Animal Model Of Preeclampsia Research Articles

Animal models of preeclampsia: translational failings and why.

Preeclampsia affects up to 8% of pregnancies worldwide and is a leading cause of both maternal and fetal morbidity and mortality. Our current understanding of the cause(s) of preeclampsia is far from complete, and the lack of a single reliable animal model that recapitulates all aspects of the disease further confounds our understanding. This is partially due to the heterogeneous nature of the disease, coupled with our evolving understanding of its etiology. Nevertheless, animal models are still highly relevant and useful tools that help us better understand the pathophysiology of specific aspects of preeclampsia. This review summarizes the various types and characteristics of animal models used to study preeclampsia, highlighting particular features of these models relevant to clinical translation. This review points out the strengths and limitations of these models to illustrate the importance of using the appropriate model depending on the research question.

Alpha-1-antitrypsin functions as a protective factor in preeclampsia through activating Smad2 and inhibitor of DNA binding 4.

Pre-eclampsia (PE) is one of the most common reason for high morbidity and mortality of maternal and prenatal infants. Production from oxidative stress results in maternal ROS system and anti-oxidation defense system imbalance to promote tissue ischemia and hypoxia, and ultimately impairs the maternal organs and placenta. Our previous study showed that exogenous Alpha-1-antitrypsin (AAT) and overexpression of AAT in umbilical vein cell (HUVEC) hypoxia-reoxygenation model could increase the activity of antioxidant enzymes, and played a protective role in preeclampsia animal model. In this study, we aim to investigate the underlying mechanism by which AAT prevents PE progress. Whole-exome sequencing was performed to screen the genes altered by AAT. We found that AAT knockdown altered the expression of Smad family and Id family genes, and further demonstrated that AAT positively regulated Id4 expression through activating Smad2. Reduced Id4 expression and Smad2 phosphorylation were observed in preeclampsia animal model, which was also confirmed in human placenta tissues. In addition, AAT protected HUVEC cells from hypoxia/reoxygenation injury and relieved preeclampsia symptoms through Smad2/Id4 axis. Our data illustrate AAT/Smad2/Id4 axis is an important mediator of placenta and vascular function during pregnancy. These findings provide insights into events governing pregnancy-associated disorders, such as preeclampsia.

Antihypertensive responses of vasoactive androgens in an in vivo experimental model of preeclampsia

Dehydroepiandrosterone (DHEA), testosterone (TES) and its 5-reduced metabolites induce a nongenomic vasorelaxation in several vascular beds of mammals; similarly these hormones produce systemic hypotensive and antihypertensive responses in normotensive and hypertensive male rats. Thus, it was hypothesized that the antihypertensive response of androgens, whose levels are elevated during gestation, protect against gestational hypertension. An animal model of preeclampsia was induced in female Wistar rats using DOCA-salt-treated pregnant (PT) and normal pregnant (NP) rats. In vivo experiments in conscious rats revealed that bolus intravenous injections of DHEA, TES, 5α- or 5β-dihydrotestosterone (-DHT) log −1.0 to 2.0μmolk−1min−1, produced substantial transient reductions in arterial blood pressure (BP), without significant changes in heart rate (HR). Mean arterial blood pressure (MAP) was reduced significantly in both groups. PT rats were more sensitive to the antihypertensive responses of androgens than NP. DHEA and 5β-DHT were the most potent to reduce MAP: 66±07 and 69±2.0mmHg in PT but only 33±0.5 and 35±1.2mmHg in NP rats, respectively. In isolated aortas of PT and NP, the concentration-response curves to each androgen (0.1–100μM) indicated that KCl-induced pre-contraction is more sensitive to all androgens than phenylephrine (Phe) pre-contractions. Notably, 5β-DHT is the greatest vasorelaxant with KCl-induced contraction than with Phe contraction of both groups, suggesting a preferential blockade on L-VOCCs. TES exhibited minor vasorelaxing effect of aortas pre-contracted with KCl, compared to its precursor DHEA and its 5-reduced metabolites. These data show that these androgens exert acute vasorelaxing effects in vitro and remarkably, reduce the BP in vivo in PT and NP at term pregnancy. Moreover, a deficit in feto-placental androgen production during pregnancy may trigger the development of preeclampsia or gestational hypertension.

Oxidative Stress in the Rostral Ventrolateral Medulla Contributes To Cardiovascular Regulation in Preeclampsia.

Background: It has been demonstrated that preeclampsia, a pregnancy-specific hypertension disorder, is characterized by high blood pressure (BP) and sympathetic overactivity. Increased reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM), a key region for controlling sympathetic tone, has been reported to contribute to high level of BP and sympathetic outflow. The aim of the present study was to determine the role of the RVLM ROS in mediating the preeclampsia-associated cardiovascular dysfunction.Methods: The animal model of preeclampsia was produced by administration of desoxycorticosterone acetate (DOCA) to pregnant rats.Results: Compared with normal pregnant rats without DOCA treatment (NP), the protein concentration and norepinephrine excretion in 24-h urine, as well as BP in pregnant rats with DOCA treatment (PDS) were significantly increased. The levels of superoxide anion and the protein expression of NADPH oxidase subtype (NOX4) in the RVLM were significantly increased in PDS than in NP groups. Furthermore, microinjection of the superoxide dismutase (SOD) mimic Tempol (5 nmol) into the RVLM significantly decreased BP, heart rate, and renal sympathetic never activity in PDS but not in NP group.Conclusion: The present data suggest that high BP and sympathetic overactivity in preeclampsia rats is associated with increased oxidative stress in the RVLM via upregulation of NOX4 expression.

Modulating circulating sFlt1 in an animal model of preeclampsia using PAMAM nanoparticles for siRNA delivery

IntroductionExcessive circulating sFlt1 plays a major role in the pathogenesis of preeclampsia (PE). Using RNAi to silence sFlt1 may be a therapy for treating PE. Because of the rapid degradation of siRNA, gene therapy in vivo remains limited. Poly-amidoamine (PAMAM) has been demonstrated to be an excellent nanocarrier for siRNA delivery with no discernible toxicity. MethodsThe aim of the present study was to investigate the therapeutic effect of siRNA-sFlt1-PAMAM on PE. The biophysical properties of siRNA-sFlt1-PAMAM complexes were analysed. Next, HTR-8/SVneo cells were incubated with the complexes. The transfection efficiency, silencing effect, and cell proliferation were examined. The timed pregnant rats were grouped to test the in vivo effect of siRNA-sFlt1-PAMAM on PE. The PE model was established by injection of tumour necrosis factor-α (TNF-α), while treatment group rats were injected with both TNF-α and siRNA-sFlt1-PAMAM. The mean arterial pressure, serum levels of sFlt1, and 24-h urinary protein were measured. The number of viable pups, and weights of individual pups and placentae were determined. ResultssiRNA-sFlt1-PAMAM complexes showed high cellular uptake and excellent siRNA encapsulation ability. siRNA-sFlt1-PAMAM significantly decreased sFlt1 secretion from HTR-8/SVneo cells (p = 0.001) with little effect on HTR-8/SVneo cell proliferation. The circulating level of sFlt1, mean arterial pressure, and urine protein level in the TNF-α group were significantly increased compared to that in the control group, while the weights of foetuses and placentae were significantly decreased compared to that in the control group (p < 0.05). All preeclamptic symptoms were greatly attenuated by siRNA-sFlt1-PAMAM (p < 0.05). ConclusionsThese data suggest that siRNA-sFlt1-PAMAM effectively decreased sFlt1 secretion and improved pregnancy outcomes in a preeclamptic rat model, which may provide a new therapeutic strategy for PE.

Treating the dysfunctional placenta.

Placental dysfunction underlies major obstetric diseases such as pre-eclampsia and fetal growth restriction (FGR). Whilst there has been a little progress in prophylaxis, there are still no treatments for placental dysfunction in normal obstetric practice. However, a combination of increasingly well-described in vitro systems for studying the human placenta, together with the availability of more appropriate animal models of pre-eclampsia and FGR, has facilitated a recent surge in work aimed at repurposing drugs and therapies, developed for other conditions, as treatments for placental dysfunction. This review: (1) highlights potential candidate drug targets in the placenta – effectors of improved uteroplacental blood flow, anti-oxidants, heme oxygenase induction, inhibition of HIF, induction of cholesterol synthesis pathways, increasing insulin-like growth factor II availability; (2) proposes an experimental pathway for taking a potential drug or treatment for placental dysfunction from concept through to early phase clinical trials, utilizing techniques for studying the human placenta in vitro and small animal models, particularly the mouse, for in vivo studies; (3) describes the data underpinning sildenafil citrate and adenovirus expressing vascular endothelial growth as potential treatments for placental dysfunction and summarizes recent research on other potential treatments. The importance of sharing information from such studies even when no effect is found, or there is an adverse outcome, is highlighted. Finally, the use of adenoviral vectors or nanoparticle carriers coated with homing peptides to selectively target drugs to the placenta is highlighted: such delivery systems could improve efficacy and reduce the side effects of treating the dysfunctional placenta.

New Models of Pregnancy-Associated Hypertension

Pregnancy-associated hypertensive disorders are leading causes of maternal and fetal mortality. These include: pre-pregnancy hypertension that persists throughout gestation (chronic/preexisting hypertension), de novo hypertension that is diagnosed after 20 weeks of gestation and resolves after birth (gestational hypertension), de novo hypertension that is diagnosed after 20 weeks of gestation with or without proteinuria and end-organ damage (preeclampsia and eclampsia), and chronic hypertension with superimposed preeclampsia during gestation. Preeclampsia is the most severe form of these disorders. Animal models have been developed by employing surgical, genetic, and pharmacological approaches in order to recapitulate the maternal symptoms of preeclampsia and other hypertensive disorders of pregnancy. The scope of this brief review is to present an up-to-date synthesis of our knowledge of experimental models of pregnancy-associated hypertensive disorders. Novel models, defined in this review as characterized within the last 5 years, will be described and critically discussed. In this review, we will also discuss established experimental models of pregnancy-associated hypertensive disorders in the context of their contribution to new advances in our knowledge about the pathophysiology of these disorders and potential therapeutics. Emphasis will be placed on animal models of preeclampsia; however, models of other hypertensive disorders in pregnancy will also be reviewed.

Increases in Cytochrome P450 Expression and 20‐HETE Production Reduce Mean Arterial Pressure in an Animal Model of Preeclampsia

Recent data suggests cytochrome P450 (CYP450) vasoactive eicosanoids in the pathophysiology of preeclampsia. Thus, we investigated whether alterations in CYP450 expression and 20‐HETE production contribute to maternal hypertension during pregnancy. In order to address this hypothesis, we utilized a newly characterized model of hypertension during pregnancy also documented to have a genetic deficiency in 20‐HETE production, the Dahl S rat. In addition, we utilized a CYP4A1 overexpression transgenic rat. Mean arterial pressure, measured via telemetry, and proteinuria were measured in 12 week old Spraque Dawley (SD), Dahl SSJr, and CYP4A1 Tg rats at baseline, prior to pregnancy, and gestational day (GD) 5, 12, and 19. Consistent with previous reports, a reduction in MAP at term during normal pregnancy was not seen in the Dahl S rat (1.5±6 mmHg, p&lt;0.05; SD, 14±1 mmHg; CYP4A1 Tg, 18±2 mmHg). Proteinuria was elevated in both Dahl SSJr (107±45 mg/day, p&lt;0.05) and CYP4A1 Tg (53±5 mg/day, p&lt;0.05) rats relative to SD (10±1 mg/day) pregnant rats on GD19. Pup number was reduced in the Dahl S (9±1, p&lt;0.05) and increased in the CYP4A1 Tg (11±1, ns) rat compared to the SD (12±1), with no differences noted in placenta to pup weight. CYP450 enzymatic activity, as measured by production of 20‐HETE, within the placenta and kidney were significantly increased in the placenta (0.002±0.0006 vs 0.4±0.2 pmol/min/mg protein) and kidney of CYP4A1 Tg rats (4.4±0.5 vs 1.9±0.7 pmol/min/mg protein). Therefore, alterations in CYP450 enzyme activity and 20‐HETE may contribute to the increases in MAP during pregnancy and may be a potential therapeutic target in the treatment of preeclampsia.Support or Funding Information14SDG20160020; HL121042

Clinical Implications

HomeHypertensionVol. 69, No. 3Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Mar 2017https://doi.org/10.1161/HYPERTENSIONAHA.117.09012Hypertension. 2017;69:383IntroductionHypertension in Former Extremely Low Birth Weight Children (p 443)Low birth weight and prematurity are forerunners of hypertension in adulthood. Few studies reported on plasma renin activity in preterm or full-term born children. In prematurely born children with birth weight <1000 g (extremely low birth weight) and healthy controls, we tested the hypothesis whether renin might modulate the pathogenesis of hypertension associated with preterm birth. In cases compared with controls, systolic blood pressure was found to be 7.5 mm Hg higher, but plasma renin activity was found to be 0.54 ng/mL per hour lower. Plasma renin activity decreased with systolic blood pressure but was unrelated to sodium excretion. Extremely low birth weight predisposes young children to a low-renin volume-expanded sodium-sensitive type of hypertension. Extremely low birth weight children might therefore benefit from a life course reduction in salt intake and, if hypertensive, are probably more responsive to diuretics than to inhibitors of the renin–angiotensin system, the currently recommended first-line treatment in children with high blood pressure. Above all, our study highlights the importance of screening for hypertension in all prematurely born infants to avoid the complications associated with high blood pressure later in life. Finally, information on birth weight and on the perinatal history of patients might provide clinically relevant cues to physicians managing hypertension in adults.Download figureDownload PowerPointInterferon Regulatory Factor 3 Modulates Atherosclerosis (p 510)Download figureDownload PowerPointAtherosclerosis is a chronic inflammatory disease in which endothelial dysfunction plays an important role. A major feature of endothelial dysfunction is enhanced adhesion molecule expression, leading to adherence and transmigration of inflammatory cells, including monocytes and macrophages. In this study, we demonstrate that IRF3 (interferon regulatory factor 3) plays an important role in this inflammatory response. IRF3 was found to promote endothelial secretion of vascular cell adhesion molecule-1 and expression of intercellular adhesion molecule-1 by directly binding to its gene promoter. IRF3 was found to be upregulated in endothelial cells in both human and mouse atherosclerotic plaques. Ablation of IRF3 decreased vascular infiltration of macrophages and ameliorated the development of atherosclerosis in apolipoprotein E–deficient mice. IRF3 ablation also improved the stability of atherosclerotic plaques. Because plaque stability is more significant than plaque size in predicting acute clinical events, IRF3 represents a promising target for the treatment of atherogenesis and for prevention of its untoward clinical outcomes.Proton Pump Inhibitors to Treat Preeclampsia (p 457)Preeclampsia is a major complication of pregnancy, responsible for 70 000 maternal deaths annually and far greater fetal losses. A treatment that can quench the disease process could be a major advance, saving the lives of many mothers and babies. Sadly, no treatment exists, except delivery. The preeclamptic placenta releases elevated levels of the antiangiogenic factors sFlt-1 (soluble fms-like tyrosine kinase-1) and soluble endoglin. They disseminate throughout the maternal circulation and cause widespread endothelial dysfunction and hypertension, which then leads to injury to multiple maternal organs. In this issue of Hypertension, Onda et al report preclinical studies showing proton pump inhibitors may have diverse biological effects that make them an unlikely candidate treatment for preeclampsia. Using many functional assays performed on primary human tissues, they show that proton pump inhibitors decrease placental (Figure) and endothelial secretion of sFlt-1 and soluble endoglin, and they decrease endothelial dysfunction. Furthermore, they found that the proton pump inhibitor esomeprazole vasodilates blood vessels isolated from pregnant women and potently decreases blood pressure in a transgenic animal model of preeclampsia where sFlt-1 is overexpressed in the placenta. Proton pump inhibitors are widely prescribed to pregnant women to relieve gastric acid reflux. Large epidemiological studies suggest that proton pump inhibitors are safe to give to pregnant women. Therefore, the exciting clinical implication is that proton pump inhibitors may have the potential to treat or prevent preeclampsia. The team has translated these findings into a phase II placebo-controlled clinical trial to see whether esomeprazole can be used to treat preterm preeclampsia.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetails March 2017Vol 69, Issue 3 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.117.09012 Originally publishedMarch 1, 2017 PDF download Advertisement

Animal models of preeclampsia: an examination of usefulness and limitations based on the metabolic domino theory

Animal models of preeclampsia: an examination of usefulness and limitations based on the metabolic domino theory

Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia.

Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta. Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean ± standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value < .05 was considered statistically significant. The sFlt-1 + Pravastatin mice had significantly higher placental protein concentrations of prosurvival/ antiapoptotic factors (activating transcription factor 2, pp38, phosphorylated c-jun N-terminal kinase, and phosphorylated extracellular signal-regulated kinase) and of heat-shock protein 27 and signal transducer and activator of transcription 3, 2 factors crucial for embryonic and placental development during oxidative stress, compared to sFlt-1 mice (P < .05) and similar to the mFc control group. No differences were noted in substrates of the proapoptotic pp53 pathway. Pravastatin ability to prevent preeclampsia phenotype may be mediated through pleiotropic mechanisms involving a prosurvival/ antiapoptotic MAPK pathway in the placenta. Our results further support continued research in the role for statins in the prevention of preeclampsia.

Effect of Red Fruit Oil (Pandanus Conoideus Lam) on Animal Model of Preeclampsia

Effect of Red Fruit Oil (Pandanus Conoideus Lam) on Animal Model of Preeclampsia

Placental Ischemia and Resultant Phenotype in Animal Models of Preeclampsia.

Preeclampsia is new onset (or worsening of preexisting) hypertension that occurs during pregnancy. It is accompanied by chronic inflammation, intrauterine growth restriction, elevated anti-angiogenic factors, and can occur with or without proteinuria. Although the exact etiology is unknown, it is thought that preeclampsia begins early in gestation with reduced uterine spiral artery remodeling leading to decreased vasculogenesis of the placenta as the pregnancy progresses. Soluble factors, stimulated by the ischemic placenta, shower the maternal vascular endothelium and are thought to cause endothelial dysfunction and to contribute to the development of hypertension during pregnancy. Due to the difficulty in studying such soluble factors in pregnant women, various animal models have been designed. Studies from these models have contributed to a better understanding of how factors released in response to placental ischemia may lead to increased blood pressure and reduced fetal weight during pregnancy. This review will highlight various animal models and the major findings indicating the importance of placental ischemia to lead to the pathophysiology observed in preeclamptic patients.

Inventory of Novel Animal Models Addressing Etiology of Preeclampsia in the Development of New Therapeutic/Intervention Opportunities.

Preeclampsia is a pregnancy-related disease afflicting 3-7% of pregnancies worldwide and leads to maternal and infant morbidity and mortality. The disease is of placental origin and is commonly described as a disease of two stages. A variety of preeclampsia animal models have been proposed, but all of them have limitations in fully recapitulating the human disease. Based on the research question at hand, different or multiple models might be suitable. Multiple animal models in combination with in vitro or ex vivo studies on human placenta together offer a synergistic platform to further our understanding of the etiology of preeclampsia and potential therapeutic interventions. The described animal models of preeclampsia divide into four categories (i) spontaneous, (ii) surgically induced, (iii) pharmacologically/substance induced, and (iv) transgenic. This review aims at providing an inventory of novel models addressing etiology of the disease and or therapeutic/intervention opportunities.

Endoglin regulates mural cell adhesion in the circulatory system.

The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter-receptor for β1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane endoglin or β1-integrin, as well as by addition of soluble endoglin (SolEng), anti-integrin α5β1 antibody or an RGD peptide. Analysis of different endoglin mutants, allowed the mapping of the endoglin RGD motif as involved in the adhesion process. In Eng+/− mice, a model for hereditary hemorrhagic telangectasia type 1, endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, an animal model for preeclampsia, show podocyturia, suggesting that SolEng is responsible for podocytes detachment from glomerular capillaries. These results suggest a critical role for endoglin in integrin-mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel maturation in normal physiology as well as in pathologies such as preeclampsia or hereditary hemorrhagic telangiectasia.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-015-2099-4) contains supplementary material, which is available to authorized users.

Reduced uterine perfusion pressure decreases functional capillary density in skeletal muscle.

The purpose of this study was to examine the functional and structural capillary density in the reduced uterine perfusion pressure (RUPP) model, which when performed during pregnancy is an established animal model of preeclampsia. We hypothesized that the RUPP model would be associated with capillary rarefaction and impaired capillary perfusion, which would be more pronounced in the pregnant state. Female Sprague-Dawley rats (n = 32) were randomized to nonpregnancy (Nonpregnant) or breeding (Pregnant) at 12 wk of age and again to RUPP or SHAM surgeries on gestational day (GD) 14 (or equivalent age in nonpregnant rats). On GD 20 (or equivalent), capillary structure and perfusion of the extensor digitorum longus were imaged using digital intravital video microscopy. Functional videos were analyzed by a blinded observer to measure capillary density, expressed as capillaries per millimeter intersecting three staggered reference lines (200 μm). Flow was scored as the percentage of capillaries having 1) continuous, 2) intermittent, or 3) stopped flow. Total capillary density was not different between groups. There was a main effect of RUPP surgery resulting in decreased continuous flow vessels (P < 0.01) and increased stopped flow (P < 0.01), which was driven by differences between pregnant animals (Continuous flow: pregnant SHAM 80.1 ± 7.8% vs. pregnant RUPP 67.8 ± 11.2%, P < 0.05) (Stopped flow: pregnant SHAM 8.7 ± 3.2% vs. pregnant RUPP 17.9 ± 5.7%, P < 0.01). Our results demonstrate that the RUPP surgery is associated with a decrease in functional capillary density in skeletal muscle that is more pronounced in the pregnant state, which may contribute to the vascular pathophysiology observed in preeclampsia.

Placental Protein 13 Administration to Pregnant Rats Lowers Blood Pressure and Augments Fetal Growth and Venous Remodeling

Reduced first-trimester concentrations of placental protein 13 (PP13) are associated with subsequent development of preeclampsia, a major pregnancy disorder. We previously showed that PP13 has a vasodilatory effect, reduces blood pressure and augments expansive remodeling of the uteroplacental vasculature in pregnant rats. In this study, slow-release osmotic pumps were implanted in gravid rats (on day 8) to provide 1 week of PP13 supplementation. Treatment was associated with a reversible blood pressure reduction that returned to normal on day 15. In addition, PP13 caused venous expansion that is larger in the venous branches closer to the placenta. Then, it increased placental and pup weights. Similar administration of a truncated PP13 variant (DelT₂₂₁) that is unable to bind carbohydrates (a rare spontaneous mutation associated with a high frequency of severe early preeclampsia among Blacks in South Africa) produced a hypotensive effect similar to the full-length molecule, but without venous remodeling and increased placental and pup weights. These results indicate the importance of PP13 carbohydrate binding for inducing vascular remodeling and improving reproductive outcome. Future studies are needed to determine whether beneficial effects would be evident in animal models of preeclampsia or in women predisposed to the development of preeclampsia.

The Effect of Angiogenic and Anti-Angiogenic Factors on Urinary Podocyte mRNA Excretion in an Animal Model of Pre-Eclampsia

Objectives: We sought to optimise and validate an L-nitroarginine methyl ester (L NAME) pre-eclamptic model with a focus on the role of serum and renal angiogenic and antiangiogenic factors on urinary podocyte mRNA excretion.

98-POS

Objectives Coffee is one of the most widely consumed beverages in the world, and caffeine is the most studied compound in coffee. Coffee consumption is associated with a decreased risk of preeclampsia. Preeclampsia is a hypertensive disorder of pregnancy, and under-perfusion of the placenta is hypothesized to be a component of the etiology of the syndrome. An accepted animal model of preeclampsia is the reduced uterine perfusion pressure (RUPP) rat model, which mimics many aspects of the syndrome including increased blood pressure and impaired vascular function. The focus of this study was to investigate if caffeine treatment prevents arterial dysfunction in RUPP rats. Methods Pregnant rats were divided into 3 groups: SHAM operated (SHAM), RUPP and RUPP+caffeine (C; 4.5 mg/day starting at gestational day 0). Maternal mesenteric arteries (MA) were isolated at late gestation and studied in an isobaric arteriograph. Results Myogenic reactivity was increased in MA from RUPP compared to those from SHAM and RUPP+C. MAs from the RUPP rats also showed an increased EC50 to methacholine (ME) indicating impaired endothelial-dependent dilation. In contrast, MA from caffeine treated RUPP rats displayed decreased ME EC50’s similar to SHAM. Arterial pressures were significantly decreased in the RUPP+C compared to RUPP rats. Conclusions RUPP displayed impaired endothelial function as evidence by vessel studies and increased blood pressures. Caffeine treatment improved endothelial function and reduced blood pressures to those of the SHAM. These data suggest a potential protective effect of caffeine consumption on vascular function during pregnancy, and may have relevance to the pregnancy complication preeclampsia. Disclosures B.A. Balser: None. J. Novak: None. R.W. Powers: None. R.J. Ramirez: None.

254-POS

Objectives Between 0.5% and 5% of all pregnancies are complicated by preeclampsia (PE), a multi-organ disease and the most significant cause of neurological symptoms during the peripartum period. Although numerous clinical studies assess neurocognitive outcome of children born to mothers with PE and various animal models of PE dealing with mechanisms and symptoms of this disease exist, there is a lack of basic and clinical research analyzing cognitive performance of mothers after PE. The aim was to critical review available literature regarding the effects of pregnancies complicated by preeclampsia on maternal cognitive functioning. Methods Analysis of current evidence from database PubMed with keywords “Preeclampsia AND cognition/memory”, “Preeclampsia AND dementia”, “Hypertensive pregnancy AND cognition/memory”, “Placental ischemia-induced hypertension AND cognition/memory”, “Transgenic preeclampsia rat model AND cognition/memory” and “Reduced uterine perfusion pressure AND cognition/memory” was performed. Publication years 1994–2014 were included in this analysis. Results Search revealed only n = 5 clinical studies dealing with the effect of PE/hypertensive pregnancies on cognitive outcome in mothers, whereas not a single report from basic research was available. Results from clinical research were rather conflicting with n = 2 reporting no effect of a former preeclamptic pregnancy on cognition and n = 3 showing impairments in cognitive functioning later in life. Conclusions Despite the fact that neurological symptoms are a well-known consequence of pregnancies complicated by PE, basic and clinical studies assessing cognitive abilities in formerly preeclamptic mothers are rare, conflicting, or even nonexistent. Given the fact that decrements in cognition and memory can not only lead to psychosocial problems but could moreover affect the interaction between mother and child, thus tremendously impacting the quality of life of both, more research relating to the origin and management of these issues is highly required. Disclosures K.M. Hillerer: None. V.R. Jacobs: None. L. Aigner: None. T. Fischer: None.