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Central Medical Journal of Obstetrics and Gynecology

Cite this article: Suzuki H, Ohkuchi A, Shirasuna K, Takahashi H, Usui R, et al. (2014) Animal Models of Preeclampsia: Insight into Possible Biomarker Can-didates for Predicting Preeclampsia. Med J Obstet Gynecol 2(2): 1031.

*Corresponding authorsAkihide Ohkuchi, Department of Obstetrics and Gynecology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan,Tel: 81-285-58-7376; Fax: 81-285-44-8505; Email:

Submitted: 26 April 2014

Accepted: 09 June 2014

Published: 10 June 2014

ISSN: 2333-6439

Copyright© 2014 Ohkuchi et al.

OPEN ACCESS

Research Article

Animal Models of Preeclampsia: Insight into Possible Biomarker Candidates for Predicting PreeclampsiaHirotada Suzuki1, Akihide Ohkuchi1*, Koumei Shirasuna2,3, Hironori Takahashi1, Rie Usui1, Shigeki Matsubara1 and Mitsuaki Suzuki1

1Department of Obstetrics and Gynecology, Jichi Medical University School of Medicine, Japan2Division of Inflammation Research, Center of Molecular Medicine, Jichi Medical University, Japan3Department of Animal Science, Tokyo University of Agriculture, Japan

Keywords•Preeclampsia•Mouse•Rat•Animal model•Prediction

Abstract

Aim: Animal models of preeclampsia (PE) have been extensively developed. Angiogenic/angiostatic balance theory bysoluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and soluble endoglin (sEng) for the genesis of PE is one of the most successful models of translational research from bench to bed. However, the balance theory of angiogenic/angiostatic factors does not explain the genesis of PE entirely. We attempted to list articles on animal models of PE and to gain insight into possible biomarker candidates for predicting PE.

Methods: We collected 64 articles animal models of PE, consisting of 25 different methods. For angiotensinogen/renin, complement component C1q, 2-methoxyoestradiol (2-ME)/catechol-O-methyltransferase (COMT), galectin-1 (Gal-1), heme oxygenase-1 (HO-1), interleukin (IL)-10, and asymmetric dimethylarginine (ADMA)/L-arginine, we searched for articles on the prediction of PE in PubMed.

Results: Angiotensinogen in the first trimester, prorenin at 8 weeks of gestation in women with type 1 diabetes, and plasma prorenin receptor in early pregnancy might predict the occurrence of PE. Low Gal-1 levels during the first trimester might predict the occurrence of PE during the second trimester. IL-10 levels did not change before the onset of PE. Maternal plasma ADMA in the second and third trimesters was higher in women with PE. We could not find any cohort or nested case-control studies on complement component C1q, 2-ME/COMT, and HO-1.

Conclusion: Clinically useful biomarkers other than angiogenesis-related factors were not found. Basic research using animal models will gain insight into possible biomarker candidates for predicting PE.

Special Issue on

Prediction of Preeclampsia

INTRODUCTIONPreeclampsia (PE) is associated with maternal and infantile

morbidity and mortality [1-3]. Recently, after the discovery of the roles of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) in the genesis of a preeclamptic rodent model showing hypertension, proteinuria, and glomerular endotheliosis [4,5], several prospective cohort studies have elucidated that serum/plasma levels of placental growth factor (PlGF), sFlt-1, sEng, and the sFlt-1/PlGF ratio may be useful to

predict the occurrence of PE [6-12]. Recently, we showed that the onset threshold of plasma levels of the sFlt-1/PlGF ratio is a highly sensitive and specific screening method for detecting the imminent onset of PE within 4 weeks after blood sampling at 19–31 weeks [13,14]. Thus, angiogenic/angiostatic balance theory by sFlt-1, PlGF and sEng for the genesis of PE is one of the most successful models of translational research from bench to bed. However, the balance theory does not explain the genesis of PE entirely, because some women with PE did not show an increased level of sFlt-1 and/or sEng, or a decreased level of

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Ohkuchi et al. (2013)Email:

Med J Obstet Gynecol 2(2): 1031 (2014) 2/12

PlGF, especially at ≥36 weeks of gestation [15,16]. Therefore, new candidates causing and/or facilitating the occurrence of PE have been searched for vigorously [17,18].

In this review, we attempted to list articles on animal models of PE and to gain insight into possible biomarker candidates for predicting PE.

METHODSH.S. searched for articles on animal models of PE in PubMed.

He found 7 articles using the angiotensinogen/renin system [19-25], 3 articles using BPH/5 [26-28], 1 article using complement component C1q [29], 1 article using a model by crossbreeding CBA and JXDBA/2 [30], 2 articles using 2-methoxyoestradiol (2-ME)/catechol-O-methyltransferase (COMT)deficiency [31,32], 1 article using an antagonist of galectin-1 (Gal-1) [33], 1 article using heme oxygenase-1 (HO-1) knockout (KO) mice [34], 1 article using chronic administration of the inhibitor of cystathionine γ-lyase (CSE, an enzyme responsible for the endogenous production of hydrogen sulfide [H2S]), DL-propargylglycine (PAG) [35], 1 article using indoleamine 2,3-dioxygenase (IDO) inhibitor, 1-methyl-L-tryptophan [36], 5 articles using IgG of human PE (angiotensin II type 1 [AT1] receptor agonistic autoantibody [AT1-AA]) [37-41], 1 article using interleukin (IL)-10 KO mice [42], 5 articles using N(omega)-nitro-L-arginine methyl ester (L-NAME) [43-47], 1 article using desoxycorticosterone acetate (DOCA), and marinobufagenin (MBG) [48], 1 article using matrix metalloproteinase-9 (MMP-9)KO mice [49], 1 article using ligand of the liver X receptor (LXR) oxygenated cholesterol derivatives (oxysterols) [50], 1 article using a model by crossbreeding p57kip heterozygous KOmice and p57kip heterozygous KO mice [51], 2 articles using phosphatidylserine/phosphatidylcholine (PSPC) [52,53], 10 articles using reduced uterine perfusion pressure (RUPP) models [54-63], 1 article using both adenovirus vector of sEng and adenovirus vector of sFlt-1 [5], 9 articles using adenovirus vector of sFlt-1 alone [4,64-71], 1 article using exogenous mouse vascular endothelial growth factor (VEGF) [72], 1 article on Storkhead box-1 (STOX1) transgenic (tg) mice [73], 2 articles using suramin [74,75], 2 articles using helper T cells type 1 (Th1) like splenocytes [76,77], and 3 articles by stimulation of Toll-like receptor (TLR)-3 or hyper-expression of TLR-3 [78-80] (Table 1).

As for angiotensinogen/renin, complement component C1q, 2-ME/COMT, Gal-1, HO-1, IL-10, and L-NAME, A.O. searched for articles on the prediction of PE using these markers in PubMed. The following combinations of key words were used: A AND B, where A was the key word of the target biomarker, and B was a constant key word. A was “angiotensinogen” OR “renin”, “C1q” AND “complement”, “2-methoxyoestradiol” OR “catechol-O-methyltransferase”, “galectin-1”, “heme oxygenase-1”, “IL-10”, or (“asymmetric dimethylarginine” OR ADMA OR L-arginine OR “nitric oxide”). B was ((preeclampsia OR “pregnancy-induced hypertension” OR “hypertension in pregnancy” OR “gestational hypertension” OR “EPH gestosis” OR “toxemia of pregnancy” OR eclampsia) AND (predict* OR predicting OR prediction OR ((cohort OR prospective OR retrospective OR “nested case-control”) AND study) OR “risk factor” OR “meta-analysis”OR “systematic review” OR combination OR multivariate OR “logistic regression”)).

RESULTS AND DISCUSSION

Angiotensinogen and renin

Increased angiotensinogen and renin in pregnant mice/rats caused PE-like changes (Table 1) [19-25], suggesting that increases of angiotensinogen and renin might be candidates for predicting PE. We searched for articles in PubMed using the key words of (“angiotensinogen” OR “renin”) AND B. Angiotensinogen in the first trimester [81], prorenin at 8 weeks of gestation in women with type 1 diabetes [82], and plasma prorenin receptor in early pregnancy [83] might predict the occurrence of PE.

Complement component C1q

Complement component C1q has an important role in trophoblast migration, spiral artery remodeling, and normal placentation [29]. Pregnant C1q-deficient (C1q-/-) mice developed PE-like changes and showed decreased placental VEGF and elevated levels of sFlt-1; treatment of C1q-/- mice with pravastatin restored angiogenic balance and reduced hypertension and albuminuria [29]. This study suggested that a decrease of C1q might be a candidate for predicting PE. We searched for articles in PubMed using the key words of (“C1q” AND complement) AND B. However, there were no hits.

COMT, 2-ME

2-ME, a natural metabolite of estradiol, is generated by COMT in the placenta and increases during pregnancy; however, placental COMT activity is suppressed in women with PE [31]. Kanasaki et al. [31] discovered that pregnant mice deficient in COMT develop PE-like changes; 2-ME ameliorated all symptoms and suppressed placental hypoxia, hypoxia-inducible factor-1α expression and sFlt-1 elevation (Table 1). In addition, the levels of COMT and 2-ME were significantly lower in women with PE [31], suggesting that the decreases of 2-ME and COMT might be candidates for predicting PE. We searched for articles in PubMed using the key words of (“2-methoxyoestradiol” OR “catechol-O-methyltransferase”) AND B. We could not find any studies on predicting PE using 2-ME and/or COMT.

Galectin-1 (Gal-1)

Gal-1, a member of a family of carbohydrate-binding proteins, is associated with placentation and the promotion of maternal tolerance toward fetal antigens [33]. Freitag et al. [33] discovered that Gal-1 exhibits proangiogenic functions during early stages of pregnancy, promoting decidual vascular expansion through VEGF receptor 2 signaling; blocking Gal-1-mediated angiogenesis results in PE-like changes in mice. In addition, low Gal-1 levels during the first trimester were associated with the occurrence of PE during the second trimester, suggesting that a low level of Gal-1 in early pregnancy might be a candidate for predicting PE (Table 1). We searched for articles in PubMed using the key words of “galectin-1” AND B, but we could not find any studies on predicting PE using Gal-1.

HO-1

HO-1 and its metabolite carbon monoxide (CO) exert protective effects against oxidative stimuli [34]. Cudmore et al. [34] discovered that adenoviral overexpression of HO-1 in

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Mole-cles/

Strain

Author, year, [ref-

erence]Species Methods Classifi-cation Symptoms Treatment

Angiotensinogen/renin systemTakimoto E, 1996 [19]

mice Angiotensinogen tg renin tg PEHypertension, proteinuria myo-cardial hypertrophy, placental edema/necrosis.

Recovery of blood pressure af-ter delivery.

Bohlender J, 2000 [20]

rats Angiotensinogen tg♀ Ｘrenin tg♂ GH Hypertension. NR: proteinuria. Amelioration of hypertension

after birth.

Brosnihan KB, 2010 [21]

rats Angiotensinogen tg♀ Ｘrenin tg♂ PE

Increased blood pressure, pro-teinuria, and FGR, lower placen-tal weight.

Geusens N, 2010 [22]

rats Angiotensinogen tg♀ Ｘrenin tg♂ PE FGR.

Falcao S, 2009 [23] mice Angiotensinogen and renin dou-

ble tg pregnant mice sPE

Hypertension, proteinuria placental necrosis, reduced pup weight, reduced placental weight, heart hypertrophy.

Genest DS, 2013 [24] mice Angiotensinogen and renin dou-

ble tg pregnant mice sPEChronic hypertension, increased blood pressure during preg-nancy, proteinuria.

Exercise training ameliorated blood pressure, proteinuria.

Hering L, 2010 [25] rats Administration of angiotensinⅡ

to pregnant rat PE

Hypertension, proteinuria, re-duced placental weight, reduced fetal weight, reduced trophob-last invasion, increased uterine artery resistance.

BPH/5

Davisson RL, 2002 [26]

mice BPH/5 x BPH/5 PE

Hypertension, proteinuria, glomerulosclerosis, reduced pup weight, reduced litter size, impaired endothelium-depend-ent relaxation in resistance arteries.

Recovery of blood pressure af-ter delivery.

Woods AK, 2011 [27]

mice BPH/5 x BPH/5, administration of Ad-VEGF at 7.5 day. PE

Hypertension, proteinuria, fetal resorption. Reduced levels of free VEGF and PlGF; unchanged sFlt-1.

Amelioration of hypertension, proteinuria, and fetal resorp-tionby the administration of Ad-VEGF.

Hoffmann DS, 2008 [28]

mice

BPH/5 x BPH/5, administra-tion of Tempol (superoxide dismutase mimetic) throughout gestation

PEFGR, fetal absorption, hyperten-sion, proteinuria. Increased ROS.

Amelioration fetal growth and survival, hypertension, pro-teinuria by the administration of Tempol.

C1q

Singh J, 2011 [29] mice C1q KO x C1q KO PE

Hypertension, proteinuria, glomerular endotheliosis, re-duced litter size, increased sFlt-1, decreased VEGF, increased STAT-3.

Amelioration by the administra-tion of pravastatin.

CBA X JXDBA/2

Ahmed A, 2010 [30] mice i) CBA/J♀ x DBA/2♂

ii) Administration of AngII to i) PE

Hypertension, albuminuria, en-dotheliosis, decreased placental VEGFand elevated placental sFlt-1.

Restoration of trophoblast invasiveness, placental blood flow, and angiogenic balance, and prevention of the onset of PE by the administration of pravastatin.

COMT KO

Kanasaki K, 2008 [31]

mice COMT KO pregnant mice PE

Hypertension, proteinuria, en-dotheliosis, reduced placental weight, reduced littersize, in-creased sFlt-1.

Amelioration of all PE-like fea-tures by the administration of 2-ME.

Table 1: Preeclampsia (PE) models (mouse/rat).

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Stanley JL, 2012 [32] mice COMT KO pregnant mice PE

Hypertension, proteinuria, FGR, abnormal umbilical Doppler waveforms.

Administration of sildenafil cit-rate improved fetal growth, and notch on the umbilical artery.

Gal-1

Freitag N, 2013 [33] mice

i) administration of antagonist of gal-1 to pregnant mice. ii) Lgals1 KO mice.

PE

Hypertension, proteinuria, re-duced placental weight, reduced litter size, reduced pup weight, increased sEng, increased AT1-AA.

HO-1KOCudmore M, 2007 [34]

mice HO-1 KO pregnant mice Increased sFlt-1, increased sEng.

Hydrogen sulfide

Wang K, 2013 [35] mice

Administration of DL-propar-gylglycine, which inhibits activ-ity of cystathionineγ-lyase (CSE), which produces a gaseous messenger, H2S, to pregnant mice.

PE

Hypertension, proteinuria, reduced pup weight, increased sFlt-1, increased sEng, liver damage.

Amelioration of angiogenic balance, fetal growth by the administration of GYY4137 (H2S release).

IDONishizawa H, 2008 [36]

mice Administration of IDO inhibitor to pregnant mice. PE

Hypertension, proteinuria, 　　　　　placental circulation impairment.

IgG of human PE(AT1-AA)

Zhou CC, 2008 [37] mice

Administration of IgG antibody-obtained from human PE or AT1-AA to pregnant mice.

PE

Hypertension, proteinuria, glomerular endotheliosis, pla-cental abnormalities, reduced pup weight, increased sFlt-1.

Amelioration of symptoms by losartan, an AT1 receptorantagonist, antibody neutraliz-ing seven–amino-acid sequence on the second extracellular loop of AT1 receptor.

Siddiqui AH, 2013 [38] mice

Administration of IgG antibody obtained from human PE to pregnant mice.

PE

Hypertension, proteinuria, 　　decreased aldosterone, cel-lular and vascular impairment of adrenal glands, increased sFlt-1.

Amelioration of symptoms by losartan, 7-aa epitope peptide, VEGF121 infusion.



PE

Hypertension, proteinuria, and renal damage. PreproET-1 mRNA and IL-6 mRNA were increased in placenta and kidney, and serum level of IL-6 was increased.

Amelioration ofhypertension, proteinuria, and renal damage-by the administration of ET-A antagonist BQ123, and anti-IL-6 antibody.



PE

Hypertension, proteinuria, and renal damage. Increased sEng, increased production of sEng in placenta, increased TNFα, increased production of TNFα in placenta.　　　　　　　　

Irani RA, 2010 [41] mice


PE

Hypertension, proteinuria, in-creased sFlt-1, increased sEng, increased production of TNFαin placenta.

IL-10 KO

Lai Z, 2011 [42] mice IL-10 KO pregnant miceunder

9.5% oxygen concentration. PE

Hypertension, proteinuria, glomerular endotheliosis, re-duced pup weight, increased sFlt-1.

Amelioration of symptoms by the administration of recom-binant IL-10.

L-NAME

Herraiz S, 2012 [43] rats Administration of L-NAME to

pregnant rats. PE Hypertension, proteinuria, FGR.

By the administration of silde-nafil citrate (SC), blood pressure was decreased, proteinuria was ameliorated, and fetal weight and survival rates were increased.

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Souza CO, 2012 [44] rats Administration of L-NAME to

pregnant rats. PEHypertension, proteinuria, FGR, low platelet counts, increased IL-1β, TNF-α, IFN-γ.

By the administration of silibinin(a flavonoid with anti-inflammatory and hepatopro-tective properties), blood pres-sure was decreased, proteinuria was decreased, fetal weight was increased, the number of fetus-es was increased, and the levels of IL-1b, Ｉｌ-10, ＩL-6, TNF-α, IFN-γ were decreased.

Talebianpoor MS, 2012 [45] rats Administration of L-NAME to

pregnant rats. PE

Hypertension, proteinuria, increasedoxidative stress markers, increased vascular sensitivity to phenylephrine and decreased sensitivity to acetyl-choline.

Blood pressure was decreased by the administration of tempol(a syntheticantioxidant and a superoxide dismutase mi-metic agent).

Yang X, 2011 [46] rats Administration of L-NAME to

pregnant rats. PEHypertension, proteinuria, FGR, increased placental concentra-tion of TNF-α, and IL-1β.

By the administration of hydro-gen-rich saline, blood pressure in the latter half of pregnancy was decreased, proteinuria was decreased, fetal weight was improved, and placental levels of TNF-α and IL-1β were decreased.

Ramesar SV, 2012 [47] rats Administration of L-NAME to

pregnant rats. PEHypertension, increased sFlt-1 and sEng, decreased plasma levels of NO.

By the administration of Kraus-sianone-2 (Kr2), blood pressure was reduced, serum levels of sFlt-1 and sEng were decreased, the level of NO was increased, fetal weight was increased, the number of fetuses was in-creased, and placental weight was increased.

MBG

Vu HV, 2005 [48] rats Administration of deoxycortico-

sterone acetate to pregnant rats PE Hypertension, proteinuria.

By the administration of resibu-fogenin (an antagonist of MBG), MBG antibody, blood pressure was decreased.

MMP-9Plaks V, 2013 [49] mice MMP-9 KO pregnant mice PE Hypertension, proteinuria, re-

duced VEGF Oxysterol

Valbuena-Diez　AC, 2012 [50]

mice

i) Venal injection of ligand of the liver X receptor (LXR)：oxygen-ated cholesterol derivatives (oxysterols) :22(R)-hydrox-ycholesterol (22-R) or LXR synthetic agonist T0901317. ii) sEngtg mice

PE i) Increased sEng, hypertension, proteinuria, ii) Hypertension

Administration of an endoglin peptide containing the consen-sus matrix metalloproteinase-14cleavage site G-L prevented the oxysterol-dependent in-crease of arterial pressure and sEng levels.

p57kip

Kanayama N, 2002 [51] mice p57kip2 heterozygous mice (p57-

/+)x p57-/+ PE

Hypertension, proteinuria, thrombocytopenia, decreased anti-thrombin III activity, and increased endothelin levels. Glomerular endotheliosis with fibrinoid or hyalinoid deposits.

PSPC

Omatsu K, 2005 [52] mice Venous administration of PSPC

to pregnant mice. PE

Hypertension, proteinuria, re-duced pup and placental weight, reduced litter size, decreased platelets, decreased AT-Ⅲ, in-creased TAT.

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Zhang Y, 2009 [53] mice Venous administration of PSPC

to pregnant mice. PEElevated SBP, proteinuria, andreduction of AT III and blood platelets.

Amelioration of symptoms by annexineX, AND (a recom-binantpolypeptide that is composed of annexin V and hirudinby connecting Pro46-Gln65 of hirudin to the C-ter-minus (Asp320) of annexin V), heparin.

RUPPAlexander BT, 2001 [54] rats Clipping of Ao of pregnant rats. PE Hypertension, proteinuria.

George EM, 2011 [55] rats Clipping of Ao of pregnant rats. PE

Hypertension, reduced pup size, reduced placental weight, in-creased sFlt-1, decreased VEGF, increased superoxide, increased preproET-1 mRNA.

Cobalt protoporphyrin (HO-1 induced) i.p. caused a signifi-cant shift in the ratio to an ang-iogenic balance, and decreased preproET-1 mRNA.

Amaral LM, 2014 [56] rats Clipping of Ao of pregnant rats. PE Hypertension, increased iNOS.

By transcutaneous administra-tion of N-[3-(aminomethyl) benzyl] acetamidine (1400 W), hypertension was improved by inhibiting the production of iNOS

Lillegard KE, 2013 [57] rats Clipping of Ao of pregnant rats. PE Hypertension, increased C3a.

By administration of a soluble form of an endog-enouscomplement regulator, soluble complement receptor 1 (sCR1),hypertension was improved.

LaMarca B, 2011 [58] rats Clipping of Ao of pregnant rats. PE Hypertension, increased serum

AT1-AA, ET-1.

By the administration of rituxi-mab (B-lymphocyte-suppres-sive agent), blood pressure and ET-1 were decreased.

Tam Tam KB, 2011 [59] rats Clipping of Ao of pregnant rats. PE Hypertension, increased uterine

artery resistive index.

By the administration of en-dothelin typeA receptor an-tagonist, blood pressure was decreased, and uterine artery resistive index was decreased.

Morton JS, 2012 [60] rats Clipping of Ao of pregnant rats. PE

Significant increase in the ex-pression of the LOX-1 receptor, endothelial NO synthase, and superoxide in thoracic aorta.

Endothelial-dependent vasodi-lator function was modestly increased in the presence of both oxidized LDL and the LOX receptor inhibitor.

Walsh SK, 2012 [61] rats Clipping of Ao of pregnant rats. PE Hypertension, endothelial dys-

function.

By the administration of PARP inhibitor (PJ34)post RUPP sur-gery, blood pressure was not changed.

McCarthy, 2011 [62] rats Clipping of Ao of pregnant rats. PE Hypertension, proteinuria, de-

creased HO-1.

By the administration of PPAR-γ agonist, rosiglitazone, blood pressure was decreased, pro-teinuria was decreased, and HO-1 was increased.

Cornelius DC [63] rats Clipping of Ao of pregnant rats. PE

Hypertension, FGR, reduced placental weight, increased ROS and AT1-AA.

T-helper17 (TH17) suppression via IL-17 recombinant recep-tor C (IL-17RC). Blood pressure was decreased, fetal weight was increased, placental weight was increased, the production of ROS in the placenta was decreased, and AT1-AA was decreased.

sEng

Venkatesha S, 2006 [5] rats Administration of AdsEng and

AdsFlt-1 to pregnant rats. PE

Hypertension, proteinuria, glomerularendotheliosis, de-creased platelets, increased liver enzyme, reduced pup weight.

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sFlt-1Maynard SE, 2003 [4] rats Administration of AdsFlt-1 to

pregnant rats PE Hypertension, proteinuria, glomerular endotheliosis.

Lu F, 2007 [64] mice Administration of AdsFlt-1 to

pregnant mice PEHypertension, reduced pup weight, reduced litter size, de-creased platelets.

Suzuki H, 2009 [65] mice Administration of AdsFlt-1 to

pregnant mice PEHypertension, proteinuria, glomerular endotheliosis, de-creased VEGF.

By the administration of rhPlGF, rhVEGF-A, hypertension was improved.

Li Z, 2007 [66] rats Administration of AdsFlt-1 to pregnant rats PE Hypertension, proteinuria,

glomerular endotheliosis.

By the administration of rVEGF, hypertension, proteinuria, and glomerular endotheliosis were improved.

Bergmann, 2010 [67] mice Administration of AdsFlt-1 to

pregnant mice PE Hypertension, proteinuria, glomerular endotheliosis.

By the administration of AdVEGF, hypertension, proteinuria,and endotheliosis were improved.

Mateus J, 2011 [68] mice Administration of AdsFlt-1 to

pregnant mice PE Hypertension. By the administration of rVEGF, hypertension was improved.

Lu F, 2007 [69] mice Administration of AdsFlt-1 to

pregnant mice PE IUGR, blood pressure increased.BP was significantly higher in male offspring born to sFlt-1-treated mothers.

Kumasawa K, 2010 [70] mice Administration of LV-sFlt-1 to

embryonic cells. PE

Hypertension, proteinuria, re-duced placental weight, reduced pup weight, increased sEng, increased AT1-AA.

By the administration of prav-astatin, hypertension, and pro-teinuria were improved, the se-rum concentration of sFlt-1 was decreased, the serum level of PlGF was increased, fetal weight was improved, and placental weight was improved.

Fox KA, 2011 [71] mice Administration of Ad-sFlt-1 to

pregnant mice PE NR: BP, proteinuria.

By the administration of prav-astatin, the production of eNOS in the aorta and liver was in-creased, the production of HO-1 in the kidney was increased.

VEGF

Murakami Y, 2005 [72] mice Administration of exogenous

murine VEGF (164) PEHypercoagulation in the placental circulation and a significant ele-vation of systolic blood pressure.

By the administration of anti-VEGF neutralized antibody, symptoms were suppressed.

STOX1

Doridot L, 2013 [73] mice STOX1 tg ♂ x Wild type ♀ PE

Hypertension, proteinuria, glomerular endotheliosis, re-duced litter size, increased sFlt-1, increased sEng.

Amelioration by the administra-tion of aspirin.

Suramin

Nash P, 2005 [74] rats Suramin i.p. to pregnant rats. GH

Hypertension, decreased renal blood flow, decreased placental blood flow, fetal growth retarda-tion; increased isoprostane 8-epi-PGF2a, increased endothelin-1

Carlstrom M, 2009 [75] rats Suramin ip to pregnant rats. GH

Hypertension, fetal growth re-tardation. Smaller placentae, in-creased renin, decreased sFlt-1, decreasedplacental vessel area

Th1

Zenclussen AC, 2004 [76] mice Administration of Th1-like

splenocytes to pregnant mice. PE

Hypertension, proteinuria, glomerulonephritis, reduced lit-ter size; increased production of cytokine of uterine lymphocytes.

McRae JL, 2013 [77] mice

WT or CD39 tg ♀ x WT ♂, fol-lowed by the administration of Th1-like splenocytes.

PEHypertension, proteinuria, glomerulonephritis in WT x WT injected Th1-like splenocytes.

Amelioration of hypertension, proteinuria, and glomerulone-phritis in pregnant CD39 tg mice.

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TLR

Chatterjee　P, 2012 [78] mice

TLR3-specific agonist poly I:C TLR7-specific agonist R-837 TLR7/8 agonist CLO97 i.p. to pregnant mice.

PEHypertension, proteinuria, FGR, early delivery, reduced placen-tal weight.

Chatterjee　P, 2011 [79] mice

IL-10 KO, pregnant mice, Ad-ministration of TLR3 agonist polyinosinepolycytidylic acid (poly I:C)

PEHypertension, proteinuria, decreased number of pups per litter, increased demise.

Kopriva SE, 2012 [80] mice Pregnant mice treated with the

TLR3 agonist poly I:C (P-PIC). PE

Hypertension, proteinuria,increased miR-210, increased HIF1α, NFκB in placenta, decreased STAT6 in placenta.

Pregnant TLR3 KO mice treated by poly I:C did not develop hypertension, and placental HIF-1α, NF-kBp50, miR-210, and STAT6 were not changed compared with pregnant TLR3 KO mice.

Abbreviations: PE: Preeclampsia; GH: Gestational Hypertension; NR: Not Reported; FGR: Fetal Growth Restriction; sPE: superimposed Preeclampsia; Ad: Adenoviral vector; VEGF; Vascular Endothelial Growth Factor; PlGF: Placental Growth Factor; ROS: Reactive Oxygen Species; KO: Knockout; sFlt-1: soluble Fms-like tyrosine kinase 1;COMT: Catechol-O-MethylTransferase; 2-ME: 2-Methoxyoestradiol; Gal-1: Galectin-1; AT1-AA: Angiotensin II type 1 (AT1) receptor Agonistic Autoantibody; HO-1: Heme Oxygenase-1; CSE: Cystathionine γ-lyase; H2S: Hydrogen Sulfide; sEng: soluble Endoglin; IDO: Indoleamine 2,3-dioxygenase; ET-1: Endothelin 1; TNF-α: Tumor Necrotizing Factor alpha; IL-10: Interleukin-10; L-NAME: N(omega)-nitro-L-arginine methyl ester; IFN-γ: Interferon Gamma; NO: Nitric Oxide; DOCA: Desoxycorticosterone Acetate; MBG: Marinobufagenin; MMP-9: Matrix Metalloproteinase-9; LXR: Liver X Receptor; PSPC: Phosphatidylserine/Phosphatidylcholine; AT-III: Aanti-Thrombin III; TAT: Thrombin Anti-Thrombin complex; RUPP: Reduced Uterine Perfusion Pressure; Ao: Aorta; iNOS: Inducible Nitric Oxide Synthase; eNOS: endothelial Nitric Oxide Synthase; PGF: Prostaglandin F; Th1: helper T cells type 1 (Th1); TLR-3: Toll-like receptor 3.

endothelial cells inhibits VEGF-mediated sFlt-1 release and interferon (IFN)-γ- and tumor necrosis factor (TNF)-α–induced sEng release, whereas HO-1 inhibition results in sFlt-1 and sEng production from endothelial cells andplacental villous explants, and mice lacking HO-1 produce higher levels of sFlt-1 and sEng than wild-type mice (Table 1). These results suggested that a decrease of HO-1 might be a candidate for predicting PE-like changes. We searched for articles in PubMed using the key wordsof “heme oxygenase 1”AND B, but there were no reports on predicting PE using the circulating level of HO-1. However, Farina et al. [84] quantified mRNA expression in tissue samples from chorionic villous sampling (CVS) of normal and PE patients at 11 weeks of gestation. HO-1 was associated with the lowest degree of aberration in PE, indicating that circulating levels of mRNA levels of HO-1 might be used for the prediction of PE. Nakamura et al. [85] measured circulating mRNA in 24 women with PE and 24 controls; the mRNA level of HO-1 was significantly decreased in women with PE. Cohort studies using not only mRNA levels but also protein levels of HO-1 are warranted in the future.

IL-10

Hypoxia affects the cytokine balance by reducing IL-10 production and inducing IL-6 and IL-8 in placental explants and trophoblasts [34]. Lai et al. [34] discovered that exposure of pregnant wild-type and IL-10-/- mice to 9.5% oxygen results in PE-like changes, suggesting that a low concentration of IL-10 might be a biomarker for predicting PE (Table 1). We searched for articles in PubMed using the key words of “IL-10” AND B. PE was associated with elevated levels of IL-10 [86]. Kronborg et al. [87] collected blood samples during pregnancy from a cohort of 1631 women. Plasma levels of IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ and granulocyte macrophage colony-stimulating factor were measured at <25th, 26th-29th, 30th-35th, and >36th weeks in 32 women with PE and 67 normative pregnant women (controls). PE was associated with increased TNF-α between 26th and 29th

week and increased IL-6 after the 36th week, but other cytokines were comparable in women with PE and controls. Therefore, IL-10 might not be a biomarker candidate for predicting PE.

Nitric oxide (NO)

Administration of L-NAME as a nitric oxide synthase (NOS) inhibitor during mid- to late gestation results in PE-like changes [43-47], suggesting that the decrease of NO might be a candidate for predicting PE (Table 1). We searched for articles in PubMed using the following key words of (“asymmetric dimethylarginine” OR ADMA OR L-arginine OR “nitric oxide”) AND B. Asymmetric dimethylarginine (ADMA) and monomethylarginine (L-NMMA) compete with L-arginine, the substrate for nitric oxide synthase NOS [88]. Maternal plasma ADMA in the second and third trimesters has been reported to be higher in women with preeclampsia [88-92], although ADAM in the first trimester was not significantly different [93]. Kahlil [93] reported that L-arginine and L-homoarginine in the first trimester were significantly reduced in women with early-onset PE with delivery at <34 weeks of gestation than in unaffected controls. Therefore, the ADAM levels in the 2nd trimester might be a biomarker candidate for predicting PE.

Coagulation activation

Omatsu et al. [12] developed a murine PE model by injecting PS/PC microvesicles into Institute of Cancer Research (ICR) pregnant mice, and diffuse fibrin deposition was observed in the placentas, indicating that coagulation activation is one of the mechanisms for the development of PE (Table 1) [52, 53]. In a systematic review by Duckitt and Harrington [94], the presence of anticardiolipin antibodies or lupus anticoagulant or both significantly increased the risk of developing preeclampsia, suggesting that screening for coagulation activation might be useful to detect women at high risk forPE.

Central



Other

Mouse models of reduced uterine perfusion pressure (RUPP) [54-63] indicate the importance of normal physiological changes of the spiral artery in humans (Table 1). In another part of this Special Issue on the ‘Prediction of Preeclampsia’, Ohkuchi et al. discuss the role of uterine artery Doppler for predicting early-onset (EO)-PE.

Mouse models using sEng and sFlt-1 [4,5,64-71] indicate the role of increased levels of sFlt-1 and/or sEng before the onset of PE (Table 1). Elsewhere in this Special Issue, Hirashima et al. Discuss the role of angiogenesis-related factors for predicting EO-PE.

CONCLUSIONIn view of the animal models of PE, we can speculate that

several candidates remain to be elucidated in the future [26-28,30,35,37-41,48-51,72-80]. Recently, it has been reported that low-dose aspirin administered at <16 weeks of gestation might be useful to prevent the later occurrence of PE [95]. Therefore, screening women at high risk for PE at <16 weeks of gestation is very important. Not only circulating levels of protein, but also circulating levels of DNA, mRNA and micro RNA (miRNA) might be candidates for predicting PE in early pregnancy. Animal studies on the genesis of PE are very important tools for searching for biomarkers to predict PE in early pregnancy.

Angiogenic/angiostatic balance theory by sFlt-1, PlGF and sEng for the genesis of PE is one of the most successful models of translational research from bench to bed. However, the balance theory does not explain the genesis of PE entirely. Until now, clinically useful biomarkers other than angiogenesis-related factors have not been found. Basic research using animal models will gain insight into possible biomarker candidates for predicting PE.

CONTRIBUTORSH.S. and A.O. systematically searched for articles and selected

eligible articles, and A.O. wrote the manuscript. K.S, H.T, R.U, S.M. and M.S. critically reviewed the manuscript.

FINANCIAL DISCLOSUREThis work was supported by Grants-in-Aid (24390383 and

24592482 to A.O.) from the Ministry of Education, Culture, Sports, Science and Technology in Japan and a research grant (3-2417-011 to S.M.) from the Japan Association of Obstetricians and Gynecologists Ogyaa Donation Foundation.

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Suzuki H, Ohkuchi A, Shirasuna K, Takahashi H, Usui R, et al. (2014) Animal Models of Preeclampsia: Insight into Possible Biomarker Candidates for Predicting Preeclampsia. Med J Obstet Gynecol 2(2): 1031.

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