Download A model of preeclampsia in rats: the reduced uterine perfusion

Am J Physiol Heart Circ Physiol 303: H1–H8, 2012.
First published April 20, 2012; doi:10.1152/ajpheart.00117.2012.
Review
A model of preeclampsia in rats: the reduced uterine perfusion pressure
(RUPP) model
Jing Li,1,2 Babbette LaMarca,1,2,3 and Jane F. Reckelhoff1,2
1
Women’s Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi; 2Department of
Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; and 3Department of Obstetrics
and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi
Submitted 9 February 2012; accepted in final form 12 April 2012
pregnancy; soluble fms-like tyrosine kinase-1; angiotensin type 1 receptor autoantibodies; endothelin; angiotensin II; immune system; tumor necrosis factor-␣
THIS REVIEW ARTICLE is part of a collection on Cardiovascular
Regulation in Pregnancy. Other articles appearing in this
collection, as well as a full archive of all Review collections,
can be found online at http://ajpheart.physiology.org/.
Introduction
Preeclampsia is a multisystem disorder that typically occurs
during the second half of pregnancy and complicates ⬃3–7%
for nulliparous and 1–3% for multiparous pregnancies (96). It
is a major cause of maternal morbidity and mortality, prenatal
death, and intrauterine growth restriction (IUGR) and contributes to ⬃15% of all preterm pregnancies (73, 96). Preeclampsia is characterized by new-onset (pregnancy-specific) maternal hypertension, proteinuria, widespread maternal endothelial
dysfunction, an imbalance of angiogenic factors and typically
occurs after 20 wk gestation (72). Although the mechanism(s)
responsible for preeclampsia are unclear, hypertension associated
with preeclampsia remits after delivery, implicating the placenta
as the culprit in the disease progression. In support of this notion,
Magann and colleagues (67) reported that curettage immediately
following delivery was more efficacious in the resolution of the
hypertension in severely hypertensive women with preeclampsia
than antihypertensive treatment with nifedipine.
Address for reprint requests and other correspondence: J. F. Reckelhoff,
Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center,
2500 N. State St., Jackson, MS 39216-4505 (e-mail: [email protected]).
http://www.ajpheart.org
Preeclampsia is Associated with Abnormal Uteroplacental
Blood Flow
It has been hypothesized that preeclampsia arises from
reductions in uteroplacental perfusion, leading to fetoplacental
ischemia (82, 83). The mechanisms leading to reduced placental perfusion in preeclampsia are not clear, but studies in
humans implicate impaired first-trimester cytotrophoblast invasion of spiral arterioles as an important factor. During weeks
8–18 of normal pregnancy, the villous cytotrophoblasts originating from the fetus invade the uterine wall through the entire
depth of the endometrium and the inner third of the myometrium (42, 82) (see Fig. 1). As a result, the spiral arteries are
extensively remodeled, replacing their smooth muscle and
endothelium by the invading cytotrophoblasts. These arteries
become widely dilated, with low resistance, and are less
responsive, or even refractory, to vasoconstrictor substances
(45). This normal invasive vascular remodeling occurring early
in placentation is abnormal in pregnant women that develop
preeclampsia (45). Thus preeclampsia is thought to be caused
by a reduction in uterine blood flow due to abnormal trophoblast invasion of the spiral arteries, a concept first suggested by
Young in 1914 (107). In support of this hypothesis, preeclamptic human placental bed biopsies indicate shallow trophoblast
invasion, compared with normal pregnancy. As a result, the
corresponding arterial segments remain undilated, leading to
insufficient blood flow to the uteroplacental unit, and the
0363-6135/12 Copyright © 2012 the American Physiological Society
H1
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
Li J, LaMarca B, Reckelhoff JF. A model of preeclampsia in rats: the reduced uterine
perfusion pressure (RUPP) model. Am J Physiol Heart Circ Physiol 303: H1–H8, 2012.
First published April 20, 2012; doi:10.1152/ajpheart.00117.2012.—Preeclampsia is defined as new-onset hypertension with proteinuria after 20 wk gestation and is
hypothesized to be due to shallow trophoblast invasion in the spiral arteries thus
resulting in progressive placental ischemia as the fetus grows. Many animal models
have been developed that mimic changes in maternal circulation or immune
function associated with preeclampsia. The model of reduced uterine perfusion
pressure in pregnant rats closely mimics the hypertension, immune system abnormalities, systemic and renal vasoconstriction, and oxidative stress in the mother,
and intrauterine growth restriction found in the offspring. The model has been
successfully used in many species; however, rat and primate are the most consistent
in comparison of characteristics with human preeclampsia. The model suffers,
however, from lack of the ability to study the mechanisms responsible for abnormal
placentation that ultimately leads to placental ischemia. Despite this limitation, the
model is excellent for studying the consequences of reduced uterine blood flow as
it mimics many of the salient features of preeclampsia during the last weeks of
gestation in humans. This review discusses these features.
Review
H2
RAT MODEL OF PREECLAMPSIA
elucidated, but adenoviral vector-mediated vascular endothelial growth factor (VEGF) 121 (46) and tempol (103) prevented
the increase in BP (103), suggesting that placental ischemia
and oxidative stress may contribute to the further elevated BP.
Models to Evaluate a Single Pathway in the Progression of
Preeclampsia
maternal circulation remains responsive to vasoconstrictors,
such as angiotensin II (ANG II) (18) and endothelin (ET-1)
(51). The ischemic placenta releases cytokines, reactive oxygen species, and anti-angiogenic factors, such as soluble fmslike tyrosine kinase-1 (sFlt-1) (35), soluble endoglin (69, 70),
and ANG II type 1 receptor autoantibodies (AT1-AA) (100),
into the circulation, making this an aggravated interaction
between maternal and fetal circulation. It should be mentioned
that studies in double-knockout Rag2⫺/⫺II2rg⫺/⫺ mice, in
which there is no spiral artery remodeling during pregnancy,
placental ischemia is present, but this does not result in IUGR
or hypertension (25). These data suggest that other mechanisms are involved in the development of preeclampsia in
addition to poor spiral artery remodeling at least in the mouse.
Animal Models for the Study of Preeclampsia
An ideal animal model to study preeclampsia should duplicate the pathogenesis of preeclampsia in women, including
failure of early immune mechanisms, impaired first-trimester
trophoblast invasion and placentation, reduced uteroplacental
perfusion, and fetoplacental ischemia, thus resulting in systemic inflammation, proteinuria, and endothelial dysfunction in
the mother and restricted growth in the fetus. However, preeclampsia is thought to occur spontaneously only in women,
and only very few cases have been reported in great apes,
including chimpanzees (49, 91) and gorillas (15, 95). The use
of nonhuman primates and other animal species as models for
preeclampsia are discussed at length in a review by Podjarny et
al. (80) and McCarthy et al. (72).
There is evidence that hypertensive inbred BPH-5 mice,
derived from brother-sister mating of borderline hypertensive
BPH/2 mice, exhibit further increases in blood pressure (BP) in
late gestation (from ⬃130 to 160 mmHg, compared with ⬃105
mmHg in control C57BL-6) that resolves within 2 days of
delivery and is accompanied by increases in proteinuria and
IUGR of the pups (26, 28). The mechanisms responsible for the
increased BP during pregnancy in this model have not been
Nitric Oxide Inhibition
Nitric oxide (NO) is an important mediator in controlling
vascular tone, endothelial function, and oxidative stress. Increased NO production plays a critical role in the maternal BP
and glomerular hemodynamic adaptation to pregnancy. NO
production is reduced in preeclampsia (22, 27). Chronic NO
synthase (NOS) inhibition in pregnant rats causes a dosedependent increase in BP, renal vasoconstriction, proteinuria,
maternal morbidity and mortality, and IUGR of pups (19, 74,
106). However, plasma from women with preeclampsia increases, rather than decreases, endothelial cell NO (16), and the
effect of pregnancy on BP in endothelial NOS knockout mice
is controversial, with one study reporting typical pregnancyinduced decreases in BP (89) while another reported a further
increase of BP during pregnancy (43).
Anti-Angiogenic Factors
Women with preeclampsia have elevated circulating sFlt-1,
a soluble VEGF receptor binding to and inactivating VEGF
and placental growth factor (PIGF), critical players in angiogenesis and placentation. Placental and amniotic sFlt-1 levels
are elevated while plasma levels of free VEGF and PIGF are
decreased (70). Adenoviral vector-mediated sFlt-1 in pregnant
rats resulted in increased BP, proteinuria, glomerular endotheliosis, and decreases in plasma free VEGF and PIGF (70).
Similar studies performed in mice resulted in similar vascular
effects with significantly lower pup and placental weight (66).
In later studies performed by Murphy et al. (17, 76), sFlt-1
infusion in rats increased vascular/placental oxidative stress,
decreased vasodilatory responses to agonists, reduced placenta
and fetal weight, decreased maternal circulating VEGF and
NO, and increased renal preproendothelin (prepro-ET-1). Importantly, the effects of sFlt-1 also occurred in a dose-dependent manner in nonpregnant controls, indicating these results
are not specific for pregnancy, suggesting that increases in
sFlt-1 under any circumstances compromise the cardiovascular
system.
Models Based on Inflammatory Mediators
Women with preeclampsia exhibit increased systemic inflammation, heightened oxidative stress, and circulating auto-
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00117.2012 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
Fig. 1. The three-stage model of preeclampsia. Stages 1 and 2 of preeclampsia
are well accepted, whereas stage 0 is hypothetical. Based on this model,
preeclampsia is proposed to arise from abnormal maternal immune response to
fetopaternal antigens in the early stage of pregnancy (stage 0), leading to
poorly perfused placenta in stage 1, which further causes multiple stresses and
the final clinical manifestations in stage 2 of preeclamplsia (82, 83).
There are several genetically manipulated mouse models of
preeclampsia that affect a single gene, such as sFlt-1, the
renin-angiotensin system, VEGF, endothelin, endothelial nitric
oxide synthase, etc. (47). These models have varying levels of
similarity with human preeclampsia, although, interestingly,
few develop new-onset hypertension close to term. Readers are
referred to a recent review by Ishida and colleagues (47) for
more information on mouse models of preeclampsia. Below we
discuss studies performed in models other than mice to learn
more about the role of specific pathways hypothesized to
contribute to the pathogenesis of preeclampsia.
Review
H3
RAT MODEL OF PREECLAMPSIA
The RUPP Model
Because preeclampsia is thought to be caused by a reduction
in uterine blood flow due to abnormal trophoblast invasion of
the spiral arteries, the development of a model that exploits this
reduction in uterine perfusion pressure and flow is a natural
alternative for study. RUPP models have been performed in
dogs (104, 105), rabbits (3, 65), sheep (23, 61), guinea pigs
(39), primates (4, 20) (see Table 1), and rats (1, 11, 29). It
should be noted that differences in placentation between animal models (e.g., sheep) and humans may alter the cardiovascular responses to the RUPP maneuvers. Furthermore, in
sheep, increased BP only occurs with RUPP when dams are
given a high-salt diet (61). The most well-characterized and
utilized is the RUPP pregnant rat model (see Table 2). To our
knowledge, there have been no studies using the RUPP model
in mice.
Method to Induce the RUPP Model in Pregnant Rats
The RUPP rat model of preeclampsia was adapted by Crews
and colleagues (24), and the clipping procedure is tightly
controlled, in terms of gestation time and silver clip position
and size. Pregnant rats weighing ⬃200 –250 g undergo clipping at day 14 of gestation, in which a silver clip (0.203 mm
ID) is placed around the aorta above the iliac bifurcation (see
Fig. 2). Because compensatory blood flow to the placenta
occurs via an adaptive increase in ovarian blood flow, both
right and left uterine arcades are also clipped (silver clip, 0.100
mm ID) (11). These procedures reduce uterine blood flow in
the gravid rat by ⬃40% (24).
Characteristics of the RUPP Model
The RUPP rat mimics numerous physiological features of
preeclampsia in women (see Table 3), including hypertension
(⬃20 –30 mmHg increase in mean arterial pressure), proteinuria (⬃5-fold increase in urinary protein excretion), impaired
renal function, as indicated by reduction in glomerular filtration rate (GFR) (⬍40%) and renal plasma flow (⬍23%), an
increase in vascular reactivity, a reduction in cardiac index
(90), and increases in leptin (14) and blood lactate (36). Fetal
IUGR also occurs in RUPP rats, with decreased litter size and
pup weight (10, 40).
RUPP rats have reductions in NO (24) and increases in
vasoconstrictor substances or response (84). Vascular smooth
muscle cells isolated from renal interlobular arteries displayed
increased contractility to ANG II via enhanced calcium entry
(75). Inhibition of ANG II synthesis with a converting-enzyme
inhibitor had no effect on the BP in RUPP rats (8), but, in
contrast, treatment of RUPP rats with losartan, the AT1R
antagonist, significantly reduced their BP (58). These findings
lead to the discovery that, just as in women with preeclampsia,
RUPP rats have increased AT1-AA that causes activation of
AT1R and is a contributor to hypertension in the model (100).
RUPP rats also exhibit increased tissue ET-1, and ETA receptor
antagonists attenuate the BP increases (93). Furthermore, as in
women with preeclampsia, sera from RUPP rats causes endothelial cell activation that is attenuated by AT1R blockade,
Table 1. Models of reduced uterine perfusion pressure in animals other than rat
Species
Method
Characteristics
Ref. No.
Dog
Occlusion of abdominal aorta below the renal arteries
3, 5, 77, 104, 105
Rabbit
Clamp or ligation of aorta proximal to the ovarian
and distal to the renal arteries
Nonhuman primate
Red, abdominal aortic blood flow below kidneys
Guinea pig
Sheep
Banding uterine arteries, ovarian arteries
Occluder around internal iliac artery or abdominal
aorta distal to renal arteries
Inc BP, UPrV, glomerular lesions, fluid retention
diffuse hemorrhagic infarction of the placenta
Inc BP, UPrV, PVR, IUGR; endothelial
swelling, inc glomerular fibrinogen RVR,
placental lesions
Inc BP, UPrV, RVR, serum uric acid, dec PRA,
endtheliosis of glomeruli, inc sFlt-1
Inc BP, UPrV, creatinine
Inc BP only with high-salt diet, IUGR
2, 3, 65
4, 20, 68, 91
39
23, 61, 94
Inc, increased; dec, decreased; BP, blood pressure; UPrV, proteinuria; PRV, peripheral vascular resistance; RVR, renal vascular resistance; PRA, plasma renal
activity; sFLT-1, soluble fms-like tyrosine kinase-1; IUGR, intrauterine growth restriction.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00117.2012 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
antibodies (AT1-AA) that bind and activate ANG II type 1
receptor (AT1R) (52, 86, 87, 100). Pregnant mice injected with
human AT1-AA developed progressive hypertension, proteinuria, and glomerular endotheliosis, all of which were blocked
by AT1R antagonism (108). More specific studies indicated
that infusion of rat AT1-AA from day 12 to day 19 of gestation
into pregnant rats resulted in hypertension, elevated plasma
sFlt-1 and renal and placental ET-1, and oxidative stress (54,
79). However, infusion of rat AT1-AA has no vascular or
tissue effects in nonpregnant rats. These findings are interesting, since they suggest that the milieu of pregnancy is necessary for AT1-AA to cause adverse cardiovascular effects.
Preeclamptic women also have elevated inflammatory mediators, such as tumor necrosis factor-␣ (TNF-␣), interleukin-6
(IL-6), and CD4⫹ T cells (52). Pregnant rats receiving TNF-␣
infusion from days 14 to 19 of gestation displayed hypertension and increases in prepro-ET-1 in placenta, aorta, and
kidneys (60). Pretreatment with the ET-1 receptor A (ETA)
antagonist abolished the BP response to TNF-␣. Infusion of
IL-6 in pregnant rats resulted in the development of hypertension and renal vasoconstriction without affecting ET-1 levels
(20). Interestingly, later studies demonstrated that infusion of
TNF-␣ or IL-6 stimulated AT1-AAs, and the resulting hypertension was completely abolished by AT1R blockade (56, 100).
Importantly, CD4⫹ T helper cells, shown to be elevated in
preeclamptic women and in reduced uterine perfusion pressure
(RUPP) rats, cause hypertension when transferred from RUPP
into normal pregnant rats (99). It is important to emphasize that
none of these factors, elevated TNF-␣, IL-6, CD4⫹ T cells, or
AT1-AA, causes hypertension in nonpregnant rats, indicating the
importance of inflammatory mediators in the progression of hypertension in response to placental ischemia and preeclampsia.
Review
H4
RAT MODEL OF PREECLAMPSIA
Table 2. Summary of studies done in rat model of RUPP
Year
Methods Employed
Characterization of the model
Blockade of endothelin ETA receptor
Blockade with CEI
2002
Blockade of thromboxane receptor
2003
Characterization of IUGR with RUPP
2004
2004
2005
2005
Blockade of eicosanoid, 20-HETE
L-Arginine infusion
Measurement of TNF-␣
Uterine arcuate artery function
2005
2005
2006
2007
2007
Measurement leptin, leptin receptors
Treatment with N-acetylcysteine
Measurement of interleukin-6
Sympathetic nerve activity (SNA)
Measurement ANG-(1-7), ACE2
2007
2008
Measurement sFlt-1
Measurement of oxidative stress infusion of tempol
2008
2008
2008
2009
2009
2010
2010
2011
2011
2011
AT1 receptor autoantibodies (AT1-AA)
blockade of TNF-␣
Soluble endoglin
17␣-Progesterone infusion
Treatment with RUPP plasma
Infusion of VEGF121
TNF-␣, AT1-AA treatment of placental explants
Role of B lymphocytes
Infusion of CD4⫹ cells from RUPP into NP
Infusion of TNF-␣ soluble receptor
2011
2011
2011
2011
2012
Middle cerebral artery myogenic response
Upregulate heme oxygenase 1 (HO-1) with cobalt
protoporphyrin (CoPP)
PPAR-␥ agonist ⫾ HO-1 antagonist
Mesenteric myogenic response
CoPP inc HO-1
2012
Poly-ADP-ribose polymerase inhibition
Inc. BP, dec GFR, RPF, nNOS
RUPP causes inc. prepro-ET mRNA, dec BP with Abt627
RUPP causes inc PRA
Enalapril has no effect on BP
RUPP causes inc TxB2
SQ-29548, no effect on BP
Inc BP at 4 wk, sex difference in BP at 12 wk, small for
gestational age catch-up growth by 12 wk
1-ABT dec BP, 20-HETE in renal cortex
Dec BP ⬎ in NP
RUPP inc serum TNF-␣
Inc response to vasoconstrictor, dec response to
vasodilators
RUPP inc plasma leptin, inc placental leptin receptor
N-AC dec BP, no effect on pups
RUPP causes threefold inc IL-6
RUPP inc renal SNA, shifts baroreflex sensitivity
RUPP dec intrarenal ANG-(1-7), no change renal ACE2
activity
RUPP inc sFlt-1
RUPP inc urinary F2-IsoP, MDA, dec renal SOD activity,
tempol dec BP
RUPP causes inc AT1-AA, and TNF-␣ losartan dec BP
Etanercept dec BP
RUPP inc soluble endoglin
Dec BP, TNF-␣, IL-6, ET-1
Dec mesenteric vasorelaxation
Dec BP, inc GFR, RPF
Inc sFlt-1, s-endoglin
Nituximab dec BP, AT1-AA, ET-1
CD4⫹ cells in NP inc sFlt-1, TNF-␣
Etanercept dec cardiomegaly, fibrosis dec BNP, inc
eNOS, oxytocin receptor
RUPP dec myogenic response, causes brain edema
CoPP dec placental SOD, prepro-ET-1 dec placental sFlt1-to-VEGF ratio
Rosiglitazone dec BP, prevented by Tin protophorphyrin
RUPP inc mesenteric myogenic response
CO and biliverdin dec placental explant sFlt-1 and
reactive oxygen species
PJ34 before RUPP surgery, dec BP dec mesenteric
nitrotyrosine
Ref. No.
11
9
8
7
63
12
53
13
14
21
30
44
50
35
88
58
55
37
97
102
38
79
57
99
41
85
32, 34
71
81
34
101
RUPP, reduced uterine perfusion pressure; GFR, glomerular filtration rate; RPF, renal plasma flow; nNOS, neuronal nitric oxide synthase; prepro-ET,
preproendothelin; ET-1, endothelin-1; ETA, ET-1 receptor A; TxB2, thromboxane B2; NP, normal pregnant; ACE2, angiotensin converting enzyme 2; eNOS,
endothelial nitric oxide synthase; SOD, superoxide dismutase; VEGF, vascular endothelial growth factor; CO, carbon monoxide.
suggesting a role for the AT1-AA in the circulation of RUPP
rats to activate the AT1R on the vascular endothelium (84).
As discussed previously, women with preeclampsia have
increases in the levels of inflammatory cytokines (52). In
RUPP rats, serum levels of TNF-␣ and IL-6 are increased, and
infusion of TNF-␣ or IL-6 increases BP in normal pregnant
rats, suggesting that inflammation could contribute to the
hypertension of RUPP rats (30, 59). Supporting this notion,
administration of a TNF-␣ soluble receptor, etanercept, attenuated the hypertension and reduced ET-1 transcript expression
and endothelial cell activation from RUPP rats (55). Sunderland and colleagues (92) recently reported similar findings with
infusion of TNF-␣ in pregnant baboons that also resulted in
increases in sFLT-1 and soluble engdoglin.
Angiostatic factors, such as sFlt-1 and soluble endoglin, may be
important in development and progression of preeclampsia in
women (69, 98). RUPP rats exhibit increased plasma and placental sFlt-1 and decreased plasma VEGF and PIGF (35). A recent
study demonstrated that chronic infusion of recombinant VEGF-
121 during late gestation restored GFR and endothelial function
and reduced BP in RUPP rats (38). Serum and placental soluble
endoglin are increased along with placental hypoxia-inducible
factor-1␣ expression, whereas placental heme oxygenase-1
(HO-1) is decreased in the RUPP rats (37). An HO-1 inducer
attenuates the increases in BP, placental superoxide, placental
sFlt-1-to-VEGF ratios, and prepro-ET-1 mRNA in RUPP rats
(33). Oxidative stress, as measured by 8-isoprostane and malondialdehyde, is also increased, and renal superoxide dismutase
activity is decreased in RUPP rats. Chronic treatment with tempol
attenuates the hypertension associated with RUPP (88). George
and colleagues (32, 34) have recently shown that the reduction in
sFlt-1 with heme oxygenase induction is mediated via production
of antioxidants, biliverdin and carbon monoxide.
Advantages of the RUPP Model
The RUPP model of preeclampsia resembles numerous features exhibited by women with preeclampsia (Table 3) and
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00117.2012 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
2001
2001
2001
Results of the Study
Review
H5
RAT MODEL OF PREECLAMPSIA
serves as a good tool for investigating potential mechanisms
underlying hypertension induced by placental ischemia in
pregnancy. Importantly, RUPP models also successfully develop fetal IUGR, which is not always seen in other animal
models of preeclampsia, and is a very useful model for studying fetal programming of cardiovascular disease. The RUPP
model has also been exploited in nonhuman primates by
Makris and colleagues (68), who find similar changes such as
hypertension and elevated sFlt-1. The RUPP model provides
the opportunity to study potential therapeutic approaches for
management of preeclampsia that may not be appropriate for
study in women due to the consideration of the health of the
fetus.
Limitations of the RUPP Model
Despite the utility of the RUPP model of preeclampsia, the
model does have several limitations. First, an increase in BP
with RUPP does not always occur in all species or even within
the same species (5). The RUPP model developed by Granger
(40), LaMarca (54 –57), Alexander (7), and colleagues in rats
requires the clipping of both the lower abdominal aorta and the
Summary
In conclusion, pregnancy in women involves unique fetal
villous trophoblast invasion and placental vascular remodeling,
namely placentation. This process is only seen in women and
Table 3. Comparison of characteristics in women with preeclampsia and the model of RUPP in the rat
Characteristic
Women with Preeclampsia
RUPP in Rats
Ref. No.
New-onset hypertension
Abnormal placentation
Proteinuria
Renal plasma flow
GFR
Inflammation (TNF-␣, IL-6, CD4⫹ T cells)
Oxidative stress
Endothelin-1
sFlt-1
VEGF, PIGF
Soluble endoglin
Placental HIF-1␣
AT1-AA
Glomerular endotheliosis
Podocyte shedding
HELLP syndrome
Fetal IUGR
Yes
Yes
Yes
Dec
Dec
Inc
Inc
Inc
Inc
Dec
Inc
Inc
Inc
Yes
Yes
In severe cases
Yes
Yes
No
Yes
Dec
Dec
Inc
Inc
Inc
Inc
Dec
Inc
Inc
Inc
No
11
42, 45, 82, 83
11
90
11
30, 59, 99
88
33
35
35
37
37
58
62
6, 31
48
7, 52
No
Yes
TNF-␣, tumor necrosis factor-␣; IL-6, interleukin-6; PIGF, placental growth factor; HIF-1␣, hypoxia-inducible factor-1␣; AT1-AA, agonistic autoantibodies
against angiotensin type 1 receptor; HELLP syndrome, hemolysis, elevated liver enzymes, low platelets.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00117.2012 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
Fig. 2. Induction of reduced uterine perfusion pressure (RUPP) model in
pregnant rats. In the rat RUPP model, laparotomy is performed through an
abdominal incision on day 14 of gestation. A silver clip with a 0.203-mm
internal diameter is placed around the aorta right above the iliac bifurcation,
and silver clips with 0.1 mm internal diameter were placed around the left and
right uterine arcade at the ovarian artery before the first segmental artery.
Uterine perfusion pressure in the gravid rat is reduced by ⬃40%. Blood
pressure is measured via a carotid arterial catheter.
uterine arteries on day 14 of gestation in ⬃250 g female rats
(78). Thus the conditions to produce the model must be
rigorous to have a successful outcome of hypertension that
recedes after delivery of the pups. The use of rats as a RUPP
model is cost effective, but somewhat limited, since the clipping is performed at day 14 of gestation, which only lasts
21–22 days. Thus the window for study is narrow in the rat.
The use of nonhuman primates for the RUPP model, as
characterized by Makris and colleagues (68), provides a longer
gestation time, placentation, and trophoblast invasion closer to
humans than rats but is significantly more costly to maintain
the animals.
A second important limitation of the RUPP model is that it
only mimics the pathogenesis responsible for the hypertension
in preeclampsia downstream of midgestational placental ischemia. Thus the RUPP model is not useful to investigate the
early immune mechanisms, trophoblast invasion, and vascular
remodeling abnormalities. Furthermore, aortic clipping may
have a hemodynamic impact on sympathetic nervous system
and cardiac output, since Sholook and colleagues (90) reported
that the RUPP procedure results in reductions in blood flow to
the heart, stomach, intestine, and skeletal muscle, without
differences in blood flow to the brain, liver, kidney, or spleen
compared with the normal pregnant rats.
A third limitation is that the RUPP model in the rat does not
mimic the glomerular endotheliosis that is one of the hallmarks
of preeclampsia (62). This may be important because several
investigators find that podocyte shedding occurs in women
with preeclampsia and may be an early marker for preeclpamsia (6, 31).
Finally, the RUPP model is not successful in mimicking
severe preeclampsia, which is characterized by the HELLP
(hemolysis, elevated liver enzymes, and low platelets) syndrome. RUPP rats do not have changes in hemoglobin, platelets, or liver function (48).
Review
H6
RAT MODEL OF PREECLAMPSIA
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
GRANTS
This work was supported by National Institutes of Health (NIH) RO1s
HL-66072, HL-69194, and PO1 HL-51971 (to J. F. Reckelhoff), American
Heart Association Frant SDG 0835472N, and NIH Grant HD-067541. (to B. B.
LaMarca).
19.
20.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
21.
AUTHOR CONTRIBUTIONS
Author contributions: J.L. and B.L. prepared figures; J.L. drafted manuscript; B.L. and J.F.R. edited and revised manuscript; J.F.R. approved final
version of manuscript.
22.
23.
REFERENCES
1. Abitbol MM. Simplified technique to produce toxemia in the rat:
considerations on cause of toxemia. Clin Exp Hypertens B 1: 93–103,
1982.
2. Abitbol MM, Driscoll SG, Ober WB. Placental lesions in experimental
toxemia in the rabbit. Am J Obstet Gynecol 125: 942–948, 1976.
3. Abitbol MM, Gallo GR, Pirani CL, Ober WB. Production of experimental toxemia in the pregnant rabbit. Am J Obstet Gynecol 124:
460 –470, 1976.
4. Abitbol MM, Ober MB, Gallo GR, Driscoll SG, Pirani CL. Experimental toxemia of pregnancy in the monkey, with a preliminary report on
renin and aldosterone. Am J Pathol 86: 573–590, 1977.
5. Abitbol MM, Pirani CL, Ober WB, Driscoll SG, Cohen MW. Production of experimental toxemia in the pregnant dog. Obstet Gynecol 48:
537–548, 1976.
6. Aita K, Etoh M, Hamada H, Yokoyama C, Takahashi A, Suzuki T,
Hara M, Nagata M. Acute and transient podocyte loss and proteinuria
in preeclampsia. Nephron Clin Pract 112: c65–c70, 2009.
7. Alexander BT. Placental insufficiency leads to development of hypertension in growth-restricted offspring. Hypertension 41: 457–462, 2003.
8. Alexander BT, Cockrell K, Cline FD, Llinas MT, Sedeek M, Granger
JP. Effect of angiotensin II synthesis blockade on the hypertensive
24.
25.
26.
27.
28.
29.
response to chronic reductions in uterine perfusion pressure in pregnant
rats. Hypertension 38: 742–745, 2001.
Alexander BT, Rinewalt AN, Cockrell KL, Massey MB, Bennett WA,
Granger JP. Endothelin type a receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure.
Hypertension 37: 485–489, 2001.
Alexander BT, Cockrell KL, Massey MB, Bennett WA, Granger JP.
Tumor necrosis factor-alpha-induced hypertension in pregnant rats results in decreased renal neuronal nitric oxide synthase expression. Am J
Hypertens 15: 170 –175, 2002.
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.
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.
Anderson CM, Lopez F, Zhang HY, Pavlish K, Benoit JN. Reduced
uteroplacental perfusion alters uterine arcuate artery function in the
pregnant Sprague-Dawley rat. Biol Reprod 72: 762–766, 2005.
Anderson CM, Lopez F, Zhang HY, Pavlish K, Benoit JN. Characterization of changes in leptin and leptin receptors in a rat model of
preeclampsia. Am J Obstet Gynecol 193: 267–272, 2005.
Baird JN Jr. Eclampsia in a lowland gorilla. Am J Obstet Gynecol 141:
345–346, 1981.
Baker PN, Davidge ST, Roberts JM. Plasma from women with preeclampsia increases endothelial cell nitric oxide production. Hypertension 26: 244 –248, 1995.
Bridges JP, Gilbert JS, Colson D, Gilbert SA, Dukes MP, Ryan MJ,
Granger JP. Oxidative stress contributes to soluble fms-like tyrosine
kinase-1 induced vascular dysfunction in pregnant rats. Am J Hypertens
22: 564 –568, 2009.
Brown CE, Gant NF, Cox K, Spitz B, Rosenfeld CR, Magness RR.
Low-dose aspirin. II Relationship of angiotensin II pressor responses,
circulating eicosanoids, and pregnancy outcome. Am J Obstet Gynecol
163: 1853–1861, 1990.
Cadnapaphornchai MA, Ohara M, Morris KG Jr, Knotek M, Rogachev B, Ladtkow T, Carter EP, Schrier RW. Chronic NOS inhibition reverses systemic vasodilation and glomerular hyperfiltration in
pregnancy. Am J Physiol Renal Physiol 280: F592–F598, 2001.
Cavanagh D, Rao PS, Knuppel RA, Desai U, Balis JU. Pregnancyinduced hypertension: development of a model in the pregnant primate
(Papio anubis). Am J Obstet Gynecol 151: 987–999, 1985.
Chang EY, Barbosa E, Paintlia MK, Singh A, Singh I. The use of
N-acetylcysteine for the prevention of hypertension in the reduced
uterine perfusion pressure model for preeclampsia in Sprague-Dawley
rats. Am J Obstet Gynecol 193: 952–956, 2005.
Choi JW, Im MW, Pai SH. Nitric oxide production increases during
normal pregnancy and decreases in preeclampsia. Ann Clin Lab Sci 32:
257–263, 2002.
Clark KE, Durnwald M, Austin JE. A model for studying chronic
reduction in uterine blood flow in pregnant sheep. Am J Physiol Heart
Circ Physiol 242: H297–H301, 1982.
Crews JK, Herrington JN, Granger JP, Khalil RA. Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rat. Hypertension 35: 367–372, 2000.
Croy BA, Burke SD, Barrette VF, Zhang J, Hatta K, Smith GN,
Bianco J, Yamada AT, Adams MA. Identification of the primary
outcomes that result from deficient spiral arterial modification in pregnant mice. Pregnancy Hypertens 1: 87–94, 2011.
Davisson RL, Hoffmann DS, Butz GM, Aldape G, Schlager G,
Merrill DC, Sethi S, Weiss RM, Bates JN. Discovery of a spontaneous
genetic mouse model of preeclampsia. Hypertension 39: 337–342, 2002.
Deng A, Engels K, Baylis C. Impact of nitric oxide deficiency on blood
pressure and glomerular hemodynamic adaptations to pregnancy in the
rat. Kidney Int 50: 1132–1138, 1996.
Dokras A, Hoffmann DS, Eastvold JS, Kienzle MF, Gruman LM,
Kirby PA, Weiss RM, Davisson RL. Severe feto-placental abnormalities precede the onset of hypertension and proteinuria in a mouse model
of preeclampsia. Biol Reprod 75: 899 –907, 2006.
Eder DJ, Macdonald MT. A role for brain angioension II in experimental pregnancy-induced hypertesnion in laboratory rats. Clin Exp
Hypertens Preg B6: 431–451, 1988.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00117.2012 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
great apes. Thus to our knowledge, preeclampsia occurs spontaneously only in women and great apes due to abnormal
placentation and the resulting placental ischemia. Thus no
animal model of preeclampsia can mimic the entire pathogenesis of the disease as seen in women. A variety of animal
models, including genetically manipulated mouse models,
have been developed based on a single mediator of preeclampsia that only reflects limited aspects of the mechanisms underlying the disease; however, these are useful to identify mechanisms that could potentially contribute to the pathogenesis of
preeclampsia. The RUPP model has been performed in various
species (see Table 1) and involves induction of placental
ischemia by reducing uterine blood flow by some maneuver,
such as placement of clips on the uterine arteries and abdominal aorta, that results in a preeclamptic state. The RUPP model
in the rat has been the most extensively studied (see Table 2)
and exhibits many of the manifestations of preeclampsia (see
Table 3). Unfortunately, the greatest limitation of the RUPP
model is its lack of suitability for the study of early placentation and the subsequent pathogenesis responsible for placental
ischemia, such as early occurring abnormal immune mechanisms or trophoblast invasion and vascular remodeling. However, the RUPP model is excellent for the study of many of the
consequences of placental ischemia, including hypertension,
vascular dysfunction, and immune dysfunction. The ability to
develop the RUPP model in both rats and nonhuman primates
makes it advantageous for many future studies. Whether the
RUPP model could be developed in mice is not clear.
Review
RAT MODEL OF PREECLAMPSIA
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
kidney of normal and hypertensive pregnant rats. Am J Physiol Regul
Integr Comp Physiol 293: R169 –R177, 2007.
Khalil RA, Granger JP. Vascular mechanisms of increased arterial
pressure in preeclampsia: lessons from animal models. Am J Physiol
Regul Integr Comp Physiol 283: R29 –R45, 2002.
Kupferminc MJ, Peaceman AM, Wigton TR, Rehnberg KA, Socol
ML. Tumor necrosis factor-alpha is elevated in plasma and amniotic
fluid of patients with severe preeclampsia. Am J Obstet Gynecol 170:
1752–1759, 1994.
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.
LaMarca B, Parrish M, Ray LF, Murphy SR, Roberts L, Glover P,
Wallukat G, Wenzel K, Cockrell K, Martin JN Jr, Ryan MJ,
Dechend R. Hypertension in response to autoantibodies to the angiotensin II type I receptor (AT1-AA) in pregnant rats: role of endothelin-1.
Hypertension 54: 905–909, 2009.
LaMarca B, Speed J, Fournier L, Babcock SA, Berry H, Cockrell K,
Granger JP. Hypertension in response to chronic reductions in uterine
perfusion in pregnant rats: effect of tumor necrosis factor-alpha blockade.
Hypertension 52: 1161–1167, 2008.
LaMarca B, Speed J, Ray LF, Cockrell K, Wallukat G, Dechend R,
Granger J. Hypertension in response to IL-6 during pregnancy: role of
AT1-receptor activation. Inter J Interferon Cytokine Med Res 3: 65–70,
2011.
LaMarca B, Wallace K, Herse F, Wallukat G, Martin JN Jr, Weimer
A, Dechend R. Hypertension in response to placental ischemia during
pregnancy: role of B lymphocytes. Hypertension 57: 865–871, 2011.
LaMarca B, Wallukat G, Llinas M, Herse F, Dechend R, Granger
JP. Autoantibodies to the angiotensin type I receptor in response to
placental ischemia and tumor necrosis factor alpha in pregnant rats.
Hypertension 52: 1168 –1172, 2008.
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.
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.
Leffler CW, Hessler JR, Green RS, Fletcher AM. Effects of sodium
chloride on pregnant sheep with reduced uteroplacental perfusion pressure. Hypertension 8: 62–65, 1986.
Lindheimer MD, Conrad KP, Karumanchi SA. Renal Physiology and
Disease in Pregnancy. In: Seldin and Giebisch’s The Kidney; Physiology
and Pathophysiology (4th ed.), edited by Alpern RJ and Hebert SC. San
Diego, CA: Academic, 2008, p. 2339 –2398.
Llinás MT, Alexander BT, Capparelli MF, Carroll MA, Granger JP.
Cytochrome P-450 inhibition attenuates hypertension induced by reductions in uterine perfusion pressure in pregnant rats. Hypertension 43:
623–628, 2004.
Llinás MT, Alexander BT, Seedek M, Abram SR, Crell A, Granger
JP. Enhanced thromboxane synthesis during chronic reductions in uterine perfusion pressure in pregnant rats. Am J Hypertens 15: 793–797,
2002.
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.
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 preeclampsia in unrestrained conscious pregnant mice. Am J Obstet Gynecol 196:
396 e391–e397, 2007.
Magann EF, Bass JD, Chauhan SP, Perry KG Jr, Morrison JC,
Martin JN Jr. Accelerated recovery from severe preeclampsia: uterine
curettage versus nifedipine. J Soc Gynecol Investig 1: 210 –214, 1994.
Makris A, Thornton C, Thompson J, Thomson S, Martin R, Ogle R,
Waugh R, McKenzie P, Kirwan P, Hennessy A. Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney Int
71: 977–984, 2007.
Masuyama H, Nakatsukasa H, Takamoto N, Hiramatsu Y. Correlation between soluble endoglin, vascular endothelial growth factor receptor-1, and adipocytokines in preeclampsia. J Clin Endocrinol Metab 92:
2672–2679, 2007.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00117.2012 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
30. Gadonski G, LaMarca BB, Sullivan E, Bennett W, Chandler D,
Granger JP. Hypertension produced by reductions in uterine perfusion
in the pregnant rat: role of interleukin 6. Hypertension 48: 711–716,
2006.
31. Garovic VD, Wagner SJ, Turner ST, Rosenthal DW, Watson WJ,
Brost BC, Rose CH, Gavrilova L, Craigo P, Bailey KR, Achenbach
J, Schiffer M, Grande JP. Urinary podocyte excretion as a marker for
preeclampsia. Am J Obstet Gynecol 196: e1–e7, 2007.
32. George EM, Arany M, Cockrell K, Storm MV, Stec DE, Granger JP.
Induction of heme oxygenase-1 attenuates sFlt-1-induced hypertension in
pregnant rats. Am J Physiol Regul Integr Comp Physiol 301: R1495–
R1500, 2011.
33. George EM, Cockrell K, Arany M, Csongradi E, Stec DE, Granger
JP. Induction of heme oxygenase 1 attenuates placental ischemia-induced hypertension. Hypertension 57: 941–948, 2011.
34. George EM, Colson D, Dixon J, Palei AC, Granger JP. Heme
oxygenase-1 attenuates hypoxia-induced sFlt-1 and oxidative stress in
placental villi through its metabolic products CO and bilirubin. Int J
Hypertens In press.
35. Gilbert JS, Babcock SA, Granger JP. Hypertension produced by
reduced uterine perfusion in pregnant rats is associated with increased
soluble fms-like tyrosine kinase-1 expression. Hypertension 50: 1142–
1147, 2007.
36. Gilbert JS, Bauer AJ, Gingery A, Banek CT, Chasson S. Circulating
and utero-placental adaptations to chronic ischemia in the rat. Placenta
33: 100 –105, 2012.
37. Gilbert JS, Gilbert SA, Arany M, Granger JP. Hypertension produced
by placental ischemia in pregnant rats is associated with increased
soluble endoglin expression. Hypertension 53: 399 –403, 2009.
38. Gilbert JS, Verzwyvelt J, Colson D, Arany M, Karumanchi SA,
Granger JP. Recombinant vascular endothelial growth factor 121 infusion lowers blood pressure and improves renal function in rats with
placentalischemia-induced hypertension. Hypertension 55: 380 –385,
2010.
39. Golden JG, Hughes HC, Lang CM. Experimental toxemia in the
pregnant guinea pig (Cavia porcellus). Lab Anim Sci 30: 174 –179, 1980.
40. Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA.
Pathophysiology of preeclampsia: linking placental ischemia/hypoxia
with microvascular dysfunction. Microcirculation 9: 147–160, 2002.
41. Gutkowska J, Granger JP, Lamarca BB, Danalache BA, Wang D,
Jankowski M. Changes in cardiac structure in hypertension produced by
placental ischemia in pregnant rats: effect of tumor necrosis factor
blockade. J Hypertens 29: 1203–1212, 2011.
42. Harris LK. IFPA Gabor Than Award lecture: Transformation of the
spiral arteries in human pregnancy: key events in the remodelling
timeline. Placenta 32, Suppl 2: S154 –S158, 2011.
43. Hefler LA, Tempfer CB, Moreno RM, O’Brien WE, Gregg AR.
Endothelial-derived nitric oxide and angiotensinogen: blood pressure and
metabolism during mouse pregnancy. Am J Physiol Regul Integr Comp
Physiol 280: R174 –R182, 2001.
44. Hines T, Beauchamp D, Rice C. Baroreflex control of sympathetic
nerve activity in hypertensive pregnant rats with reduced uterine perfusion. Hypertens Pregnancy 26: 303–314, 2007.
45. Hladunewich M, Karumanchi SA, Lafayette R. Pathophysiology of
the clinical manifestations of preeclampsia. Clin J Am Soc Nephrol 2:
543–549, 2007.
46. Hoffmann DS, Weydert CJ, Lazartigues E, Kutschke WJ, Kienzle
MF, Leach JE, Sharma JA, Sharma RV, Davisson RL. Chronic
tempol prevents hypertension, proteinuria, and poor feto-placental outcomes in BPH/5 mouse model of preeclampsia. Hypertension 51: 1058 –
1065, 2008.
47. Ishida J, Matsuoka T, Saito-Fujita T, Inaba S, Kunita S, Sugiyama
F, Yagami K, Fukamizu A. Pregnancy-associated homeostasis and
dysregulation: lessons from genetically modified animal models. J
Biochem 150: 5–14, 2011.
48. Isler CM, Bennett WA, Rinewalt AN, Cockrell KL, Martin JN Jr,
Morrison JC, Granger JP. Evaluation of a rat model of preeclampsia
for HELLP syndrome characteristics. J Soc Gynecol Investig 10: 151–
153, 2003.
49. Johne J. Pregnancy toxaemia in a multiparous chimpanzee at Dallas
Zoo. Int Zoo Yearb 11: 239 –241, 1971.
50. Joyner J, Neves LA, Granger JP, Alexander BT, Merrill DC, Chappell MC, Ferrario CM, Davis WP, Brosnihan KB. Temporal-spatial
expression of ANG-(1–7) and angiotensin-converting enzyme 2 in the
H7
Review
H8
RAT MODEL OF PREECLAMPSIA
90. 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.
91. Stout C, Lemmon WB. Glomerular capillary endothelial swelling in a
pregnant chimpanzee. Am J Obstet Gynecol 105: 212–215, 1969.
92. Sunderland NS, Thomson SE, Heffernan SJ, Lim S, Thompson J,
Ogle R, McKenzie P, Kirwan PJ, Makris A, Hennessy A. Tumor
necrosis factor ␣ induces a model of preeclampsia in pregnant baboons
(Papio hamadryas). Cytokine 56: 192–199, 2011.
93. Tam Tam KB, George E, Cockrell K, Arany M, Speed J, Martin JN
Jr, Lamarca B, Granger JP. Endothelin type A receptor antagonist
attenuates placental ischemia-induced hypertension and uterine vascular
resistance. Am J Obstet Gynecol 204: 330 e331–e334, 2011.
94. Thatcher CD, Keith JC Jr. Pregnancy-induced hypertension: development of a model in the pregnant sheep. Am J Obstet Gynecol 155:
201–207, 1986.
95. Thornton JG, Onwude JL. Convulsions in pregnancy in related gorillas. Am J Obstet Gynecol 167: 240 –241, 1992.
96. Uzan J, Carbonnel M, Piconne O, Asmar R, Ayoubi JM. Preeclampsia: pathophysiology, diagnosis, management. Vasc Health Risk
Manag 7: 467–474, 2011.
97. Veillon EW Jr, Keiser SD, Parrish MR, Bennett W, Cockrell K, Ray
LF, Granger JP, Martin JN Jr, LaMarca B. 17-Hydroxyprogesterone
blunts the hypertensive response associated with reductions in uterine
perfusion pressure in pregnant rats. Am J Obstet Gynecol 201: e1–e6,
2009.
98. 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 contributes to the pathogenesis of preeclampsia. Nat Med 12: 642–649, 2006.
99. Wallace K, Richards S, Dhillon P, Weimer A, Edholm ES, Bengten
E, Wilson M, Martin JN Jr, LaMarca B. CD4⫹ T-helper cells
stimulated in response to placental ischemia mediate hypertension during
pregnancy. Hypertension 57: 949 –955, 2011.
100. 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 autoantibodies against the angiotensin AT1 receptor. J Clin Invest 103:
945–952, 1999.
101. Walsh S, English F, Crocker I, Johns E, Kenny L. Contribution of
poly(ADP-ribose) polymerase to endothelial dysfunction and hypertension in a rat model of pre-eclampsia. Br J Pharmacol In press.
102. Walsh SK, English FA, Johns EJ, Kenny LC. Plasma-mediated vascular dysfunction in the reduced uterine perfusion pressure model of
preeclampsia: a microvascular characterization. Hypertension 54: 345–
351, 2009.
103. Woods AK, Hoffmann DS, Weydert CJ, Butler SD, Zhou Y, Sharma
RV, Davisson RL. Adenoviral delivery of VEGF121 early in pregnancy
prevents spontaneous development of preeclampsia in BPH/5 mice.
Hypertension 57: 94 –102, 2011.
104. Woods LL. Importance of prostaglandins in hypertension during reduced
uteroplacental perfusion pressure. Am J Physiol Regul Integr Comp
Physiol 257: R1558 –R1561, 1989.
105. Woods LL, Brooks VL. Role of the renin-angiotensin system in hypertension during reduced uteroplacental perfusion pressure. Am J Physiol
Regul Integr Comp Physiol 257: R204 –R209, 1989.
106. Yallampalli C, Garfield RE. Inhibition of nitric oxide synthesis in rats
during pregnancy produces signs similar to those of preeclampsia. Am J
Obstet Gynecol 169: 1316 –1320, 1993.
107. Young J. The aetiology of eclampsia and albuminuria and their relation
to accidental haemorrhage: an anatomical and experimental investigation. Proc R Soc Med 7: 307–348, 1914.
108. Zhou CC, Zhang Y, Irani RA, Zhang H, Mi T, Popek EJ, Hicks MJ,
Ramin SM, Kellems RE, Xia Y. Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med 14: 855–862,
2008.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00117.2012 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on June 16, 2017
70. 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.
71. McCarthy FP, Drewlo S, Kingdom J, Johns EJ, Walsh SK, Kenny
LC. Peroxisome proliferator-activated receptor-␥ as a potential therapeutic target in the treatment of preeclampsia. Hypertension 58: 280 –286,
2011.
72. McCarthy FP, Kingdom JC, Kenny LC, Walsh SK. Animal models of
preeclampsia; uses and limitations. Placenta 32: 413–419, 2011.
73. Meis PJ, Goldenberg RL, Mercer BM, Iams JD, Moawad AH,
Miodovnik M, Menard MK, Caritis SN, Thurnau GR, Bottoms SF,
Das A, Roberts JM, McNellis D. The preterm prediction study: risk
factors for indicated preterm births. Maternal-Fetal Medicine Units
Network of the National Institute of Child Health and Human Development. Am J Obstet Gynecol 178: 562–567, 1998.
74. Molnar M, Suto T, Toth T, Hertelendy F. Prolonged blockade of nitric
oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation. Am J Obstet
Gynecol 170: 1458 –1466, 1994.
75. Murphy JG, Herrington JN, Granger JP, Khalil RA. Enhanced
[Ca2⫹]i in renal arterial smooth muscle cells of pregnant rats with
reduced uterine perfusion pressure. Am J Physiol Heart Circ Physiol 284:
H393–H403, 2003.
76. Murphy SR, Lamarca B, Cockrell K, Arany M, Granger JP. L-Arginine supplementation abolishes the blood pressure and endothelin response to chronic increases in plasma sFlt-1 in pregnant rats. Am J
Physiol Regul Integr Comp Physiol 302: R259 –R263, 2012.
77. Ogden E, Hildebrand GJ, Page EW. Rise of blood pressure during
ischemia of the gravid uterus. Proc Soc Exp Biol Med 43: 49 –51, 1940.
78. Ojeda NB, Grigore D, Alexander BT. Intrauterine growth restriction:
fetal programming of hypertension and kidney disease. Adv Chronic
Kidney Dis 15: 101–106, 2008.
79. Parrish MR, Murphy SR, Rutland S, Wallace K, Wenzel K, Wallukat G, Keiser S, Ray LF, Dechend R, Martin JN, Granger JP,
LaMarca B. The effect of immune factors, tumor necrosis factor-alpha,
and agonistic autoantibodies to the angiotensin II type I receptor on
soluble fms-like tyrosine-1 and soluble endoglin production in response
to hypertension during pregnancy. Am J Hypertens 23: 911–916, 2010.
80. Podjarny E, Losonczy G, Baylis C. Animal models of preeclampsia.
Semin Nephrol 24: 596 –606, 2004.
81. Ramirez RJ, Debrah J, Novak J. Increased myogenic responses of
resistance-sized mesenteric arteries after reduced uterine perfusion pressure in pregnant rats. Hypertens Pregnancy 30: 45–57, 2011.
82. Redman CW. Preeclampsia: a multi-stress disorder. Rev Med Interne 32,
Suppl 1: S41–S44, 2011.
83. Redman CW, Sargent IL. Immunology of pre-eclampsia. Am J Reprod
Immunol 63: 534 –543, 2010.
84. 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.
85. Ryan MJ, Gilbert EL, Glover PH, George EM, Masterson CW,
McLemore GR Jr, LaMarca B, Granger JP, Drummond HA. Placental ischemia impairs middle cerebral artery myogenic responses in the
pregnant rat. Hypertension 58: 1126 –1131, 2011.
86. Saito S, Shiozaki A, Nakashima A, Sakai M, Sasaki Y. The role of the
immune system in preeclampsia. Mol Aspects Med 28: 192–209, 2007.
87. Schiessl B. Inflammatory response in preeclampsia. Mol Aspects Med 28:
210 –219, 2007.
88. Sedeek M, Gilbert JS, LaMarca BB, Sholook M, Chandler DL,
Wang Y, Granger JP. Role of reactive oxygen species in hypertension
produced by reduced uterine perfusion in pregnant rats. Am J Hypertens
21: 1152–1156, 2008.
89. Shesely EG, Gilbert C, Granderson G, Carretero CD, Carretero OA,
Beierwaltes WH. Nitric oxide synthase gene knockout mice do not
become hypertensive during pregnancy. Am J Obstet Gynecol 185:
1198 –1203, 2001.