Am J Physiol Heart Circ Physiol 294: H541–H550, 2008.

First published November 30, 2007; doi:10.1152/ajpheart.01113.2007. Invited Review

Pathophysiology of hypertension during preeclampsia: linking placental

ischemia with endothelial dysfunction
Jeffrey S. Gilbert, Michael J. Ryan, Babbette B. LaMarca, Mona Sedeek, Sydney R. Murphy,
and Joey P. Granger
Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University
of Mississippi Medical Center, Jackson, Mississippi

Gilbert JS, Ryan MJ, LaMarca BB, Sedeek M, Murphy SR, Granger JP.
Pathophysiology of hypertension during preeclampsia: linking placental ischemia
with endothelial dysfunction. Am J Physiol Heart Circ Physiol 294: H541–H550,
2008. First published November 30, 2007; doi:10.1152/ajpheart.01113.2007.—
Studies over the last decade have provided exciting new insights into potential
mechanisms underlying the pathogenesis of preeclampsia. The initiating event in
preeclampsia is generally regarded to be placental ischemia/hypoxia, which in turn
results in the elaboration of a variety of factors from the placenta that generates
profound effects on the cardiovascular system. This host of molecules includes
factors such as soluble fms-like tyrosine kinase-1, the angiotensin II type 1 receptor
autoantibody, and cytokines such as tumor necrosis factor-␣, which generate
widespread dysfunction of the maternal vascular endothelium. This dysfunction
manifests as enhanced formation of factors such as endothelin, reactive oxygen
species, and augmented vascular sensitivity to angiotensin II. Alternatively, the
preeclampsia syndrome may also be evidenced as decreased formation of vasodi-
lators such as nitric oxide and prostacyclin. Taken together, these alterations cause
hypertension by impairing renal pressure natriuresis and increasing total peripheral
resistance. Moreover, the quantitative importance of the various endothelial and
humoral factors that mediate vasoconstriction and elevation of arterial pressure
during preeclampsia remains to be elucidated. Thus identifying the connection
between placental ischemia/hypoxia and maternal cardiovascular abnormalities in
hopes of revealing potential therapeutic regimens remains an important area of
investigation and will be the focus of this review.
kidney; pregnancy; nitric oxide; vascular endothelial growth factor; cytokines

PREECLAMPSIA, a pregnancy-specific syndrome characterized by development of suitable animal models for mechanistic re-
new onset hypertension and proteinuria, is a considerable search of this disease (72). Consequently, it is held by many
obstetric problem and a significant source of maternal and that more effective strategies for prevention and treatment of
neonatal morbidity and mortality (12, 95). Although pre- preeclampsia shall be forthcoming with the recent progress in
eclampsia and related hypertensive disorders of pregnancy developing animal models that allow careful mechanistic in-
continue to affect ⬃8% of all pregnancies, the incidence of vestigation of the underlying pathophysiological mechanisms
preeclampsia has seen a 40% increase in recent years (81). involved in preeclampsia (32).
Moreover, it has recently been recognized that women who
endure preeclampsia are at a greater risk for cardiovascular Placental Ischemia/Hypoxia and the Etiology
disease than nonpreeclamptic women and the men who fa- of Preeclampsia
thered those preeclamptic pregnancies (37). Despite thorough
characterization of the preeclamptic syndrome and a suite of Although the pathophysiology of preeclampsia remains un-
contributing circulating factors (12, 77, 80, 95), the mecha- defined, placental ischemia/hypoxia is widely regarded as a
nisms underlying the pathogenesis of this troubling condition key factor (24, 28, 80). Inadequate trophoblast invasion leading
remain nebulous. Interestingly, it has been proposed that not to incomplete remodeling of the uterine spiral arteries is
only are increased circulating factors responsible for much of considered to be a primary cause of placental ischemia (24).
the preeclamptic syndrome, but they may also predispose the Thus the poorly perfused and hypoxic placenta is thought to
maternal cardiovascular system to subsequent endothelial dys- synthesize and release increased amounts of vasoactive factors
function as the mother ages (20). such as soluble fms-like tyrosine kinase-1 (sFlt-1), cytokines,
The uncertainties regarding the mechanisms of preeclampsia and possibly the angiotensin II (ANG II) type 1 receptor
are at least partially attributable to difficulties faced in the autoantibodies (AT1-AA) (24, 66, 78, 79, 111). Figure 1
illustrates a model by which these and other candidate mole-
Address for reprint requests and other correspondence: J. P. Granger, Dept. of
cules are thought to induce widespread activation/dysfunction
Physiology and Biophysics, Univ. of Mississippi Medical Ctr., 2500 N. State St., of the maternal endothelium in vessels of the kidney and other
Jackson, MS 39216-4505 (e-mail: jgranger@physiology.umsmed.edu). organs that ultimately results in hypertension.
http://www.ajpheart.org 0363-6135/08 $8.00 Copyright © 2008 the American Physiological Society H541
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
Invited Review
H542 PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION
Fig. 1. Pathways by which reduced uterine perfusion pressure
(RUPP) and placental ischemia may lead to endothelial and
cardiovascular dysfunction during pregnancy. Placental ischemia
results in increased synthesis of soluble fms-like tyrosine kinase-1
(sFlt-1), TNF-␣ and IL-6, angiotensin II type 1 receptor autoan-
tibodies (AT1-AA), and thromboxane (TX). Elevations in these
factors are proposed to result in endothelial dysfunction by
decreases in bioavailable nitric oxide (NO) and increased reactive
oxygen species (ROS) and endothelin-1 (ET-1), which in turn
results in altered renal function, increased total peripheral resis-
tance (TPR), and ultimately hypertension. PlGF, placental growth
factor.
Perhaps the most prominent molecule postulated to play a
key role in the pathogenesis of preeclampsia is sFlt-1. Several
lines of evidence (15, 41, 42, 47, 50, 51, 74, 93, 103, 104, 117)
support the hypothesis that the ischemic placenta contributes to
endothelial cell dysfunction in the maternal vasculature by
inducing an alteration in the balance of circulating levels of
angiogenic/antiangiogenic factors such as vascular endothelial
growth factor (VEGF), placental growth factor (PlGF), and
sFlt-1. Although recent data suggest that circulating sFlt-1
concentrations may presage the clinical onset of preeclamptic
symptoms (47, 51, 75, 106), several studies indicate that
placental hypoxia and poor placental perfusion may initiate this
imbalance of angiogenic factors (61, 71). Nevertheless, it
remains unclear whether impaired placental perfusion initiates
preeclamptic symptoms such as hypertension, endothelial dys-
function, and increased sFlt-1 or whether inadequate placental
development occurs initially and is followed by a pathological
rise in sFlt-1 expression and secretion (41).
Hypertension associated with preeclampsia develops during
late pregnancy and remits after delivery or termination of the
pregnancy, suggesting that the placenta is a central culprit in
the disease. The foremost hypothesis regarding the initiating
event in preeclampsia is postulated to be reduced placental
perfusion that, in turn, leads to widespread dysfunction of the
maternal vascular endothelium. Although numerous other fac-
tors including genetic, immunological, behavioral, and envi-
ronmental influences have been implicated in the pathogenesis
of preeclampsia (95, 96), the main focus of this review is to
describe the links between placental ischemia/hypoxia and the
cardiovascular dysfunction that is widely recognized as a part
of the preeclampsia syndrome.
Reduced Uterine Perfusion Pressure as a Model to Study the
Pathophysiology of Hypertension During Pregnancy
The physiological mechanisms that mediate the alterations
in cardiovascular and renal function that are requisite for a
successful pregnancy have been studied in great detail. None-
AJP-Heart Circ Physiol • VOL
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
theless, experimental data investigating the mechanisms under-
lying preeclampsia have been limited because of the difficulty
in performing mechanistic studies in pregnant women. Al-
though several animal models have been developed to study
preeclampsia, none to date completely represents the protean
characteristics of the human syndrome. Furthermore, informa-
tion on the mechanisms mediating the long-term increase in
vascular resistance and arterial pressure associated with pla-
cental ischemia is lacking.
Experimental induction of chronic uteroplacental ischemia
appears to be a promising animal model to study potential
mechanisms of preeclampsia since reductions in uteroplacental
blood flow in a variety of animals lead to a hypertensive state
that has many of the manifestations present in preeclamptic
women (5–7, 9 –11, 18, 22, 31, 33, 48, 49, 61, 94). It is
important to note that the reduced uterine perfusion pressure
(RUPP) model of placental ischemia-induced hypertension in
pregnancy most closely relates to severe premature/preterm
preeclampsia and not late-onset preeclampsia. The former is
characterized by intrauterine growth restriction, hypertension,
and proteinuria, whereas the latter is not regarded as mediated
by placental ischemia and is usually not associated with intra-
uterine growth restriction. Thus a considerable strength of the
RUPP model is that it allows mechanistic investigation of the
preterm ischemic placenta and the factors it elaborates.
The relationship between reduced uteroplacental perfusion
and hypertension during pregnancy has been demonstrated in a
variety of animals, mostly those with hemochorial placenta-
tion. Previous studies have shown that chronic RUPP via
partial ligation or placement of silver clips on the lower
abdominal aorta or uterine arteries results in proteinuric hyper-
tension in the baboon (18, 19, 61), rhesus monkeys (22, 124),
rabbit (5, 59), and the dog (6, 35). Our laboratory has estab-
lished a RUPP model in the pregnant rat (7, 9 –11, 31, 33, 48,
49, 94). In this model, uteroplacental perfusion is reduced by
⬃40% by the placement of silver clips on the aorta and ovarian
arteries on day 14 of a 21-day gestation (94). On gestation day
294 • FEBRUARY 2008 • www.ajpheart.org
 Invited Review
PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION H543
19, the RUPP animals display increased mean arterial pressure
(MAP), decreased glomerular filtration rate, decreased renal
pressure natriuresis, decreased renal plasma flow and protein-
uria, and endothelial dysfunction (7, 9 –11, 26, 31, 33, 48, 49).
Recently, we demonstrated that these pregnant RUPP rats have
increased total peripheral resistance, decreased cardiac index,
and decreased uteroplacental blood flow (94), indicating that
these animals have marked cardiovascular dysfunction similar
to what is observed in preeclamptic women (11a, 17, 94, 109).
We have also recently shown that RUPP hypertension in the rat
is associated with an imbalance of angiogenic factors, in
particular increased sFlt-1 and decreased VEGF and PlGF (30).
Thus these models of preeclampsia have many of the features
common in preeclamptic women and provide researchers with
a valuable substrate from which to investigate the mechanisms
of hypertension during pregnancy.
The role of a variety of endothelial, autacoid, and hormonal
factors that mediate the cardiovascular and renal dysfunction
produced by chronic reductions in uteroplacental perfusion
pressure will be the primary focus of the remaining portion of
this review. In the present review, we will also focus on the
effects of reductions in uteroplacental perfusion pressure on
vascular endothelial function since factors that emanate from
the ischemic placenta are thought to be responsible for wide-
spread chronic long-term alterations in arterial pressure.

Mediators of Endothelial Dysfunction in Response to

Placental Ischemia
The maternal vascular endothelium appears to be an impor-
tant target of factors that are triggered by placental ischemia/
hypoxia in preeclampsia. The endothelium is a single-cell
lining that covers the luminal side of blood vessels. This
strategic location permits it to signal alterations in hemody-
namics and humoral factors by synthesizing and releasing
vasoactive substances. Thus a critical balance exists between
endothelium-derived relaxing and contracting factors that
maintain vascular homeostasis. When this delicate balance is
disrupted, the vasculature is predisposed to vasoconstriction,
leukocyte adherence, mitogenesis, prooxidation, and vascular
inflammation (100, 101). Furthermore, markers of endothelial
dysfunction may serve as predictors of the syndrome in women
that develop preeclampsia since many are often elevated weeks
before observance of clinical manifestations.
Nitric oxide. Substantial evidence indicates that nitric oxide
(NO) production is elevated in normal pregnancy and that these
increases appear to play an important role in the renal vasodi-
latation of pregnancy (97). In contrast, the role of NO in
preeclampsia remains enigmatic (25, 76, 91).Taken together,
these studies underscore the need for continued investigation
into the (patho)physiological role of NO in preeclampsia.
Studies from several laboratories indicate that chronic NO
synthase inhibition in pregnant rats produces hypertension
associated with peripheral and renal vasoconstriction, protein-
uria, intrauterine growth restriction, and increased fetal mor-
bidity (23, 43). We have previously reported similar cardio-
vascular perturbations exist in the NO inhibition and RUPP
models, the latter illustrated in Fig. 2 (94). In addition, we have
also previously shown that placental ischemia results in the
impairment of acetylcholine-mediated vasorelaxation and that
nitrite and nitrate productions in aortic strips are both de-
AJP-Heart Circ Physiol • VOL
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
Fig. 2. Reduced uterine perfusion pressure elicits increased mean arterial
pressure (MAP; A), decreased cardiac index (CI; cardiac output/body weight;
B), and increased TPR (C) in late gestation rats. NP, normal pregnant. All data
are expressed as means ⫾ SE. *P ⬍ 0.05. Graph adapted from Sholook et al.
(Ref. 94).
creased in the RUPP rat compared with normal pregnant rats,
shown in Fig. 3 (26). Chronic RUPP in pregnant rats also
decreases renal protein expression of neuronal NO synthase but
not urinary nitrite/nitrate excretion relative to control pregnant
rats (9). Although no difference in urinary nitrite/nitrate excre-
tion was found between RUPP and control pregnant rats, we
have found that basal and stimulated release of NO from
isolated vascular strips were significantly lower in RUPP rats
(13). Although, whether there is a reduction in NO production
in this spontaneous model of pregnancy-induced hypertension
remains unclear.
Oxidative stress. During oxidative stress, an imbalance of
pro- and antioxidant factors results in endothelial dysfunction,
either by direct actions on the vasculature or through reduc-
tions in the bioavailability of vasoactive mediators (113).
Oxidative stress may mediate endothelial cell dysfunction and
contribute to the pathophysiology of preeclampsia based on
evidence of increased prooxidant activity along with decreased
antioxidant protection. During preeclampsia, oxidative stress
294 • FEBRUARY 2008 • www.ajpheart.org
Invited Review
H544 PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION
Fig. 3. Acetylcholine (ACh)-induced relaxation of vascular strips precon-
stricted with phenylephrine (3 ⫻ 10⫺7 mol/l) (A) and the basal and ACh-
induced nitrite/nitrate production (B) in endothelium-intact aortic strips of NP
and RUPP rats. Adapted from Crews et al. (Ref. 26).
may result from interactions between the maternal component
that may include preexisting conditions such as obesity, dia-
betes, and hyperlipidemia and/or the placental component that
may involve secretion of lipid peroxides (79).
Several important antioxidants are significantly decreased in
women with preeclampsia. Vitamin C, vitamin A, vitamin E,
␤-carotene, glutathione levels, and iron-binding capacity are
lower in the maternal circulation of women with preeclampsia
than in women with a normal pregnancy. Interestingly, sup-
plementation does not appear to ameliorate the incidence of
preeclampsia in multicenter clinical trials (73, 83). Reduced
superoxide dismutase (SOD) levels and decreased SOD activ-
ity have been reported in neutrophils and placentas of women
with preeclampsia (113). The decrease in SOD levels and
activity in women with preeclampsia is important as diminished
SOD occurs within both the maternal and placental components.
Consequently, there appears to be a decreased total antioxidant
protective capacity in women with preeclampsia.
Experimental data reveal that there is an intimate relation-
ship among reactive oxygen species, NO activity, and blood
pressure in rats (85). Thus it is not surprising that there is
increased oxidative stress in the hypertensive pregnant RUPP
rat (87– 89). Whereas antioxidant treatment with vitamins C
and E does not decrease blood pressure, the SOD mimetic,
Tempol, does attenuate RUPP hypertension (88, 89). Similarly,
apocynin, an NADP(H) oxidase inhibitor, attenuates but does
not normalize the increased blood pressure observed in RUPP
AJP-Heart Circ Physiol • VOL
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
hypertension (89), suggesting that there may be other pathways
generating reactive oxygen species in this model. Although
oxidative stress is implicated in the pathogenesis of preeclamp-
sia, it remains unclear whether it is a primary or secondary
mediator of increased blood pressure and deranged renal func-
tion.
Endothelin. Another endothelial-derived factor that may
play a role in preeclampsia is the vasoconstrictor endothelin-1
(ET-1) (63, 67, 102). Since endothelial damage is a known
stimulus for ET-1 synthesis, increases in the production of
endothelin may participate in the pathophysiology of pre-
eclampsia (12). Furthermore, ET-1 is also reported to increase
oxidative stress in placental villi (27). Thus endothelin may
have additional effects on the maternal cardiovascular system
not only by direct actions on the vasculature but also indirectly
via oxidative stress.
Previously, we have investigated the role of endothelin in
mediating RUPP hypertension in conscious, chronically instru-
mented pregnant rats (11). Furthermore, we have shown that
RUPP elicits increased renal cortical and medullary expression
of preproendothelin and that chronic administration of the
selective endothelin type A (ETA) receptor antagonist (ABT-
627, 5 mg䡠kg⫺1 䡠day⫺1 for 10 days) markedly attenuates the
increased mean arterial pressure in these rats (11). In contrast,
ETA receptor blockade had no significant effect on blood
pressure in the normal pregnant animal, suggesting that ET-1
plays an important role in mediating the hypertension produced
by chronic RUPP pregnant rats (11). Furthermore, recent work
in our laboratory has shown that sera from pregnant rats
exposed to chronic RUPP increase ET-1 production by cul-
tured endothelial cell and that this increase is mediated via the
AT1 receptor (82). Although the exact mechanism linking
enhanced production of ET-1 to placental ischemia in pregnant
rats or in preeclamptic women remains unknown, possibilities
include the production of an agonistic AT1-AA and/or in-
creased TNF-␣ as we shall describe later.
Arachidonic acid metabolites. Several lines of evidence
suggest that changes in the metabolites of arachidonic acid may
play a role in mediating the renal dysfunction and increase in
arterial pressure during preeclampsia (114). Significant alter-
ations in the balance of prostacyclin and thromboxane produc-
tion occur in women with preeclampsia (46, 68, 114). Thus,
although there is evidence that AA metabolites play a part in
preeclampsia, their role is not clearly defined.
Experimental studies in animals have endeavored to deter-
mine the role of AA metabolites such as thromboxane in
preeclampsia. Such evidence derives from studies indicating
that short-term increases in systemic arterial pressure produced
by acute RUPP in pregnant dogs can be prevented by throm-
boxane receptor antagonism (119). Furthermore, we have pre-
viously reported that urinary excretion of thromboxane B2 was
increased in the RUPP rats compared with normal pregnant rats
at day 19 of gestation (56). Additionally, inhibition of cyto-
chrome P-450 enzymes with 1-aminobenzotriazole attenuated
the hypertension and increased renal vascular resistance, 20-
HETE formation, and cytochrome P-450 4A expression in the
renal cortex normally observed in the RUPP rat (55). Never-
theless, experimental data are limited in this area, and the
quantitative importance of prostaglandins in mediating long-
term reduction in renal hemodynamics and increased arterial
294 • FEBRUARY 2008 • www.ajpheart.org

PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION
pressure produced by chronic RUPP in pregnant rats remains
unclear.
Renin-angiotensin system. The renin-angiotensin system
(RAS) plays an important role in the long-term regulation of
renal function and arterial pressure during a variety of physi-
ological and pathophysiological conditions, and pregnancy and
preeclampsia are no exception. During normal pregnancy,
plasma renin concentration, renin activity, and ANG II levels
are all elevated, yet vascular responsiveness to ANG II appears
to be reduced (12, 92). In contrast, during preeclampsia, there
appears to be a marked increase in the sensitivity to ANG II
(92), although the mechanisms underlying these observations
remain unclear.
Recent studies in preeclamptic women have revealed several
exciting findings regarding the RAS. AbdAlla and colleagues
(1, 2) have shown that the AT1 receptor forms heterodimers
with the bradykinin B2 receptor and results in enhanced ANG
II sensitivity. Furthermore, these authors (1, 2) have shown that
AT1-B2 heterodimers are present in greater abundance in
preeclamptic women, suggesting that this heterodimerization
may play a part in the long-observed increased ANG II sensi-
tivity in preeclampsia. Another intriguing observation regard-
ing the involvement of the RAS in the pathophysiology of
preeclampsia is the demonstration of increased circulating
concentrations of an agonistic AT1-AA in preeclamptic women
(111, 112). Interestingly, the AT1-AA appear to be responsible
for a variety of effects in several different tissues ranging from
increased intracellular Ca2⫹ mobilization to monocyte activa-
tion and stimulation of IL-6 production from mesangial cells
(16, 99, 115, 120). Another effect that has recently been
attributed to the AT1 receptor is stimulation of sFlt-1 expres-
sion from trophoblast cells but not endothelial cells via cal-
cineurin signaling (123). Although these findings potentially
implicate AT1 as a central mediator of several pathways in
preeclampsia, both the specific mechanisms that lead to excess
production and the mechanisms whereby AT1-AA increase
blood pressure during pregnancy remain unclear. Conse-
quently, this has become an area of intense interest.
Increased vascular responsiveness to ANG II during pre-
eclampsia does not prove it is an important endogenous medi-
ator of vasoconstriction or hypertension in experimental mod-
els of preeclampsia since it could merely reflect low endoge-
nous ANG II formation. As such, the importance of increased
ANG II to the control of renal function and blood pressure
during preeclampsia remains to be determined. Early experi-
ments in our laboratory indicated that chronic oral administra-
tion of converting enzyme inhibitor enalapril (250 mg/l for 6
days) decreased MAP to a similar extent in pregnant rats with
RUPP and normal pregnant rats, suggesting that the RAS does
not play a major role in mediating the hypertension produced
by chronic reductions in uterine perfusion pressure in pregnant
rats (7). Nevertheless, we have recently found that AT1 recep-
tor antagonism attenuated the blood pressure response to pla-
cental ischemia and that RUPP rats have increased circulating
levels of the AT1-AA (54). As described in Endothelin and
illustrated in Fig. 4, we have also shown that serum from
pregnant rats exposed to reductions in uterine perfusion en-
hances endothelin production by endothelial cells via AT1
receptor activation (82). Although the initial findings by our
laboratory and others are exciting, there remains much to be
AJP-Heart Circ Physiol • VOL
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
Invited Review
H545
Fig. 4. Effect of losartan, an AT1 receptor antagonist, on medium endothelin
concentration after exposure of human umbilical vein endothelial cells to
serum from RUPP rats or NP rats. *P ⬍ 0.05 vs. control pregnant rats. All data
are expressed as means ⫾ SE. Adapted from Roberts et al. (Ref. 82).
investigated with respect to the manner in which the AT1-AA
contribute to the pathophysiology of preeclampsia.
Cytokines. Several groups have suggested that the etiology
of preeclampsia may involve a hypoxia-induced upregulation
of placental inflammatory cytokines (24, 78, 116). Although
IL-6 and TNF-␣ are reportedly elevated in preeclamptic
women, the importance of these cytokines in mediating the
cardiovascular and renal dysfunction in response to placental
ischemia during pregnancy remains unclear. We have previ-
ously shown that serum levels of TNF-␣ and IL-6 are elevated
in RUPP rats and that chronic infusion of TNF-␣ (Fig. 5) or IL-
6 into pregnant rats at concentrations similar to what is ob-
served in preeclamptic women increases arterial pressure and
decreases renal plasma flow and glomerular filtration rate (8,
29, 49). Furthermore, we have found that a low-dose infusion
of TNF-␣ results in decreased renal neuronal NO synthase
expression (8) while also increasing ET-1 mRNA in the kid-
ney, placenta, and vasculature (49). Likewise, we have also
reported that ET-1 is complicit in the mediation of this form of
pregnancy-induced hypertension since the increased MAP in
response to TNF-␣ is completely abolished in pregnant rats
treated with an ETA receptor antagonist (49). Collectively,
these findings suggest that TNF-␣-induced hypertension in
pregnant rats is mediated in part by endothlelin, via ETA
receptor activation. These studies also suggest that selective
ETA receptor antagonists for the treatment of hypertension in
women with preeclampsia should receive further attention.
Another mechanism by which cytokines may contribute to
hypertension during pregnancy is through the modulation of
sympathetic nerve activity. Previous studies have shown that
women with preeclampsia have increased sympathetic tone
(34, 86). Although few studies have examined the effect of
specific inflammatory cytokines on blood pressure and the
regulation of sympathetic activity, one recent experiment has
demonstrated that an acute forebrain infusion of TNF-␣ in rats
increased arterial pressure, heart rate, and renal sympathetic
nerve activity, effects mediated by prostaglandins in the para-
ventricular nucleus (122). Similarly, another study showed that
intracisternal or intravenous infusion of IL-1␤ increases blood
pressure in a prostaglandin-dependent manner in rats (121).
294 • FEBRUARY 2008 • www.ajpheart.org
Invited Review
H546 PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION

resulted in increased arterial pressure and proteinuria and

Fig. 5. Changes in MAP in response to TNF-␣ infusion and treatment with an
endothelin type A (ETA) receptor antagonist in NP rats. (*P ⬍ 0.05 vs. NP
rats). All data are expressed as means ⫾ SE. Adapted from LaMarca et al.
(Ref. 49).
decreased plasma-free VEGF and PlGF concentrations similar
to that observed in the preeclamptic patients. The authors (66)
also showed that sFlt-1 impaired VEGF- and PlGF-induced
vasorelaxation. Subsequently, similar observations using ade-
novirus transfection have been reported in the mouse (60).
Recently, we have developed a model of increased circulating
sFlt-1 in pregnant rats using recombinant sFlt-1 delivered via
osmotic minipump placed intraperitoneally and found that the
dams are hypertensive, have smaller placentae and fetuses, are
proteinuric, and show evidence of impaired vascular function
on day 18 of gestation (J. P. Granger, unpublished observa-
tions). Although these studies have established the importance
of sFlt-1 as an important preeclamptic factor, further studies
are needed to elucidate mechanisms governing the expression
and actions of this protein.

Whether chronic elevations in inflammatory cytokines contrib-

ute to the increased sympathetic activity during preeclampsia
remains to be determined.
Angiogenic factors. Although VEGF is primarily recognized
for its potent angiogenic and mitogenic effects on endothelial
cells, it has also been recognized as an important contributor to
cell homeostasis, in particular with respect to the balance of
oxidative stress (3, 4). VEGF exerts its actions mainly by two
receptors, VEGF receptor-1 and -2, also known as Flt-1 and the
kinase domain region (Flk/KDR), respectively. A soluble and
endogenously secreted form of Flt-1 is produced mainly in the
placenta by alternative splicing and contains the extracellular
ligand-binding domain but not the transmembrane and cyto-
plasmic portions (21, 44, 45). sFlt-1 disrupts VEGF signaling
either by binding VEGF and PlGF or by forming heterodimers
with the KDR receptor (45). Although sFlt-1 is not a vasocon-
strictor, it does significantly inhibit the dilatory actions of both
VEGF and PlGF in vitro, and chronic elevations in circulating
concentrations result in increased blood pressure (60, 66). An
additional antiangiogenic factor, soluble endoglin (sEng), has
also been revealed as a factor in the pathogenesis of preeclamp-
sia (64, 108). Endoglin is a component of the TGF-␤ receptor
complex and is a hypoxia-inducible protein associated with
cellular proliferation and NO signaling (38, 52). sEng, on the
other hand, has been shown to be antiangiogenic since it is
thought to impair TGF-␤1 binding to cell surface receptors
(38, 108).
Considerable clinical evidence has accumulated that pre-
eclampsia is strongly linked to an imbalance between proan-
giogenic (VEGF and PlGF) and antiangiogenic (sFlt-1) factors
in the maternal circulation (47, 50, 51, 66, 74, 93, 103, 104,
117). Both plasma and amniotic fluid concentrations of sFlt-1
are increased in preeclamptic patients, as well as placental
sFlt-1 mRNA (41, 47, 60, 65, 66, 107, 110). Recently, studies
have reported that increased sFlt-1 may have a predictive value
in diagnosing preeclampsia since concentrations seem to in-
crease before manifestation of overt symptoms (e.g., hyperten-
sion and proteinuria) (47, 51). Similarly, recent clinical evi-
dence also suggests that sEng may also presage the onset of Fig. 6. Plasma concentrations of sFlt-1 (A) were increased in RUPP (n ⫽ 18)
preeclampsia (50). pregnant rats compared with NP (n ⫽ 18) controls at day 19 of pregnancy.
Plasma concentrations of VEGF (B) and PlGF (C) were decreased in RUPP
In an elegantly designed study reported several years ago, (n ⫽ 18) pregnant rats compared with NP (n ⫽ 18) controls at day 19 of
Maynard et al. (66) reported that exogenous administration of pregnancy. All data are expressed as means ⫾ SE. *P ⬍ 0.05. Adapted from
sFlt-1 into pregnant rats via adenovirus-mediated gene transfer Gilbert et al. (Ref. 30).

AJP-Heart Circ Physiol • VOL 294 • FEBRUARY 2008 • www.ajpheart.org

Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.

PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION
Recently, Li and coworkers (53) showed that VEGF infusion
attenuates the increased blood pressure and renal damage
observed in pregnant rats overexpressing sFlt-1. Thus, from
this study, it can be gleaned that sFlt-1 plays a role in the
hypertension and renal dysfunction in preeclampsia; however,
these observations did not shed any light on the matter of
pathological sFlt-1 overexpression. To this end, we have re-
cently demonstrated that uteroplacental ischemia increased
plasma and placental sFlt-1, and this is associated with de-
creased VEGF and PlGF in the late gestation pregnant rat (30)
(Fig. 6). Similarly, Makris and colleagues (61) have reported
that uteroplacental ischemia increases sFlt-1 in the baboon as
well.
Recent work investigating sEng has furthered progress with
respect to the role of antiangiogenic factors in preeclampsia
(108). Venkatesha et al. (108) have shown that sEng inhibits
in vitro endothelial cell tube formation to a similar extent as
sFlt-1. Furthermore, the authors reported in vivo data in the
pregnant rat, indicating that an adenovirus-mediated increase
of sFlt-1 and sEng in concert exacerbated the effects of either
factor alone and resulted in fetal growth restriction, severe
hypertension, and nephritic range proteinuria (108). Thus there
is compelling experimental evidence that compliments the clinical
observations that sEng is an important factor in the pathogenesis
of preeclampsia.
Metabolic factors. There are other comorbid conditions that
have been proposed as potential contributors to endothelial
dysfunction in preeclampsia. Recent studies have indicated a
relationship between elements of the metabolic syndrome such
as elevated serum triglycerides and free fatty acids (40, 57),
insulin resistance (14, 36, 62, 90, 118), and glucose intolerance
(39, 98) and the occurrence of preeclampsia. In fact, several
authors have suggested that insulin resistance may presage the
manifestation of preeclampsia (98, 118), whereas Thadhani
et al. (105) have proposed that insulin resistance during preg-
nancy may collude with other conditions such as impaired
angiogenesis to generate a preeclamptic phenotype.
Fatty acids may contribute to endothelial dysfunction by
serving as substrates to generate lipid peroxides that are sig-
nificantly increased in plasma from women with preeclampsia
(69). Therefore, the generation of free radicals, lipid peroxides,
and reactive oxygen species may be an important mechanism
contributing to endothelial dysfunction in preeclampsia (101).
Although plasma levels of lipids are increased during normal
pregnancy, plasma concentrations of both triglyceride-rich li-
poproteins and nonesterified fatty acids are significantly in-
creased in women that develop preeclampsia relative to normal
pregnant women (57, 58). This significantly increased plasma
triglycerides in women with preeclampsia correlates with an
increased plasma of concentrations low-density lipoproteins
(84). The nature of this correlative data has provided difficulty
in determining a causal effect for abnormal lipid metabolism in
the pathogenesis of preeclampsia.
Because there was no definitive data indicating whether or
not metabolic derangements were sequelae or potential con-
tributors to placental ischemia, we recently tested this question
in our RUPP model. Data obtained from the RUPP model
suggest that metabolic derangements similar to the metabolic
syndrome X are not a direct consequence of RUPP (31).
Rather, it appears that factors associated with metabolic abnor-
malities may contribute to cardiovascular dysfunction in pre-
AJP-Heart Circ Physiol • VOL
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
Invited Review
H547
eclampsia rather than resulting from poor placental perfusion
(31). Further studies are underway to determine what influence
obesity may exert during experimental placental ischemia.
Summary
Despite being one of the leading causes of maternal death
and a major contributor of maternal and perinatal morbidity,
the mechanisms responsible for the pathogenesis of preeclamp-
sia remain enigmatic. The initiating event in preeclampsia has
been postulated to be reduced uteroplacental perfusion as a
result of abnormal cytotrophoblast invasion of spiral arterioles.
Placental ischemia is thought to lead to widespread activation/
dysfunction of the maternal vascular endothelium that results
in enhanced formation of endothelin, thromboxane, and super-
oxide, increased vascular sensitivity to ANG II, and decreased
formation of vasodilators such as NO and prostacyclin. These
endothelial abnormalities, in turn, cause hypertension by im-
pairing renal-pressure natriuresis and increasing total periph-
eral resistance (summarized in Fig. 1). The quantitative impor-
tance of the various endothelial and humoral factors in medi-
ating vasoconstriction and increased arterial pressure during
preeclampsia remains unclear.
Although recent studies support a role for angiogenic fac-
tors, the AT1-AA, cytokines, and other factors as potential
mediators of endothelial dysfunction, finding the link between
placental ischemia and maternal endothelial and vascular ab-
normalities remains an important area of investigation. Mi-
croarray analysis of genes within the ischemic/hypoxic pla-
centa of women with preeclampsia and in animal models of
preeclampsia should provide new insights into novel factors
that may provide additional links between placental ischemia/
hypoxia and hypertension. More effective strategies for the
prevention of preeclampsia should be forthcoming once the
underlying pathophysiological mechanisms that are involved
in preeclampsia are completely understood.
GRANTS
This work was supported by National Heart, Lung, and Blood Institute
Grants HL-51971, HL-38499, and HL-90269.
REFERENCES
1. AbdAlla S, Lother H, el Massiery A, Quitterer U. Increased AT1
receptor heterodimers in preeclampsia mediate enhanced angiotensin II
responsiveness. Nat Med 7: 1003–1009, 2001.
2. AbdAlla S, Lother H, Quitterer U. AT1-receptor heterodimers show
enhanced G-protein activation and altered receptor sequestration. Nature
407: 94 –98, 2000.
3. Abid M, Schoots I, Spokes K, Wu S, Mawhinney C, Aird W. Vascular
endothelial growth factor-mediated induction of manganese superoxide
dismutase occurs through redox-dependent regulation of forkhead and
I␬B/NF-␬B. J Biol Chem 279: 44030 – 44038, 2004.
4. Abid M, Tsai J, Spokes K, Deshpande S, Irani K, Aird W. Vascular
endothelial growth factor induces manganese-superoxide dismutase ex-
pression in endothelial cells by a Rac1-regulated NADPH oxidase-
dependent mechanism. FASEB J 15: 2548 –2550, 2001.
5. Abitbol MM, Gallo GR, Pirani CL, Ober WB. Production of experi-
mental toxemia in the pregnant rabbit. Am J Obstet Gynecol 124:
460 – 470, 1976.
6. Abitbol MM, Pirani CL, Ober WB, Driscoll SG, Cohen MW. Pro-
duction of experimental toxemia in the pregnant dog. Obstet Gynecol 48:
537–548, 1976.
7. Alexander BT, Cockrell K, Cline FD, Llinas MT, Sedeek M, Granger
JP. Effect of angiotensin II synthesis blockade on the hypertensive
response to chronic reductions in uterine perfusion pressure in pregnant
rats. Hypertension 38: 742–745, 2001.
294 • FEBRUARY 2008 • www.ajpheart.org
Invited Review
H548 PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION
8. Alexander BT, Cockrell KL, Massey MB, Bennett WA, Granger JP.
Tumor necrosis factor-alpha-induced hypertension in pregnant rats re-
sults in decreased renal neuronal nitric oxide synthase expression. Am J
Hypertens 15: 170 –175, 2002.
9. Alexander BT, Kassab SE, Miller MT, Abram SR, Reckelhoff JF,
Bennett WA, Granger JP. Reduced uterine perfusion pressure during
pregnancy in the rat is associated with increases in arterial pressure and
changes in renal nitric oxide. Hypertension 37: 1191–1195, 2001.
10. Alexander BT, Llinas MT, Kruckeberg WC, Granger JP. L-Arginine
attenuates hypertension in pregnant rats with reduced uterine perfusion
pressure. Hypertension 43: 832– 836, 2004.
11. Alexander BT, Rinewalt AN, Cockrell KL, Massey MB, Bennett WA,
Granger JP. Endothelin type a receptor blockade attenuates the hyper-
tension in response to chronic reductions in uterine perfusion pressure.
Hypertension 37: 485– 489, 2001.
11a.Anonymous. National High Blood Pressure Education Program Working
Group Report on High Blood Pressure in Pregnancy. Am J Obstet
Gynecol 163: 1691–1712, 1990.
12. August P, Lindheimer M. Pathophysiology of preeclampsia. In: Hyper-
tension, edited by Laragh J and Brenner BM. New York: Raven, 1995, p.
2407–2426.
13. Barron LA, Giardina JB, Granger JP, Khalil RA. High-salt diet
enhances vascular reactivity in pregnant rats with normal and reduced
uterine perfusion pressure. Hypertension 38: 730 –735, 2001.
14. Bartha J, Romero-Carmona R, Torrejon-Cardoso R, Comino-Del-
gado R. Insulin, insulin-like growth factor-1, and insulin resistance in
women with pregnancy-induced hypertension. Am J Obstet Gynecol 187:
735–740, 2002.
15. Bdolah Y, Sukhatme VP, Karumanchi SA. Angiogenic imbalance in
the pathophysiology of preeclampsia: newer insights. Semin Nephrol 24:
548 –556, 2004.
16. Bobst SM, Day MC, Gilstrap LC 3rd, Xia Y, Kellems RE. Maternal
autoantibodies from preeclamptic patients activate angiotensin receptors
on human mesangial cells and induce interleukin-6 and plasminogen
activator inhibitor-1 secretion. Am J Hypertens 18: 330 –336, 2005.
17. Bosio P, Mckenna P, Conroy R, O’Herlihy C. Maternal central
hemodynamics in hypertensive disorders of pregnancy. Obstet Gynecol
94: 978 –984, 1999.
18. Cavanagh D, Rao PS, Tsai CC, O’Connor TC. Experimental toxemia
in the pregnant primate. Am J Obstet Gynecol 128: 75– 85, 1977.
19. Cavanagh D, Rao PS, Tung KS, Gaston L. Eclamptogenic toxemia: the
development of an experimental model in the subhuman primate. Am J
Obstet Gynecol 120: 183–196, 1974.
20. Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner
JS. Association of maternal endothelial dysfunction with preeclampsia.
JAMA 285: 1607–1612, 2001.
21. Clark DE, Smith SK, He Y, Day KA, Licence DR, Corps AN,
Lammoglia R, Charnock-Jones DS. A vascular endothelial growth
factor antagonist is produced by the human placenta and released into the
maternal circulation. Biol Reprod 59: 1540 –1548, 1998.
22. Combs CA, Katz MA, Kitzmiller JL, Brescia RJ. Experimental
preeclampsia produced by chronic constriction of the lower aorta: vali-
dation with longitudinal blood pressure measurements in conscious
rhesus monkeys. Am J Obstet Gynecol 169: 215–223, 1993.
23. Conrad KP. Animal models of pre-eclampsia: do they exist? Fetal
Medicine Review 2: 67– 88, 1990.
24. Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of
preeclampsia. Am J Reprod Immunol 37: 240 –249, 1997.
25. Conrad KP, Kerchner LJ, Mosher MD. Plasma and 24-h NOx and
cGMP during normal pregnancy and preeclampsia in women on a
reduced NOx diet. Am J Physiol Renal Physiol 277: F48 –F57, 1999.
26. Crews JK, Herrington JN, Granger JP, Khalil RA. Decreased endo-
thelium-dependent vascular relaxation during reduction of uterine perfu-
sion pressure in pregnant rat. Hypertension 35: 367–372, 2000.
27. Fiore G, Florio P, Micheli L, Nencini C, Rossi M, Cerretani D,
Ambrosini G, Giorgi G, Petraglia F. Endothelin-1 triggers placental
oxidative stress pathways: putative role in preeclampsia. J Clin Endocri-
nol Metab 90: 4205– 4210, 2005.
28. Fisher SJ, Roberts JM. Defects in placentation and placental perfusion.
In: Chelsey’s Hypertensive Disorders in Pregnancy, edited by Lindhei-
mer MD, Roberts JM, and Cunningham FG. Stanford, CT: Appleton &
Lange, 1999, p. 377–394.
29. Gadonski G, LaMarca BB, Sullivan E, Bennett W, Chandler D,
Granger JP. Hypertension produced by reductions in uterine perfusion
AJP-Heart Circ Physiol • VOL 294 • FEBRUARY 2008 •
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
in the pregnant rat: role of interleukin 6. Hypertension 48: 711–716,
2006.
30. Gilbert JS, Babcock SA, Granger JP. Hypertension produced by
reduced uterine perfusion pressure in pregnant rats is associated with
increased soluble sFlt-1 expression. Hypertension 50: 1142–1147, 2007.
31. Gilbert JS, Dukes M, LaMarca BB, Cockrell K, Babcock SA,
Granger JP. Effects of reduced uterine perfusion pressure on blood
pressure and metabolic factors in pregnant rats. Am J Hypertens 20:
686 – 691, 2007.
32. Granger JP, Alexander BT, Bennett WA, Khalil RA. Pathophysiology
of pregnancy-induced hypertension. Am J Hypertens 14: 178S–185S,
2001.
33. Granger JP, LaMarca BB, Cockrell K, Sedeek M, Balzi C, Chandler
D, Bennett W. Reduced uterine perfusion pressure (RUPP) model for
studying cardiovascular-renal dysfunction in response to placental ischemia.
Methods Mol Med 122: 383–392, 2006.
34. Greenwood JP, Scott EM, Stoker JB, Walker JJ, Mary DA. Sympa-
thetic neural mechanisms in normal and hypertensive pregnancy in
humans. Circulation 104: 2200 –2204, 2001.
35. Hodari AA. Chronic uterine ischemia and reversible experimental “toxemia
of pregnancy.” Am J Obstet Gynecol 97: 597– 607, 1967.
36. Innes KE, Wimsatt JH, McDuffie R. Relative glucose tolerance and
subsequent development of hypertension in pregnancy. Obstet Gynecol
97: 905–910, 2001.
37. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long-term mortality of
mothers and fathers after pre-eclampsia: population based cohort study.
BMJ 323: 1213–1217, 2001.
38. Jerkic M, Rivas-Elena JV, Prieto M, Carron R, Sanz-Rodriguez F,
Perez-Barriocanal F, Rodriguez-Barbero A, Bernabeu C, Lopez-
Novoa JM. Endoglin regulates nitric oxide-dependent vasodilatation.
FASEB J 18: 609 – 611, 2004.
39. Joffe G, Esterlitz J, Levine R, Clemens J, Ewell M, Sibai B, Catalano
P. The relationship between abnormal glucose tolerance and hyperten-
sive disorders of pregnancy in healthy nulliparous women. Am J Obstet
Gynecol 179: 1032–1037, 1998.
40. Kaaja R, Tikkanen MJ, Viinikka L, Ylikorkala O. Serum lipopro-
teins, insulin, and urinary prostanoid metabolites in normal and hyper-
tensive pregnant women. Obstet Gynecol 85: 353–356, 1995.
41. Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the
“chicken-and-egg” question. Endocrinology 145: 4835– 4837, 2004.
42. Karumanchi SA, Maynard SE, Stillman IE, Epstein FH, Sukhatme
VP. Preeclampsia: a renal perspective. Kidney Int 67: 2101–2113, 2005.
43. Kassab S, Miller MT, Hester R, Novak J, Granger JP. Systemic
hemodynamics and regional blood flow during chronic nitric oxide
synthesis inhibition in pregnant rats. Hypertension 31: 315–320, 1998.
44. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth
factor activity by an endogeneously encoded soluble receptor. Proceed
Natl Acad Sci USA 90: 10705–10709, 1993.
45. Kendall RL, Wang G, Thomas KA. Identification of a natural soluble
form of the vascular endothelial growth factor receptor, FLT-1, and its
heterodimerization with KDR. Biochem Biophys Res Commun 226:
324 –328, 1996.
46. Klockenbusch W, Goecke TW, Krüssel JS, Tutschek BA, Crombach
G, Schrör K. Prostacyclin deficiency and reduced fetoplacental blood
flow in pregnancy-induced hypertension and preeclampsia. Gynecol
Obstet Invest 50: 103–107, 2000.
47. Lam C, Lim KH, Karumanchi SA. Circulating angiogenic factors in
the pathogenesis and prediction of preeclampsia. Hypertension 46: 1077–
1085, 2005.
48. LaMarca BB, Bennett WA, Alexander BT, Cockrell K, Granger JP.
Hypertension produced by reductions in uterine perfusion in the pregnant
rat: role of tumor necrosis factor-alpha. Hypertension 46: 1022–1025,
2005.
49. LaMarca BB, Cockrell K, Sullivan E, Bennett W, Granger JP. Role
of endothelin in mediating tumor necrosis factor-induced hypertension in
pregnant rats. Hypertension 46: 82– 86, 2005.
50. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai
BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA. Soluble
endoglin and other circulating antiangiogenic factors in preeclampsia.
N Engl J Med 355: 992–1005, 2006.
51. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF,
Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM,
Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the
risk of preeclampsia. N Engl J Med 350: 672– 683, 2004.
www.ajpheart.org

PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION
52. Li C, Issa R, Kumar P, Hampson IN, Lopez-Novoa JM, Bernabeu C,
Kumar S. CD105 prevents apoptosis in hypoxic endothelial cells. J Cell
Sci 116: 2677–2685, 2003.
53. Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, Lam A,
O’Young G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA,
Protter AA, Pollitt NS. Recombinant vascular endothelial growth factor
121 attenuates hypertension and improves kidney damage in a rat model
of preeclampsia. Hypertension 50: 686 – 692, 2007.
54. Llinas M, Wallukat G, Dechend R, Mueller DN, Luft FC, Alexander
BT, LaMarca B, Granger JP. Agonistic autoantibodies to the AT1
receptor in a rat model of preeclampsia induced by chronic reductions in
uterine perfusion pressure (RUPP) (Abstract). Hypertension 46: 884,
2005.
55. Llinas MT, Alexander BT, Capparelli MF, Carroll MA, Granger JP.
Cytochrome P-450 inhibition attenuates hypertension induced by reduc-
tions in uterine perfusion pressure in pregnant rats. Hypertension 43:
623– 628, 2004.
56. Llinas MT, Alexander BT, Seedek M, Abram SR, Crell A, Granger
JP. Enhanced thromboxane synthesis during chronic reductions in uter-
ine perfusion pressure in pregnant rats. Am J Hypertens 15: 793–797,
2002.
57. Lorentzen B, Drevon CA, Endresen MJ, Henriksen T. Fatty acid
pattern of esterified and free fatty acids in sera of women with normal and
pre-eclamptic pregnancy. Br J Obstet Gynaecol 102: 530 –537, 1995.
58. Lorentzen B, Henriksen T. Plasma lipids and vascular dysfunction in
preeclampsia. Semin Reprod Endocrinol 16: 33–39, 1998.
59. Losonczy G, Brown G, Venuto RC. Increased peripheral resistance
during reduced uterine perfusion pressure hypertension in pregnant
rabbits. Am J Med Sci 303: 233–240, 1992.
60. Lu F, Longo M, Tamayo E, Maner W, Al-Hendy A, Anderson GD,
Hankins GD, Saade GR. The effect of over-expression of sFlt-1 on
blood pressure and the occurrence of other manifestations of preeclamp-
sia in unrestrained conscious pregnant mice. Am J Obstet Gynecol 196:
e1– e7, 2007.
61. Makris A, Thornton C, Thompson J, Thomson S, Martin R, Ogle R,
Waugh R, McKenzie P, Kirwan P, Hennessy A. Uteroplacental isch-
emia results in proteinuric hypertension and elevated sFLT-1. Kidney Int
71: 977–984, 2007.
62. Martinez Abundis E, Gonzalez Ortiz M, Quiñones Galvan A, Fer-
rannini E. Hyperinsulinemia in glucose-tolerant women with preeclamp-
sia. A controlled study. Am J Hypertens 9: 610 – 614, 1996.
63. Mastrogiannis DS, O’Brien WF, Krammer J, Benoit R. Potential role
of endothelin-1 in normal and hypertensive pregnancies. Am J Obstet
Gynecol 165: 1711–1716, 1991.
64. Masuyama H, Nakatsukasa H, Takamoto N, Hiramatsu Y. Correla-
tion between soluble endoglin, vascular endothelial growth factor recep-
tor-1, and adipocytokines in preeclampsia. J Clin Endocrinol Metab 92:
2672–2679, 2007.
65. Maynard SE, Venkatesha S, Thadhani R, Karumanchi SA. Soluble
Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogen-
esis of preeclampsia. Pediatr Res 57: 1R–7R, 2005.
66. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S,
Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH,
Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like
tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction,
hypertension, and proteinuria in preeclampsia. J Clin Invest 111: 649 –
658, 2003.
67. McMahon LP, Redman CW, Firth JD. Expression of the three endo-
thelin genes and plasma levels of endothelin in pre-eclamptic and normal
gestations. Clin Sci (Lond) 85: 417– 424, 1993.
68. Mills JL, DerSimonian R, Raymond E, Morrow JD, Roberts LJ,
Clemens JD, Hauth JC, Catalano P, Sibai B, Curet LB, Levine RJ.
Prostacyclin and thromboxane changes predating clinical onset of pre-
eclampsia: a multicenter prospective study. JAMA 282: 356 –362, 1999.
69. Murai JT, Muzykanskiy E, Taylor RN. Maternal and fetal modulators
of lipid metabolism correlate with the development of preeclampsia.
Metabolism 46: 963–967, 1997.
71. Nevo O, Soleymanlou N, Wu Y, Xu J, Kingdom J, Many A, Zamudio
S, Caniggia I. Increased expression of sFlt-1 in in vivo and in vitro
models of human placental hypoxia is mediated by HIF-1. Am J Physiol
Regul Integr Comp Physiol 291: R1085–R1093, 2006.
72. Podjarny E, Losonczy G, Baylis C. Animal models of preeclampsia.
Semin Nephrol 24: 596 – 606, 2004.
AJP-Heart Circ Physiol • VOL 294 • FEBRUARY 2008 •
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
Invited Review
H549
73. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and
vitamin E in pregnant women at risk for pre-eclampsia (VIP trial):
randomised placebo-controlled trial. Lancet 367: 1145–1154, 2006.
74. Rajakumar A, Michael HM, Rajakumar PA, Shibata E, Hubel CA,
Karumanchi SA, Thadhani R, Wolf M, Harger G, Markovic N.
Extra-placental expression of vascular endothelial growth factor recep-
tor-1, (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear
cells (PBMCs) in normotensive and preeclamptic pregnant women.
Placenta 26: 563–573, 2005.
75. Rana S, Karumanchi SA, Levine RJ, Venkatesha S, Rauh-Hain JA,
Tamez H, Thadhani R. Sequential changes in antiangiogenic factors in
early pregnancy and risk of developing preeclampsia. Hypertension 50:
137–142, 2007.
76. Ranta V, Viinikka L, Halmesmaki E, Ylikorkala O. Nitric oxide
production with preeclampsia. Obstet Gynecol 93: 442– 445, 1999.
77. Redman CW. Current topic: pre-eclampsia and the placenta. Placenta
12: 301–308, 1991.
78. Rinehart BK, Terrone DA, Lagoo-Deenadayalan S, Barber WH,
Hale EA, Martin JN Jr, Bennett WA. Expression of the placental
cytokines tumor necrosis factor alpha, interleukin 1beta, and interleukin
10 is increased in preeclampsia. Am J Obstet Gynecol 181: 915–920,
1999.
79. Roberts JM, Taylor RN, Goldfien A. Clinical and biochemical evi-
dence of endothelial cell dysfunction in the pregnancy syndrome pre-
eclampsia. Am J Hypertens 4: 700 –708, 1991.
80. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA,
McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J
Obstet Gynecol 161: 1200 –1204, 1989.
81. Roberts JM, Pearson G, Cutler J, Lindheimer M. Summary of the
NHLBI working group on research on hypertension during pregnancy.
Hypertension 41: 437– 445, 2003.
82. Roberts L, LaMarca BB, Fournier L, Bain J, Cockrell K, Granger
JP. Enhanced endothelin synthesis by endothelial cells exposed to sera
from pregnant rats with decreased uterine perfusion. Hypertension 47:
615– 618, 2006.
83. Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS,
the Study Group ACTS. Vitamins C and E and the risks of preeclamp-
sia and perinatal complications. N Engl J Med 354: 1796 –1806, 2006.
84. Sattar N, Greer IA, Louden J, Lindsay G, McConnell M, Shepherd
J, Packard CJ. Lipoprotein subfraction changes in normal pregnancy:
threshold effect of plasma triglyceride on appearance of small, dense low
density lipoprotein. J Clin Endocrinol Metab 82: 2483–2491, 1997.
85. Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood
pressure and renal vascular resistance in shr with a membrane-permeable
superoxide dismutase mimetic: role of nitric oxide. Hypertension 32:
59 – 64, 1998.
86. Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE. Pre-
eclampsia—a state of sympathetic overactivity. N Engl J Med 335:
1480 –1485, 1996.
87. Sedeek MH, Alexander BT, Sholook MM, Chandler DL, Abram SR,
Granger JP. Renal cortical NADPH oxidase and superoxide dismutase
activity in response to reduced uterine perfusion pressure in pregnant rats
(Abstract). FASEB J 18: A740, 2004.
88. Sedeek MH, Sholook MM, Blazli C, Abram SR, Chandler DL,
Granger JP. Tempol, but not vitamin E & C, decreases the blood
pressure response to a chronic reduction in uterine perfusion pressure in
pregnant rats (Abstract). FASEB J 18: A740, 2004.
89. Sedeek MH, Wang YP, Granger JP. Increased oxidative stress in a rat
model of preeclampsia (Abstract). Am J Hypertens 17: 142A, 2004.
90. Seely EW, Solomon CG. Insulin resistance and its potential role in
pregnancy-induced hypertension. J Clin Endocrinol Metab 88: 2393–
2398, 2003.
91. Shaamash AH, Elsnosy ED, Makhlouf AM, Zakhari MM, Ibrahim
OA, El-Dien HM. Maternal and fetal serum nitric oxide (NO) concen-
trations in normal pregnancy, pre-eclampsia and eclampsia. Int J Gynaecol
Obstet 68: 207–214, 2000.
92. Shah DM. Role of the renin-angiotensin system in the pathogenesis of
preeclampsia. Am J Physiol Renal Physiol 288: F614 –F625, 2005.
93. Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C,
Bodnar LM, Crombleholme WR, Ness RB, Roberts JM, Hubel CA.
Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in
normotensive pregnancies with small-for-gestational-age neonates: rela-
tionship to circulating placental growth factor. J Clin Endocrinol Metab
90: 4895– 4903, 2005.
www.ajpheart.org
Invited Review
H550 PLACENTAL ISCHEMIA AND CARDIOVASCULAR DYSFUNCTION
94. Sholook MM, Gilbert JS, Sedeek MH, Huang M, Hester RL,
Granger JP. Systemic hemodynamic and regional blood flow changes in
response to chronic reductions in uterine perfusion pressure in pregnant
rats. Am J Physiol Heart Circ Physiol 293: H2080 –H2084, 2007.
95. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 365: 785–
799, 2005.
96. Sibai B, Ewell M, Levine R, Klebanoff M, Esterlitz J, Catalano P,
Goldenberg R, Joffe G. Risk factors associated with preeclampsia in
healthy nulliparous women. Am J Obstet Gynecol 177: 1003–1010, 1997.
97. Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy.
Am J Physiol Regul Integr Comp Physiol 272: R441–R463, 1997.
98. Solomon CG, Graves SW, Greene MF, Seely EW. Glucose intolerance
as a predictor of hypertension in pregnancy. Hypertension 23: 717–721,
1994.
99. Stepan H, Faber R, Wessel N, Wallukat G, Schultheiss HP, Walther
T. Relation between circulating angiotensin II type 1 receptor agonistic
autoantibodies and soluble fms-like tyrosine kinase 1 in the pathogenesis
of preeclampsia. J Clin Endocrinol Metab 91: 2424 –2427, 2006.
100. Taylor RN, Roberts JM. Endothelial cell dysfunction. In: Chelsey’s
Hypertensive Disorder’s of Pregnancy, edited by Lindheimer M, Roberts
JM, and Cunningham FG. Stanford, CT: Appleton & Lange, 2007, p.
395– 429.
101. Taylor RN, de Groot CJ, Cho YK, Lim KH. Circulating factors as
markers and mediators of endothelial cell dysfunction in preeclampsia.
Semin Reprod Endocrinol 16: 17–31, 1998.
102. Taylor RN, Varma M, Teng NN, Roberts JM. Women with pre-
eclampsia have higher plasma endothelin levels than women with normal
pregnancies. J Clin Endocrinol Metab 71: 1675–1677, 1990.
103. Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme
VP, Ecker J, Karumanchi SA. First trimester placental growth factor
and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin
Endocrinol Metab 89: 770 –775, 2004.
104. Thadhani RI, Johnson RJ, Karumanchi SA. Hypertension during
pregnancy: a disorder begging for pathophysiological support. Hyperten-
sion 46: 1250 –1251, 2005.
105. Thadhani R, Ecker JL, Mutter WP, Wolf M, Smirnakis KV,
Sukhatme VP, Levine RJ, Karumanchi SA. Insulin resistance and
alterations in angiogenesis: additive insults that may lead to preeclamp-
sia. Hypertension 43: 988 –992, 2004.
106. Tranquilli AL, Bezzeccheri V, Giannubilo SR, Scagnoli C, Mazzanti
L, Garzetti GG. Amniotic vascular endothelial growth factor (VEGF)
and nitric oxide (NO) in women with subsequent preeclampsia. Eur J
Obstet Gynecol Reprod Biol 113: 17–20, 2004.
107. Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A,
Schaaps JP, Cabrol D, Frankenne F, Foidart JM. Overexpression of
the soluble vascular endothelial growth factor receptor in preeclamptic
patients: pathophysiological consequences. J Clin Endocrinol Metab 88:
5555–5563, 2003.
108. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim
YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE,
Roberts D, D’Amore PA, Epstein FH, Sellke FW, Romero R,
Sukhatme VP, Letarte M, Karumanchi SA. Soluble endoglin contrib-
utes to the pathogenesis of preeclampsia. Nat Med 12: 642– 649, 2006.
AJP-Heart Circ Physiol • VOL 294 • FEBRUARY 2008 •
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (036.084.226.018) on February 5, 2018.
Copyright © 2008 American Physiological Society. All rights reserved.
109. Visser W, Wallenburg HC. Central hemodynamic observations in
untreated preeclamptic patients. Hypertension 17: 1072–1077, 1991.
110. Vuorela P, Helske S, Hornig C, Alitalo K, Weich H, Halmesmaki E.
Amniotic fluid-soluble vascular endothelial growth factor receptor-1 in
preeclampsia. Obstet Gynecol 95: 353–357, 2000.
111. Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B,
Jupner A, Baur E, Nissen E, Vetter K, Neichel D, Dudenhausen JW,
Haller H, Luft FC. Patients with preeclampsia develop agonistic auto-
antibodies against the angiotensin AT1 receptor. J Clin Invest 103:
945–952, 1999.
112. Wallukat G, Neichel D, Nissen E, Homuth V, Luft FC. Agonistic
autoantibodies directed against the angiotensin II AT1 receptor in patients
with preeclampsia. Can J Physiol Pharmacol 81: 79 – 83, 2003.
113. Walsh SW. Maternal-placental interactions of oxidative stress and anti-
oxidants in preeclampsia. Semin Reprod Endocrinol 16: 93–104, 1998.
114. Walsh SW. Eicosanoids in preeclampsia. Prostaglandins Leukot Essent
Fatty Acids 70: 223–232, 2004.
115. Walther T, Wallukat G, Jank A, Bartel S, Schultheiss HP, Faber R,
Stepan H. Angiotensin II type 1 receptor agonistic antibodies reflect
fundamental alterations in the uteroplacental vasculature. Hypertension
46: 1275–1279, 2005.
116. Wang Y, Walsh SW. TNF alpha concentrations and mRNA expression
are increased in preeclamptic placentas. J Reprod Immunol 32: 157–169,
1996.
117. Wolf M, Shah A, Lam C, Martinez A, Smirnakis KV, Epstein FH,
Taylor RN, Ecker JL, Karumanchi SA, Thadhani R. Circulating
levels of the antiangiogenic marker sFLT-1 are increased in first versus
second pregnancies. Am J Obstet Gynecol 193: 16 –22, 2005.
118. Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R. First
trimester insulin resistance and subsequent preeclampsia: a prospective
study. J Clin Endocrinol Metab 87: 1563–1568, 2002.
119. Woods LL. Importance of prostaglandins in hypertension during reduced
uteroplacental perfusion pressure. Am J Physiol Regul Integr Comp
Physiol 257: R1558 –R1561, 1989.
120. Xia Y, Wen H, Bobst S, Day MC, Kellems RE. Maternal autoantibod-
ies from preeclamptic patients activate angiotensin receptors on human
trophoblast cells. J Soc Gynecol Investig 10: 82–93, 2003.
121. Ye S, Mozayeni P, Gamburd M, Zhong H, Campese VM. Interleukin-
1beta and neurogenic control of blood pressure in normal rats and rats
with chronic renal failure 1. Am J Physiol Heart Circ Physiol 279:
H2786 –H2796, 2000.
122. Zhang ZH, Wei SG, Francis J, Felder RB. Cardiovascular and renal
sympathetic activation by blood-borne TNF-alpha in rat: the role of
central prostaglandins 1. Am J Physiol Regul Integr Comp Physiol 284:
R916 –R927, 2003.
123. Zhou CC, Ahmad S, Mi T, Xia L, Abbasi S, Hewett PW, Sun C,
Ahmed A, Kellems RE, Xia Y. Angiotensin II induces soluble fms-like
tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy.
Circ Res 100: 88 –95, 2007.
124. Zhou Y, Chiu K, Brescia RJ, Combs CA, Katz MA, Kitzmiller JL,
Heilbron DC, Fisher SJ. Increased depth of trophoblast invasion after
chronic constriction of the lower aorta in rhesus monkeys. Am J Obstet
Gynecol 169: 224 –229, 1993.
www.ajpheart.org