Eric M. George and Joey P. Granger
Linking Placental Ischemia and Hypertension in Preeclampsia: Role of Endothelin 1
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Linking Placental Ischemia and Hypertension
Role of Endothelin 1
Eric M. George, Joey P. Granger
sion presenting after the 20th week of gestation and is
accompanied by increasing levels of proteinuria and often
edema.1The overall prevalence of preeclampsia is ?8% with
higher incidence in specific ethnic subpopulations, notably
blacks.2,3The disorder is predominantly a complication of
primiparous women, who have a 3-fold higher incidence rate
than multiparous women. There are a number of known
factors that convey elevated risk of developing preeclampsia,
notably elevated body mass index, and a previous incidence
of preeclampsia, because women who experienced pre-
eclampsia in previous pregnancies are 7 times more likely to
exhibit preeclamptic symptoms in subsequent pregnancies
than those with no history of preeclampsia.4It has also been
shown that high body mass index can double the risk of
preeclampsia, and the scale of obesity correlates directly with
the increase risk of developing the disorder.5Although the
link between these risk factors seem logical, there are also a
number of other risk factors (maternal age, induced abortions,
interpregnancy interval, and socioeconomic factors) for
which the links to preeclampsia are not as clear.6More
research is warranted into the mechanistic effect of these
factors in the etiology of preeclampsia.
There are currently no definitive treatment options for the
resolution of preeclampsia. Available interventions are con-
fined to magnesium sulfate for the prophylaxis of seizures
and the administration of one of various antihypertensive
agents, although normalization of blood pressure is not
normally possible, and the disease continues to progress.1
Indeed, the only effective resolution of preeclampsia is
delivery of the placenta, because delivery of the fetus alone is
not sufficient.7,8It is this fact that suggested the pathological
origins of the development of preeclampsia. Although the
underlying molecular mechanisms that lie at the root of
preeclampsia are not clear, it is believed that a major
causative agent is placental insufficiency resulting from
inadequate remodeling of the maternal vasculature.9During
normal pregnancy, fetally derived cytotrophoblasts invade the
ne of the most pervasive disorders of pregnancy is
preeclampsia, which is defined as new-onset hyperten-
maternal spiral arteries of the uterus, replace the maternal
endothelium, and undergo differentiation into an endothelial-
like phenotype. This causes a conversion of the high-
resistance, small-diameter vessels into high-capacitance, low-
resistance vessels and ensures adequate delivery of maternal
blood to the developing uteroplacental unit.7,10In the pre-
eclamptic patient, unknown errors in this carefully orches-
trated scheme lead to inadequate delivery of blood to the
developing uteroplacental unit and create hypoxia and
chronic ischemia within the placenta.11In response, the
placenta produces pathogenic factors that enter the maternal
bloodstream and are responsible for the clinical manifesta-
tions of the disorder. Among the factors known to be
released, antiangiogenic and autoimmune/inflammatory fac-
tors have received a great deal of attention. Interestingly,
recent evidence suggests that these agents have a final
common pathway, activation of the endothelin 1 (ET-1)
There are several lines of evidence that suggest a patho-
genic role for ET-1 in the preeclamptic patient. A number of
studies looking at circulating levels of ET-1 in preeclamptic
women have generally demonstrated significantly higher
levels of circulating ET-1 in the plasma of preeclamptic
patients when compared with healthy controls, with some
suggestion that a genetic polymorphism could play a role in
the variation of ET-1 levels.12–16However, circulating levels
of ET-1 are not necessarily good indicators of ET-1 produc-
tion in the tissues because of the fact that ET-1 secretion is
directional, with a larger proportion of the peptide being
released on the basolateral side of the endothelium, and tissue
levels may not be accurately reflected in the levels of ET-1 in
the circulation. Studies indicating elevations in ET-1 in
preeclamptic placental cells are perhaps more telling, al-
though this is not a universal finding.17,18Finally, one report
has indicated an increase in endothelin-converting enzyme in
the circulation of preeclamptic patients compared with nor-
mal pregnant controls, suggesting a potential mechanism for
enhanced local production of ET-1.19These data support
earlier studies demonstrating increased endothelin-converting
Received March 6, 2012; first decision March 19, 2012; revision accepted April 12, 2012.
From the Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular Research, University of Mississippi Medical
Center, 2500 N State St, Jackson, MS.
This paper was sent to Robert M. Carey, Consulting editor, for review by expert referees, editorial decision, and final disposition.
Correspondence to Joey P. Granger, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson,
MS 39216. E-mail firstname.lastname@example.org
© 2012 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.orgDOI: 10.1161/HYPERTENSIONAHA.112.194845
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enzyme production by endothelial cells exposed to pre-
eclamptic serum.20There are also indications that matrix
metalloproteinase 2, which can also cleave big endothelin
women.21,22These findings suggest at least a correlation
between ET-1 and preeclampsia in humans and warrant
Because studies on pregnant women are, at best, compli-
cated, a number of experimental animal models have been
used to examine the etiology and development of preeclamp-
sia. One that we and others have used with great success is the
reduced uterine perfusion pressure (RUPP) model, which
mechanically restricts blood flow to the placenta, leading to
hypoxia and ischemia. This model has been used in species
ranging from rats to nonhuman primates and mimics a
number of the pathological features of human preeclampsia,
including hypertension, angiogenic imbalance, renal injury,
proteinuria, and endothelial dysfunction.23–25In studies
where human endothelial cells were exposed to serum from
RUPP rats in vitro¸ it was shown that RUPP sera significantly
induced production of ET-1 from the endothelial cells when
compared with those exposed to serum from normal pregnant
animals, suggesting that circulating factors produced by
placental ischemia are responsible for increased vascular
ET-1 production.26Initial in vivo studies suggested that both
the renal cortex and medulla of RUPP rats express signifi-
cantly higher levels of the ET-1 precursor, preproendothelin,
at the mRNA level when compared with normal pregnant
controls (Figure 1B and 1C). Crucially, when an endothelin A
(ETA) receptor antagonist was administered to the RUPP rats,
the associated hypertension was abolished (Figure 1A), and
there was a trend for increased renal function.27These studies
suggest that placental ischemia induces factors that activate
the production of ET-1 in the vasculature, which acts through
ETAreceptors to mediate the hypertension seen in this model.
Whether similar ETAantagonism could prove effective in
preeclamptic women remains to be seen.
Soluble Fms-Like Tyrosine Kinase 1
One of the most intensely studied pathways in the manifes-
tation of preeclampsia is the vascular endothelial growth
factor (VEGF) signaling pathway. VEGF, other than its role
in angiogenesis, has an important role in the maintenance of
proper endothelial cell function and health. This signaling
pathway came to prominence with the discovery of elevated
circulating and placental levels of the soluble form of the
VEGF receptor, Flt-1, denominated soluble Fms-like tyrosine
kinase 1 (sFlt-1).28,29sFlt-1 acts as a direct inhibitor of VEGF
by binding to the protein and preventing it from being
available for its normal function.30Subsequent studies look-
ing at the regulation of sFlt-1 in cell culture and placental
tissue in vitro have demonstrated that sFlt-1 is released from
placental villi and trophoblast cells in response to reduced
oxygen tensions similar to that seen in the ischemic pla-
centa.31–33A promising recent pilot study demonstrated that
sFlt-1 could be removed from the maternal circulation by
apheresis safely and that this therapy reduced both blood
pressure and proteinuria, with a trend toward increased
A number of groups have also reported that artificial
elevation of sFlt-1 in animal models, either by direct infusion
or by viral overexpression, leads to hypertension, renal injury,
and proteinuria, all symptomatic of preeclampsia.29,35–41
These results are supported by clinical data showing that
patients receiving the anti-VEGF antibody therapy Bevaci-
zumab, which functions in much the same way as sFlt-1,
exhibit marked proteinuria and hypertension.42Kappers et
al43also reported that Sunitinib, a tyrosine kinase inhibitor
which targets the VEGF receptor, induces a reversible rise in
BP in patients and in rats associated with activation of the
ET-1 system and generalized microvascular dysfunction.
Finally, the same group recently reported that VEGF inhibi-
tion with Sunitinib in pigs results in endothelin-mediated
hypertension in pigs.44This suggests that another potential
mechanism whereby VEGF blockade could increase BP is by
enhancing ET-1 synthesis.
Several reports have been made into the role of the ET-1
system in models of sFlt-1 overexpression in preg-
nancy.29,35,36In support of ET-1 as a mediator of sFlt-1–
induced hypertension, our group has reported recently that
continuous infusion of sFlt-1 in pregnant rats directly in-
creased the level of ET-1 in the renal cortex and resulted in an
increase in the mean arterial pressure of ?20 mmHg (Figure
2). Tellingly, with coadministration of an ETAreceptor
antagonist, the hypertension associated with this model was
completely abolished, strongly supporting ET-1 as an impor-
tant mediator of sFlt-1–induced hypertension.36
One of the earliest and most persistent theories about the
origins of preeclampsia view it as a disorder of immunity. In
NP RUPP NP RUPP
Figure 1. Effect of endothelin A (ETA)
antagonism on reduced uterine perfusion
pressure (RUPP)–induced hypertension.
As seen in A, RUPP-treated animals
exhibit significant hypertension when
compared with normal pregnant con-
trols. This hypertensive response is com-
pletely blocked by administration of an
ETAselective antagonist. In both the
renal cortex (B) and medulla (C), RUPP
treatment significantly increases the
expression of preproendothelin relative
to ?-actin mRNA as determined by
RNase protection assays. (*P?0.05).
Adapted from Alexander et al.27
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fact, there is a growing realization that autoimmunity plays a
pivotal role in the symptomatic phase of the disorder and
perhaps the early etiology of the disease as well.45–47The
autoimmune components of preeclampsia can be compart-
mentalized into 2 headings, the production of autoantibodies
and the innate immune response. In the first category, much
attention has been focused on the production of agonistic
angiotensin II type 1 receptor autoantibodies (AT1-AAs),
which have been found in the circulation of women with
preeclampsia and verified in several experimental models.
Even more clearly characterized is the innate inflammatory
response mediated by inflammatory cytokines. The impor-
tance of these 2 components has begun to be elucidated, and
several experimental approaches have been used to under-
stand their role in the development of preeclampsia.
One well-characterized component of the innate immune
response to preeclampsia is the production of tumor necrosis
factor-? (TNF-?), which is elevated in both preeclamptic
women and rodents undergoing chronic placental isch-
emia.48–50Previous studies in vitro demonstrated that produc-
tion of ET-1 by endothelial cells could be driven by exposure
to TNF-?.51Studies from our group have demonstrated that
administration of the soluble TNF-? receptor Etanercept is
capable of attenuating the hypertension associated with pla-
cental ischemia in pregnant rats. This treatment is associated
with reduced expression of the preproendothelin in the renal
cortex and medulla, as well as the placenta itself.50It has also
been shown that infusion of TNF-? directly induced hyper-
tension in pregnant rats, producing an ?20-mmHg increase
in mean arterial pressure in late gestation. This is associated
with a significant increase in the expression of preproendo-
thelin in the maternal vasculature, placenta, and kidney. As in
the RUPP model, coadministration of an ETAreceptor antag-
onist in these animals completely abolished the associated
hypertension (Figure 3).52Together, these data suggest that
TNF-? is an important component of the hypertensive re-
sponse to placental ischemia and that ET-1, acting through
the ETAreceptor, is a crucial mediator of TNF-?–induced
A relatively recent addition to the immune component of
preeclampsia is the agonistic AT1-AAs. These antibodies
were originally isolated just over a decade ago in preeclamp-
tic women and have since been found in the circulation of rats
undergoing placental ischemia.53,54Interestingly, these anti-
bodies appear to be induced by the production of TNF-?,
because infusion of TNF-? to pregnant rats also results in
production of the antibody at levels comparable to those seen
in pregnant women and the RUPP rat.54It has also been
demonstrated that infusion of the AT1-AAs directly into
pregnant rats results in moderate hypertension that is associ-
ated with increased preproendothelin expression in both the
renal cortex and placenta. Again, administration of an ETA
receptor antagonist abrogated the hypertensive response to
the AT1-AA, suggesting its importance in the manifestation
of AT1-AA–induced hypertension (Figure 4).55However, the
pathogenic importance of these antibodies remains to be fully
elucidated, because their presence has been noted postpartum
in a subset of preeclamptic patients with no discernible
phenotype.56,57It is likely, then, that these antibodies act
NP sFlt-1 NP sFlt-1
PreproET-1 (fold change)
Figure 2. Soluble Fms-like tyrosine kinase 1 (sFlt-1) induces
hypertension through endothelin 1 (ET-1) induction. Infusion of
sFlt-1 significantly increases mean arterial pressure (MAP) in preg-
nant rats. This hypertensive response is completely blunted with
administration of an endothelin A (ETA)-selective antagonist (A).
Production of preproendothelin mRNA is significantly increased in
the renal cortex by sFlt-1 infusion (B). *P?0.05 vs controls;
#P?0.05 vs sFlt-1–infused rats. Adapted from Murphy et al.36
NP TNF NP TNF
Figure 3. Tumor necrosis factor (TNF)-? induces hypertension
through endothelin 1 (ET-1) induction. Infusion of TNF-? signifi-
cantly increases mean arterial pressure (MAP) in pregnant rats.
This hypertensive response is completely blunted with adminis-
tration of an endothelin A (ETA)–selective antagonist. *P?0.05 vs
controls, #P?0.05 vs TNF-?–infused rats. Adapted from
LaMarca et al.52
NP AT1-AA NP AT1-AA
Figure 4. Angiotensin II type 1 receptor autoantibody (AT1-AA)
induces hypertension through endothelin 1 (ET-1) induction. Infu-
sion of AT1-AA significantly increases mean arterial pressure (MAP)
in pregnant rats, an effect that is blocked by an endothelin A (ETA)–
selective antagonist. *P?0.05 vs controls, #P?0.05 vs AT1-AA–
infused rats. Reprinted from LaMarca et al55with permission of the
publisher. Copyright © 2009, American Heart Association, Inc.
George and GrangerEndothelin 1 in Preeclampsia
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more as modulators of the hypertensive phenotype begun by
other pathogenic factors rather than as first-cause agents
directly, possibly by enhancing the response of the ET-1
system. Further studies are needed to determine how these
antibodies interact with the other pathogenic agents in pre-
eclampsia to produce the clinical phenotype.
Given the myriad of experimental models of preeclampsia
(placental ischemia, sFlt-1 infusion, TNF-? infusion, and
AT1-AA infusion), which have proven susceptible to ETA
antagonism, could the ET-1 system be a therapeutic approach
in managing the hypertension associated with preeclampsia?
Excitement at this approach has been tempered by work
showing that genetic knockout of the ETAreceptor leads to
birth defects and eventual embryonic lethality in mice.58As a
result, administration of endothelin receptor antagonists is
contraindicated in pregnancy.59However, studies that have
examined pharmacological antagonism of the ETAreceptor
during pregnancy in rats have identified specific windows of
development in early and midgestation in which the agents
caused phenotypes similar to that seen in the knockout.
Administration of the ETAantagonist only during late gesta-
tion was not performed, and it is entirely possible that ETA
receptor antagonists might prove safe and efficacious in later
pregnancy, when the symptoms of preeclampsia are most
severe.60We have also demonstrated recently that induction
of heme oxygenase 1 in both placental ischemia and sFlt-1–
induced hypertension significantly blunts blood pressure, in
part by reducing vascular production of preproendothelin 1,
suggesting another mechanism through which the ET-1 sys-
tem could be targeted for the management of preeclampsia
(Figure 5).61,62Alternatively, development of ETAreceptor
antagonists that do not cross the placental barrier would
circumvent these problems altogether. Further work to deter-
mine the transmission of existing agents, as well as the
development of new antagonists, could provide a truly
effective therapy for the management of hypertension in the
Sources of Funding
This work was supported by National Institutes of Health grants
HL51971, HL108618–01, and 1T32HL105324–01 and a postdoctoral
fellowship from the American Heart Association (11POST7840039).
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George and Granger Endothelin 1 in Preeclampsia
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