal clearance rates.
Inflammatory factors. Proper maternal immune cell function
B is critical for establishment of the uteroplacental circulation.
*
0.08
Adipose
Evidence implicates a strong role of the innate immune system

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in the regulation of trophoblast function. Indeed, resident
sFlt-1 (pg/mg)

0.06
uterine natural killer (uNK) cells, which are the most abundant
leukocytes in early human and mouse decidua, regulate the
0.04 invasiveness of trophoblast cells and uterine vascular remod-
eling and angiogenesis. Knockout mouse studies have empha-
sized this whereby adoptive transfer of NK cells from Rag2⫺/⫺
0.02
mice (having NK cells but not T or B lymphocytes) into
BALB/c-Rag2⫺/⫺Il2⫺/⫺ mice (having no NK, T, or B cells)
0.00 fully reversed the uterine vascular defects found in the latter
MC4R+/+ MC4R+/- mouse (68). Moreover, coculture experiments of human uNK
and extravillous trophoblast cells with isolated spiral arteries
demonstrated that uNK cells certainly mediate spiral artery
C 1.0
Placenta
remodeling (149). In contrast, these cells isolated from women
0.8 destined to develop PE secrete less trophoblast invasion-pro-
sFlt-1 (pg/mg)

moting factors (145).

0.6 There are also findings that excessive activation of the innate
immune system promotes the etiopathology of PE (134). Im-
0.4 munohistochemical studies revealed that there is increased
expression of the CD14 macrophage marker in the decidua
0.2
basalis from preterm preeclamptic versus preterm control preg-
nancies (157). Interestingly, placental tissue from Type 1
0.0
diabetic women and from streptozotocin (STZ) diabetic rats
MC4R+/+ MC4R+/- had markers of increased pro-inflammatory M1 and decreased
anti-inflammatory M2 macrophages (166). In vitro experi-
Fig. 4. The soluble fms-like tyrosine kinase 1 (sFlt-1) levels in obese
MC4R⫹/⫺ versus MC4R⫹/⫹ pregnant rats are slightly but not significantly
ments from these investigators found that high glucose levels
elevated the circulation (A), elevated in adipose tissue (B); but similar in
placental tissue (C). The sFlt-1 was quantified using a mouse Flt-1 ELISA from
R&D Systems. *P ⬍ 0.05 vs. MC4R⫹/⫹ pregnant rats. From Spradley FT et 3000
al. (171).

*
sFlt-1 (pg/mg)

that placental ischemia raises sFlt-1 to a greater extent in obese

2000
pregnancies. These findings implicate metabolic factors as a
potential cause of angiogenic imbalance and further reduced
vasorelaxation in obese pregnancies. There are novel adipokine
factors including the serine protease adipsin, also known as 1000
factor D in the complement system, that are shown to be
released to a greater extent from placentas from obese pregnant
women (167) and whose levels are found to be greater in the 0
urine from preeclamptic women (167, 190). MC4R+/+ MC4R+/-
Human studies have also demonstrated reduced levels of 1% O2
placental factors such as sFlt-1 in obese preeclamptic women.
Straughen et al. (174) demonstrated that there are reduced Fig. 5. The release of sFlt-1 is greater under hypoxic conditions in placental
sFlt-1 levels in obese compared with normal weight pre- villous explants isolated from obese MC4R⫹/⫺ (n ⫽ 10) versus lean MC4R⫹/⫹
(n ⫽ 6) pregnant rats. Placental explant studies were conducted as previously
eclamptic women. However, one confounding factor could be described (55). The sFlt-1 was quantified using a mouse Flt-1 ELISA from
increased plasma volume during obese pregnancies, which has R&D Systems. Data are means ⫾ SE. *P ⬍ 0.05 vs. MC4R⫹/⫹ pregnant rats.
been demonstrated in pregnant rats fed a cafeteria-style diet These data are unpublished.

AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org


LINKING OBESITY TO PREECLAMPSIA RISK
activated pro-inflammatory genes belonging to TLR-dependent
pathways isolated rat placental macrophages. These data im-
plicate obesity and metabolic factors in promoting a pro-
inflammatory environment in the placenta.
The adaptive immune system has caught the attention of
researchers in the field of PE. Whereas normal pregnancy is
associated with a T helper (Th) 2 anti-inflammatory state, a
subpopulation of pro-inflammatory CD4⫹ T lymphocytes
termed Th17 cells characterized by production of the cytokine
IL-17 are increased in the peripheral blood of preeclamptic
patients in the third trimester compared with a control group
(35). A direct role for this immune cell population was defined
by LaMarca’s group (30) whereby an IL-17 inhibitor signifi-
cantly reduced RUPP-induced hypertension and AT1-AA lev-
els and that adoptive transfer of Th17 cells from RUPP rats
elicits increases in blood pressure and AT1-AA in normal
pregnant rats. Additionally, administration of a CD20 blocker
that acts through B lymphocyte depletion into RUPP rats
decreased circulating levels of AT1-AA and resulted in a
blunted blood pressure response to placental ischemia (90).
This group had also previously shown that CD4⫹ cells con-
tribute to circulating placental ischemia pro-inflammatory fac-
tors like TNF-␣ and can also activate B cells to produce
AT1-AA (124, 188). A direct role for obesity in activation of
the immune system during pregnancy and PE should be ad-
dressed as studies in other pro-inflammatory diseases such as
colitis have found that leptin receptors on CD4⫹ cells quicken
disease progression (165).
Inflammatory mechanisms have been shown to mediate
placental ischemia-induced production of sFlt-1 is via action of
AT1-AA on AT1 receptors in the placenta. We have shown
that RUPP increases circulating levels of AT1-AA (91). More-
over, AT1-AA infusion into normal pregnant rats increases
blood pressure and plasma sFlt-1 levels along with release of
sFlt-1 from placental explants from the same animals. These
effects were blocked by the AT1 receptor antagonist losartan
(130). Interestingly, we have recent evidence suggesting that
the placenta may not be the only source of circulating sFlt-1
levels in response to elevated circulating AT1-AA. With re-
spect to obesity, we showed in normal pregnant obese versus
lean rats that adipose tissue levels of sFlt-1 were significantly
greater accompanying a slight but nonstatistical increase in
circulating sFlt-1 with no difference in placental levels (171).
These data suggest that adipose tissue may contribute to the
circulating pool of sFlt-1. Data from Herse and colleagues (66)
showed that mature adipocytes isolated from humans do ex-
press and release sFlt-1 (Fig. 6). To determine whether in fact
AT1-AA can stimulate the release of sFlt-1 from adipose
tissue, we conducted adipose tissue explants studies. AT1-AA
was capable of increasing the release of sFlt-1 into culture
media verging on statistical significance (Fig. 6). However, it is
important to note that these acute studies were conducted using
adipose tissue from normal pregnant Sprague-Dawley rats.
Therefore, in the face of placental ischemia, obese pregnant
animals may have exaggerated circulating levels of sFlt-1, as a
consequence of a synergistic action of AT1-AA in the placenta
and adipose tissue, and a more profound pro-hypertensive
phenotype.
Release of the pro-inflammatory cytokine TNF-␣ is in-
creased in response to placental ischemia/hypoxia (132). We
have evidence showing that placental ischemia-induced hyper-
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
Review
R1333
tension increases placental mRNA and protein levels of TNF-␣
in pregnant rats (89). Supplementation with the TNF-␣ inhib-
itor etanercept significantly attenuates the development of
placental ischemia-induced hypertension in rats (89). In addi-
tion, we have recently demonstrated in vitro that acute hypoxia
increases TNF-␣ secretion from normal pregnant rat placental
explants (122). Similarly, hypoxia stimulated the release of
TNF-␣ from placental explants isolated from normal pregnant
women (11, 12, 132). Although hypoxia stimulated the same
degree of release of TNF-␣ from placental explants from
preeclamptic women, the levels under room oxygen and hyp-
oxia were actually less in this group (12). These data are
supported by in vivo studies from Conrad’s group (12) sug-
gesting that, at delivery, the placenta does not secrete greater
amounts of TNF-␣ during PE; this was because the peripheral
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and uterine venous TNF-␣ levels were 1.0, which was similar
to the values found in normal pregnant women. Even so, these
preeclamptic women did have greater peripheral and uterine
venous levels of TNF-␣ than normal pregnant women. This
study concluded that other sources than the placenta must
contribute to the greater circulating levels of TNF-␣ during PE.
In support of this notion, in already-preeclamptic women,
TNF-␣ mRNA levels were greater in peripheral blood leuko-
cytes from healthy pregnant women versus those with PE (26).
Future investigations should be carried out to determine
whether initial insults to the placenta, such as in placental
ischemia, lead first to increases in placental TNF-␣ levels that
may subsequently feedforward to activation of placental and
circulating immune cells levels that then autonomously main-
tain elevated cytokine levels instead of the diseased placenta
during the clinical manifestations of PE.
With regard to obesity, TNF-␣ mRNA levels have been
demonstrated to be greater in peripheral blood mononuclear
cells and placental macrophages isolated from obese compared
with lean pregnant women (24). We found that circulating
levels of TNF-␣ are increased in obese MC4R⫹/⫺ pregnant rats
along with elevations in circulating leptin (171). While human
data have shown that hyperleptinemia is positively associated
with PE (114), the long-term effect of hyperleptinemia on
blood pressure during pregnancy is unknown. We recently
tested the hypothesis that chronic circulating leptin elevations
in pregnant rats increases blood pressure and placental factors
known to play a role in PE (126). On gestational day 14,
normal pregnant rats were infused with leptin at a rate to mimic
plasma levels in obesity. We found that hyperleptinemia in
pregnancy resulted in significant increases in blood pressure
and placental TNF-␣ expression despite reductions in food
intake and body weight. The blood pressure response to leptin
observed in our pregnant rats [change in mean arterial pressure
(⌬MAP) ⬃ 20 mmHg] was higher than that documented in
previous studies using male rats (⌬MAP ⬃ 6 – 8 mmHg) (160).
Interestingly, a recent report found that acute intracerebroven-
tricular infusion of leptin enhances renal sympathetic activity,
but not MAP, in nonpregnant female rats (162). This effect of
leptin on stimulating renal nerves was observed only during the
estrous phase, suggesting that high estrogen levels may exag-
gerate the blood pressure response to hyperleptinemia.
Whether the exaggerated blood pressure response to leptin
during pregnancy is due to the hyperestrogenemic state of
pregnancy or to an effect of leptin on placental function is
unknown and remains to be investigated.
Review
R1334 LINKING OBESITY TO PREECLAMPSIA RISK

sFlt-1 release (fmoles/g/48h)

30 1500
* 20
*
15

sFlt- (pg/ml)
20 1000
sFlt-1/18s

10

10 500
5
n.d n.d * *
0 0 0
ADSC mature Control ADSC 3 days 5 days Tissue- SC cells mature
Adipocytes nonfat cells Adipocytes
mature Adipocytes

20
P=0.056

Downloaded from http://ajpregu.physiology.org/ by 10.220.33.2 on June 8, 2017

Media sFlt-1 (pg/mg)

15

10

0
ue

A
-A
ss

T1
Ti

+A
se

ue
po

ss
di

Ti
A
P

se
N

po
di
A
P
N

Fig. 6. Top, left: mRNA expression of sFlt-1 in isolated adipose-derived stem cells (ADSCs) and isolated mature adipocytes from human adipose tissue; *P ⬍
0.01. Middle: release of sFlt-1 from ADSCs incubated for 5 days and mature adipocytes incubated for 3 or 5 days; *P ⬍ 0.05 for 3 vs. 5 days; n.d., not detectable.
Right: release of sFlt-1 from adipose tissue nonfat cells, stromal vascular cells (SV cells) and mature adipocytes; *P ⬍ 0.01 vs. adipose tissue nonfat cells. From
Herse et al. (66). Bottom: stimulation with AT1-AA promotes sFlt-1 release from adipose tissue explants isolated from normal pregnant (NP) Sprague-Dawley
rats. Adipose explant (⬃100 mg) were incubated in F12K supplemented with media (DMEM containing 4 mM L-glutamin, 4,500 mg/l glucose, 1 mM sodium
pyruvate, 1,500 mg/l sodium bicarbonate, 4 g/l BSA, and 1% PenStrep) in the presence or absence of AT1-AA (1:100 dilution) for 48 h, at which time media
were collected and assayed for sFlt-1 as previously described (171). n ⫽ 3 rats/group. Data are means ⫾ SE. Data in bottom panel are unpublished.

There are limitations in currently available animal models Effects of Obesity on Placental Ischemia-Induced
of PE. Although the RUPP model serves as an excellent Endothelial and Arterial Smooth Muscle Cell Dysfunction
system to study the impact of placental ischemia on mater- and Hypertension
nal cardiovascular-renal function, which will be discussed
in the succeeding section, this system does not provide The endothelium is very important in the control of vascular
mechanistic insight into earlier causes of placental dysfunc- tone homeostasis and blood pressure. Studies using the RUPP
tion such as trophoblast-mediated spiral artery remodeling. rat model of placental ischemia have shown that placental
This is because the symptoms in the RUPP model are ischemia/hypoxia stimulates production of soluble inflamma-
induced after midpregnancy. However, a spontaneous model tory and anti-angiogenic placental factors that are capable of
of superimposed PE in the Dahl salt-sensitive rat has been entering into the maternal circulation where they target the
evaluated (60). These animals have hypertension before endothelium. These factors cause vascular dysfunction by
pregnancy and develop dramatic pregnancy-induced in- reducing nitric oxide (NO) bioavailability and increasing ET-1
creases in blood pressure all the while being maintained on production (36, 83). Endothelial dysfunction has been detected
normal-salt rodent chow compared with spontaneously hy- in obese pregnancies. A study comparing obese versus lean
pertensive rats (SHR) that are hypertensive before preg- pregnant women demonstrated that obesity was associated with
nancy and normotensive Sprague-Dawley controls. This elevated blood pressure and reduced endothelium-dependent
model has great promise for studying the early pathogenesis vasorelaxation in skin arteries (142, 173). It was not shown
of PE and the potential for deleterious actions of obesity and whether this was dependent on reductions in NO levels or
related metabolic factors on this process. activity of the endothelial enzyme that produces NO (endothe-

AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org


LINKING OBESITY TO PREECLAMPSIA RISK
lial NOS; NOS3). However, these investigators did find that
there was reduced responsiveness to the exogenous NO donor
sodium nitroprusside (SNP) in these arteries suggesting that
this dysfunction lies in part to reduced smooth muscle respon-
siveness to NO. These data are reminiscent to findings in male
rabbits fed a high-cholesterol diet,which has been shown in
other studies to elicit increases in serum total and LDL cho-
lesterol and reduced serum HDL cholesterol, where there was
reduced proximal descending aortic response to acetylcholine
as well as NO (195). With regard to the latter, it was found that
isolated smooth muscle cells from these hypercholesterolemic
rats had reduced responsiveness to NO-mediated inhibition of
ANG II-induced increases in intracellular calcium suggestive
of attenuation in the capacity of NO to buffer vasoconstriction.
These data collectively show an association between obesity
and its accompanying metabolic dysfunction, such as hyper-
cholesterolemia, and disruption of NO signaling in control of
blood vessel tone. Furthermore, they suggest that obesity
increases the sensitivity for developing endothelial and smooth
muscle dysfunction, and thus hypertension, in response to
placental ischemia factors due to reduced bioavailability and
the vasoconstrictive buffering power of NO.
The studies mentioned above also showed that obese women
enter pregnancy with preexisting endothelial dysfunction.
However, it seems that the degree that pregnancy increased
endothelium-dependent relaxation was similar between the
obese versus lean groups even though the absolute values were
still greater in the lean pregnant women (173). These data
indicate that pregnancy-induced vasorelaxation is not altered
by obesity. It should be examined whether these mechanisms
are similar between obese and lean pregnancies. A complete
understanding of these mechanisms could lead to discoveries
about novel targets of placental ischemia during obesity. Fur-
thermore, studies should examine the association of maternal
obesity with PE in the context of obesity-induced preexisting
endothelial dysfunction versus pregnancy-induced vascular
dysfunction that may occur during excessive gestational weight
gain. It was found in women having supra-physiological ges-
tational weight gain, that is, rates of weight gain of ⬎0.42
kg/wk, presented with markers of reduced NOS3 activity and
vasorelaxation in isolated umbilical vein rings (129).
Studies in humans and animals support that elevated mater-
nal sFlt-1 promotes the development of hypertension accom-
panied by reduced NO production in systemic and renal circu-
lations (109, 120). The infusion of sFlt-1 into pregnant
Sprague-Dawley rats elicits hypertension and reduces both
endothelium-dependent vasorelaxation responses to acetylcho-
line and smooth muscle responsiveness to SNP in carotid artery
rings (16, 178). This endothelial dysfunction was significantly
curtailed by treating the rings with the oxidative stress scav-
enger tiron, whereas the reduced response to SNP was not as
influenced by tiron. Thus sFlt-1-induced hypertension is ac-
companied by oxidative stress-mediated endothelial dysfunc-
tion. The reduced NO responsiveness of the underlying vascu-
lar smooth muscle cells seems to be dependent on alterations in
calcium flux across the plasma membrane. Indeed, smooth
muscle cells isolated from renal interlobular arteries from
RUPP rats, which have increased circulating levels of sFlt-1,
have enhanced and maintained ANG II-, KCl-, and calcium
channel antagonist-induced intracellular calcium levels and
cell contraction compared with normal pregnant rats (119).
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
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R1335
These data support that placental ischemia elicits endothelial
and vascular smooth muscle cell dysfunction.
Indirect evidence to support that obesity exaggerates the
deleterious effects of sFlt-1 on pregnancy was demonstrated by
the finding that diet-induced obese pregnant mice infused with
sFlt-1 have offspring that go on to develop the highest blood
pressures when compared nonobese and noninfused controls
(20).More direct data about the combined actions of sFlt-1 and
obesity on maternal vascular function comes from studies
showing that pro-angiogenic factors are important for vasore-
laxation responses to hormones during healthy pregnancy.
Indeed, treatment of rat and mouse small renal arteries with
recombinant human relaxin significantly attenuated myogenic
constriction, which was blocked by VEGF receptor antago-
nism, VEGF neutralizing antibodies, or NOS inhibition. In-
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triguingly, it has been shown in high-fat diet-induced over-
weight female Wistar Hannover rats that there is reduced
effectiveness of relaxin to promote flow-mediated vasodilation
and blunt phenylephrine-induced vasoconstriction and the
myogenic response, which was in part mediated by reduced
signaling to NOS (113, 183). Thus aberrations in the action of
VEGF to promote the ability of relaxin to stimulate NOS in the
blood vessel wall could consequently allow for exaggerated
dysfunction in response to placental factors like sFlt-1 in
obesity. This is perhaps especially true if the blood vessel is
strongly dependent on NO signaling to maintain vascular tone.
Foremost, we have shown that pregnancy dramatically in-
creases the control of blood pressure on NOS whereby NOS
inhibition in Sprague-Dawley rats increases blood pressure
more in pregnant rats versus age-matched nonpregnant con-
trols. We have shown that sFlt-1 infusion blunts glomerular
NO production much to the extent as seen with maximal NOS
inhibition implicating the NO system as the target of sFlt-1-
mediated hypertension during placental ischemia. With regard
to obesity, it seems that obese females have increased NO
bioavailability whereby nitrite/nitrate levels, as a surrogate
marker of NO, are positively correlated with body fat in obese
women (28). This may be an explanation to why high-fat
diet-induced obesity promotes greater hypertension in male
than female mice (63). Along these lines, we have shown
greater endothelium-dependent vasorelaxation to acetylcholine
(ACh) and to the NO donor SNP in small mesenteric arteries
from genetically obese MC4R⫹/⫺ pregnant rats (Fig. 7) (171).
The latter suggests that vascular tone control in these obese rats
is more dependent on NO signaling. However, it is not yet
understood what is the cause of this increased NO signaling.
Perhaps there is a change in the components of ACh-induced
relaxation in these mesenteric arteries from the genetically
obese pregnant rats, such as a shift from endothelial hyperpo-
larizing factor (EDHF)-mediated to NO-mediated relaxation. It
was shown in male Wistar rats with diet-induced obesity that
ACh-mediated vasorelaxation in coronary arterioles is main-
tained similar to that of their lean counterparts because of
increased smooth muscle response to NO, which was mediated
by increased soluble guanylate cyclase (sGC) function (78). As
a result, the SNP response was increased in these obese rats.
This is in contrast to conduit arteries like the aorta, which
typically have reduced ACh response with no change in SNP
responsiveness all accompanied by reduced endothelial NOS
expression. For instance, this occurs in the face of high-fat
diet-induced obesity in female mice (84). These data suggest
Review
R1336 LINKING OBESITY TO PREECLAMPSIA RISK
A
Relaxation (% of PE)
0
25
50
75
100
Fig. 7. Endothelial-dependent responses to
acetylcholine (ACh) (A; left: concentration-
response curve, right: logEC50 sensitivity)
and endothelial-independent responses to so-
dium nitroprusside (SNP) (B; left: concentra-
tion-response curve, right: logEC50 sensitiv-
ity) are enhanced in third-order mesenteric
arteries from obese MC4R⫹/⫺ pregnant ver- B
sus lean MC4R⫹/⫹ pregnant rats. *P ⬍ 0.05
0
Relaxation (% of PE)
vs. MC4R⫹/⫹ pregnant rats. From Spradley et
al. (171).
25
50
75
100
that the potentially compensatory increase in NO signaling in
small and resistance arteries during obesity in pregnancy may
predispose these types of blood vessels to greater vascular
dysfunction in response to soluble placental ischemic factors,
which are known to reduce NO bioavailability. Future studies
will probe whether this holds true in the uteroplacental and
renal circulations. Further studies should address whether there
is increased sGC function in our obese model and whether
there are regional differences NO-sGC signaling during obesity
in pregnancy, such as in mesenteric versus uteroplacental
arteries. Whether this increased NO vasorelaxation is also
dependent on deficiency of the MC4R receptor itself or if it is
mediated by increased body weight or altered circulating met-
abolic factors such as their elevated leptin levels is yet to be
determined. In this regard, it is has been shown that exogenous
leptin has the capability to increase NO dependency of blood
pressure regulation (87). Moreover, leptin infusion into male
mice resulting in levels similar to those in our obese pregnant
rats attenuated ANG II-induced endothelial dysfunction (10).
Thus the contribution of NO and NO-dependent mechanisms to
vascular dysfunction during obesity in pregnancy and pre-
eclampsia is still unclear. In summary, it is not clear what role
NO sensitivity of blood vessel tone has on placental ischemia-
induced hypertension in obesity. From the above discussions,
we propose that obesity exaggerates placental ischemia-in-
duced release of soluble placental factors such as sFlt-1 sub-
sequently leading to greater reduction in NO bioavailability
culminating in accentuated placental ischemia-induced hyper-
tension during obesity.
Inflammatory cytokines such TNF-␣ have also been impli-
cated in PE and many other cardiovascular diseases including
patients with essential hypertension (191, 200). Our previous
studies showed that placental ischemia stimulates production
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
15
ACh
*
-logEC50, M
10
5
MC4R+/+
MC4R+/-
0
15 14 13 12 11 10 9 8 7 6 5 MC4R+/+ MC4R+/-
-log[ACh, M]
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9 SNP
*
-logEC50, M
8
7
MC4R+/+
MC4R+/-
6
10 9 8 7 6 5 MC4R+/+ MC4R+/-
-log[SNP, M]
of placental TNF-␣ and increases circulating levels of this
cytokine in pregnant rats (92). Furthermore, we have shown
that infusion of TNF-␣ into normal pregnant rats elicits hyper-
tension and reductions in renal and systemic vascular NO
systems (3, 57). Circulating, adipose tissue, and placental
levels of TNF-␣ levels are increased in obese women (18, 19,
24, 86). Founds et al. (50) performed a study to examine
whether TNF-␣ may be a potential mechanistic link between
obesity and PE. They used four groups of pregnant women,
namely, lean, lean preeclamptic, obese, and obese preeclamptic
(50). There are several important observations to be gleaned
from this study: 1) obese preeclamptic women had the greatest
blood pressures, 2) blood pressure and TNF-␣ levels were
increased in obese versus lean control subjects, and 3) TNF
levels were the greatest in the preeclamptic patients but were
not different from the obese and lean preeclamptic groups. On
the surface, this third finding may seem disappointing. How-
ever, this might indicate that more TNF-␣ is bound to its
receptor thereby exerting more biological activity and vascular
dysfunction in obese preeclamptic women or that, in obesity,
less TNF-␣ is needed to promote vascular dysfunction. In
support of this theory, although only performed in male mice,
it was demonstrated that HFD-induced obesity is associated
with greater TNF-␣-induced impairment of endothelium/NO-
mediated vasorelaxation in resistance arteries isolated from
white adipose tissue even though plasma levels of this cytokine
were similar between normal diet and HFD groups (41). It
should be considered that this phenomenon may result from
local production of TNF-␣ in adipose or the vasculature per se
that can impact arterial function without reaching the circula-
tion. Thus future studies should assess both circulating TNF-␣
levels and local vascular levels of not only TNF-␣ but also the
TNF receptor in obese preeclamptic women. While existing

LINKING OBESITY TO PREECLAMPSIA RISK
8
TNF-α alone
20 μU/mL insulin
Media ET-1 (pg/mL)
6
4
* preeclamptic group (153), with some studies suggesting that
2 of the peptide. Local renal and endothelial production of ET-1
0 soluble placental ischemia factors TNF-␣, AT1-AA, or sFlt-1
0 5 50
TNF-α (ng/mL)
Fig. 8. Insulin exaggerates tumor nerosis factor-␣ (TNF-␣)-induced release of
endothelin-1 (ET-1) from human umbilical vein endothelial cells (HUVECs).
One million cells were seeded into 6-well plates and allowed to grow until 70%
confluent at which time they were serum starved for 36 h then treated with
TNF-␣ or in combination with insulin at levels observed in obese preeclamptic
women (20 ␮U/ml) for 8 h. ET-1 levels were measured in HUVEC-condi-
tioned media as previously described (89). n ⫽ 3– 6 wells/group. Data are
means ⫾ SE. *P ⬍ 0.05 vs. 0 TNF-␣; †P ⬍ 0.05 vs. corresponding TNF-␣
group. These data are unpublished.
data suggest that placental ischemia-induced endothelial dys-
function and hypertension may be exaggerated in obese versus
lean pregnancies via a TNF-␣-dependent mechanism, the im-
portance of inflammatory cytokines in the pathophysiological
mechanisms whereby obesity increases the risk for developing
PE remains unclear. Moreover, whether maternal immune
tolerance mechanisms that include interactions between regu-
latory CD4⫹ T cells and uNK cells play a role in obese
pregnancies also remains to be determined.
Recent studies have also suggested an important role for
ET-1 in the pathophysiology of PE. ET-1 is the most potent
vasoconstrictor known. ET-1 is derived from a longer 203
amino acid precursor known as preproendothelin, and the
active peptide is proteolytically cleaved into its final 21 amino
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
Review
R1337
acid form. ET-1 exerts its powerful vasoconstrictor effects via
the endothelin type A (ETA) receptor located on vascular
smooth muscle cells. Multiple studies have examined circulat-
ing levels of ET-1 in normal and preeclamptic pregnant
women. They have found elevated levels of plasma ET-1 in the
the level of circulating ET-1 correlates with the severity of the
disease symptoms (123), although this is not a universal
finding (158). ET-1, however, is produced locally in the vas-
culature and plasma levels typically do not reflect tissue levels
is exaggerated in placental ischemic conditions (121, 148). We
have shown that the hypertensive responses to infusion of the
into normal pregnant rats and in response to RUPP are pre-
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vented by antagonism of the ETA receptor (88, 93, 121, 177).
It is thought that the increased production of ET-1 and its
hypertensive actions during placental ischemia are a result of
reduced NO bioavailability. Support for this comes from in
vivo studies in male rats showing that falls in single nephron
GFR (SNGFR) and glomerular plasma flow following systemic
NOS inhibition with NG-nitro-L-arginine methyl ester (L-
NAME) were prevented with the ETA/ETB antagonist bosentan
(137). More recent ex vivo functional data have gone on to
demonstrate that the concomitant ET-1-mediated reductions in
SNGFR and plasma flow seem to be dependent on signaling
through the ETA receptor to produce stronger vasoconstriction
in mouse microperfused afferent over efferent arterioles. L-
NAME was able to exaggerate ET-1-induced constriction only
in the latter (156). With regard to pregnancy, L-NAME reduces
renal blood flow by 35% by the end of gestation in Sprague-
Dawley rats (1), and we have shown that sFlt-1 and L-NAME
induce similar degrees of hypertension and reductions in glo-
merular production of NO (120). In sFlt-1-infused pregnant
rats, the increase in renal cortical mRNA levels of preproET-1,
which is the precursor to ET-1, was reduced by supplementa-
tion with the NOS cofactor L-arginine. Together, support that
NOS functionally tempers the production and hemodynamic
effects of ET-1 in the kidney, and that when NOS is targeted
Fig. 9. Hypothetical scheme whereby obesity and obesity-
related metabolic factors act in the cascade of events lead-
ing to enhancement of placental ischemia-induced hyper-
tension. We propose that these metabolic factors may act
individually or in combination to potentiate dysfunctional
uteroplacental vascular remodeling, exaggerate the release
of soluble placental factors into the maternal circulation,
and to exaggerate the maternal cardiovascular-renal re-
sponses to these soluble placental-ischemia factors. This
may occur in a feed-forward fashion subsequently exagger-
ating the downstream actions of these metabolic factors.
Review
R1338 LINKING OBESITY TO PREECLAMPSIA RISK
and inhibited by placental ischemic factors like sFlt-1, this
allows ET-1 to elicit the development of maternal hyperten-
sion.
Obesity is associated with over activation of the ET system.
Overweight and obese humans have enhanced ET-1-mediated
endothelial dysfunction (194). An ETA receptor antagonist
attenuated HFD-induced hypertension in rats having increased
visceral obesity and leptin levels (34). Indirect evident suggests
that this pathway is augmented in obese preeclamptic situa-
tions. For example, studies in nonpregnant animals and humans
have demonstrated that obesity is associated with increased
ET-1-induced vasoconstriction and ET-1-mediated reductions
in endothelium-dependent vasorelaxation (117, 194). Intrigu-
ingly, there are data showing that the adipokine chemerin,
whose levels are increased in PE (172), augments ET-1-
induced vasoconstriction (99). In summary, we believe that one
potential mechanism whereby obesity and obesity-related met-
abolic factors may increase the risk of developing PE is by
enhancing placental factor (sFlt-1, TNF-␣, AT-1AA)-induced
production of ET-1. In fact, we have novel data showing that
TNF-␣-induced ET-1 production from human umbilical vein
endothelial cells (HUVECs) is exaggerated in the presence of
high obese levels of insulin (Fig. 8).
It is recognized that both obesity and PE are complex health
disorders associated with multiple genetic and environmental
traits. Although they share many pathophysiological mecha-
nisms as we have discussed in the review, not all obese
pregnant women develop PE. Indeed, a 30% increase in the
risk, as most epidemiological studies examining the impact of
obesity on the rates of PE have found, predicts that only 10%
of obese women will develop the disease (146). Human studies
suggest that preeclamptic patients express exaggerated meta-
bolic profiles, including hyperleptinemia, hyperinsulinemia,
insulin resistance, and hyperlipidemia, which precedes the
appearance of the clinical symptoms (25, 38, 100, 169). In-
triguingly, in vitro and in vivo studies have shown that de-
pending on the concentration of obesity-related metabolic fac-
tors, there are beneficial or detrimental effects on placental-
fetal development and vascular function (33, 62). We and
others (146) believe that obese pregnant women having an
extremely abnormal metabolic profile are at increased risk to
develop PE. Furthermore, as obese pregnant women have
endothelial dysfunction before the development of PE, it is
likely that obesity may decrease the threshold at which the
combination of obesity-related metabolic factors and soluble
placental ischemic factors elicit cardiovascular dysfunction and
hypertension. Thus, the greater the BMI is during pregnancy,
the greater the likelihood of decreasing this threshold for
developing PE.
Perspectives and Significance
Growing evidence implicates obesity as a major risk factor
for the development of PE, a hypertensive disease of preg-
nancy (14). This is bolstered by demographic data indicating
that there is a high prevalence of PE in the southern United
States, a region with significantly high obesity rates. Impor-
tantly, the concurrence of obesity and PE is a worldwide
phenomenon. Confirmation of a relationship between obesity
and PE has been shown in Brazil, Colombia, United Kingdom,
Finland, Japan, Kazakhstan, Portugal, Trinidad, Tobego, and
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00178.2015 • www.ajpregu.org
Australia. This highlights the importance of understanding the
mechanisms linking these two pathologies. Foremost, the
pathophysiology of PE is a two-stage process with placental
and maternal origins. Reductions in cytotrophoblast migration
and uterine spiral artery remodeling are strongly tied to pla-
cental ischemia. This insult stimulates the placenta to release
soluble antiangiogenic and inflammatory factors into the ma-
ternal circulation favoring endothelial and vascular dysfunction
and hypertension. Because this cascade of events is thought to
play an important role in the pathogenesis of PE, it is likely that
obesity-related metabolic factors may increase the risk of
developing PE by impinging on these pathophysiological pro-
cesses. Therefore, in this review, we propose that obesity
impacts the various stages thought to encompass the pathogen-
esis of PE by 1) acting on the placenta causing cytotrophoblast
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.2 on June 8, 2017
dysfunction and placental ischemia and dysfunction, 2) en-
hancing ischemia/hypoxia-induced release of soluble placental
factors, and 3) increasing the sensitivity by which placental
ischemia-factors are able to promote endothelial dysfunction
and hypertension (Fig. 9). Because of the alarming increase in
the prevalence of obesity, the strong correlation between BMI
and PE rates, and the fact that PE is a major cause of maternal
and perinatal morbidity and mortality, a better understanding
of how obesity impacts the pathogenesis of PE remains to be a
critical area of investigation.
GRANTS
This work was supported by National Heart, Lung, and Blood Institute
Grants 5P01HL051971-22 and 1R01HL108618-01 (to J. P. Granger),
2T32HL105324-06 (to F. T. Spradley), and 14POST18970005 (to A. C. Palei).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: F.T.S., A.C.P., and J.P.G. conception and design of
research; F.T.S. and A.C.P. interpreted results of experiments; F.T.S. prepared
figures; F.T.S. drafted manuscript; F.T.S., A.C.P., and J.P.G. edited and
revised manuscript; F.T.S., A.C.P., and J.P.G. approved final version of
manuscript.
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