Experimental Preeclampsia Research Articles

Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia

Introduction: Preeclampsia remains one of the most common causes of maternal and perinatal mortality worldwide. A significant role in the pathogenesis of this pathology is assigned to placental ischemia and endothelial dysfunction. Therefore, the aim of the present study was to study the effectiveness of asialized erythropoietin and arginase II selec­tive inhibitors: KUD-259 and KUD-974 in the correction of morphofunctional disorders of the cardiovascular system in experimental preeclampsia.
 Materials and methods: The study was performed in 260 female Wistar rats, each weighing 250–300 g. An AD­MA-like preeclampsia was reproduced in the experiment. To assess the emerging morphofunctional disorders, the fol­lowing parameters were used: blood pressure, coefficient of endothelial dysfunction, microcirculation in the placenta, proteinuria, fluid content in the omentum, concentration of terminal metabolites in the blood plasma, and morphometric parameters of fetuses.
 Results and discussion: The administration of arginase II selective inhibitor KUD-974 in combination with asialized erythropoietin leads to a pronounced correction of emerging changes: a decrease in systolic and diastolic blood pres­sure in 1.5 and 1.7 times, a decrease in proteinuria in 3.6 times and a decrease in fluid content in the omentum. When arginase II selective inhibitor KUD 974 and asialized erythropoietin are used with methyldopa, the positive effects of the former are enhanced.
 Conclusion: Arginase II selective inhibitors KUD-259 and KUD-974 and asialized erythropoietin have a pronounced positive effect on the correction of morphofunctional disorders in animals with ADMA-like preeclampsia.

INFLUENCE OF PEPTIDE IMITATING A-SPIRAL OF B ERYTHROPOETHIN ON THE DEVELOPMENT OF MORPHOFUNCTIONAL DISORDERS IN EXPERIMENTAL PRECLAMPPS

Preeclampsia remains a formidable disease in the second half of pregnancy. Therefore, the search for new drugs for the treatment and prevention of preeclampsia is an urgent task of modern pharmacology. Materials and methods. The experiment was performed on female Wistar rats. The studied drugs were administered from 10 to 21 days of pregnancy. Functional tests were performed on the 21st day of pregnancy. Results. The use of a peptide that imitates erythropoietin а-helix B in experimental preeclampsia leads to a pronounced correction of pathological changes: blood pressure decreased, microcirculation in the placenta increased, and the morphological picture in the placenta improved. Resume. The results indicate the promise of the use of a peptide imitating а-helix B erythropoietin in experimental preeclampsia.

Effects of Gaba Derivatives on Anxious and Compulsive Behavior in Offspring of Rats with Experimental Preeclampsia.

We studied the effects of GABA derivatives on anxious and compulsive behavior of progeny of rats with experimental preeclampsia provoked by replacement of drinking water for 1.8% NaCl solution from the first day of pregnancy to delivery. In comparison with progeny of health rats, the offspring of dams with complicated pregnancy demonstrated high level of anxiety and the development of obsessive-compulsive disorder both at the early (40 and 70 days) and late (6 and 12 months) stages of ontogeny. GABA derivatives succicard, salifen, and phenibut reduced symptoms of experimental preeclampsia in offspring of various age by decreasing the level of anxiety and reducing compulsive behavior. The efficacy of the examined derivatives was similar to that of the reference drug Pantogam.

CHANGE OF THE OXIDANT AND ANTIOXIDANT STATUS IN THE OFFSPRING FROM RATS WITH EXPERIMENTAL PREECLAMPSIA UNDER THE EFFECT OF GABA DERIVATIVES

The effect of course intragastric administration of gamma-aminobutyric acid derivatives (GABA) such as succicard 22 mg/kg, salifen 7,5 mg/kg, phenibut 25 mg/kg and comparison of drug pantogam 50 mg on the concentration of malondialdehyde (MDA) and the activity of catalase and superoxide dismutase (SOD) in the plasma of offspring at the age of 8, 14 and 20 months, who was born from rats with experimental preeclampsia (EP), was studied. EP has decreased the activity of antioxidant enzymes and increased concentration of lipid peroxidation products in offspring from females with EP in long periods of ontogenesis (8, 14 and 20 months). The GABA derivatives administration from 40 to 70 days of life to the progeny from rats with EP has decreased MDA level in animals at the age of 8 months treated with salifen, in 14 months - in those receiving succicard and comparison of drug pantogam, in 20 months - pantogam. In addition, the activity of SOD has increased at the age of 14 months in rats, which were treated by succicard, salifen, phenibut, and pantogam, and at 8 and 20 months in those receiving pantogam. An increase in catalase activity was observed at the age of 8 months in the offspring who were treated with phenibut and salifen, at 14 months - who received succicard.

Отдаленные последствия у потомства, рожденного крысами с экспериментальной преэклампсией

Отдаленные последствия у потомства, рожденного крысами с экспериментальной преэклампсией

Study of the effect of selective inhibitor of Arginase II KUD 975 and of low doses of Acetylsalicylic acid on the functional parameters of the cardiovascular system In experimental preeclampsia

Introduction: Over the past decade, preeclampsia has been the subject of an increased attention, as this complication is the most common cause of maternal mortality, triggering every third case of obstetric morbidity and taking lives of up to 50.000 young women worldwide each year. Despite a large number of ongoing studies, no clear algorithm for monitoring pregnant women with this pathology has been developed yet.
 Materials and methods: The study was conducted on 220 female Wistar rats weighing 250–300 g. In the experiment, ADMA-like preeclampsia model was used.
 Results and discussion: The introduction of L-NAME to the animals from the 14th till the 20th day of pregnancy causes the following disturbances: a rise in systolic and diastolic blood pressure in 1.4 and 1.5 times, an increase in proteinuria in 3.3 times and an increase in the content of fluid in the greater omentum from 44.39 ± 1.62% to 55.02 ± 1.74%, all of which correspond to the disorders in pregnant women in case of preeclampsia. The use of the selective inhibitor of arginase II KUD 975 (3mg/kg/day) in combination with acetylsalicylic acid (10mg/ kg/day) leads to a pronounced correction in the emerging changes: a decrease in systolic and diastolic blood pressure in 1.2 and 1.3 times, a decrease in proteinuria in 1.9 times and a decrease in the fluid content in the greater omentum.
 Conclusion: Selective inhibitor of arginase II KUD 975 and small doses of acetylsalicylic acid have a pronounced positive effect in the correction of morphofunctional disorders in animals with ADMA-like preeclampsia.

Role of the Nitric Oxide (NO) in the Regulation of Steroidogenesis in Placenta During Physiological Pregnancy and Preeclampsia (Experimental Study)

Abstract The aim of the study was to establish the role of nitric oxide (NO) in the regulation of steroidogenesis in the placenta during physiological pregnancy and experimental preeclampsia (PE) in rats. EPR centers of the placenta, free NO and its metabolites were determined by the Electron Paramagnetic Resonance (EPR) method. At the last stage of pregnancy in the EPR spectra of the rats’ placenta with PE alterations of the signals intensity of mitochondrial steroidogenic electron transport proteins were detected: the FeS-centers of adrenodoxin decreased, the ferricytochrome P-450 increased, the free NO content decreased, and the complexes of NO with heme (HbNO) and non-heme iron (FeSNO) were detected. These data indicate the violation of placental steroidogenesis, which is confirmed by a decrease in the level of progesterone in blood. Therefore, the nitrosylation of mitochondrial proteins is an important redox-dependent mechanism of regulation of the intensity of steroidogenesis.

Antibody against Na/K-ATPase Inhibitor Lowers Blood Pressure and Increases Vascular Fli1 in Experimental Preeclampsia.

Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE. We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6-19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/ml) for 4 hours. PE was associated with higher blood pressure (117 ± 2 vs. 107 ± 2 mm Hg; P < 0.01), plasma MBG levels (1.54 ± 0.34 vs. 0.49 ± 0.11 nmol/L; P < 0.01), protein excretion (26 vs. 12 mg/24 hours), sFlt-1 (3-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all P < 0.01). In 12 rats treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mm Hg) and Fli1 was decreased much less (2-fold; P < 0.01 vs. nontreated rats). These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1.

Effect of placental growth factor in models of experimental pre-eclampsia and trophoblast invasion.

Placental growth factor (PlGF) is decreased in early gestation of pregnant women who subsequently develop pre-eclampsia. In this study, pre-emptive treatment with PlGF to prevent pre-eclampsia was evaluated in an in vivo rodent model of experimental pre-eclampsia (EPE) induced by TNF-α and in an in vitro model of human first-trimester trophoblast invasion. Pregnant C57/BL6 mice were treated with recombinant mouse placental growth factor-2 (rmPlGF-2) 100μg/kg/day IP from gestational day (gd) 10. Animals had EPE induced by continuous TNF-α infusion on gd 13 and were subject to either continuous blood pressure monitoring by radiotelemetry throughout pregnancy or live placenta T2 -weighted magnetic resonance imaging (MRI) to demonstrate placental function on gd 17. There was no difference in BP (P>.99), proteinuria (P=.9) or T2 values on MRI (P=.9) between control and rmPlGF-2-treated animals. On gd 13, animals treated with rmPlGF-2 demonstrated increased placenta PlGF (P=.01) and Toll-like receptor-3 (P=.03) mRNA expression as compared with controls. Fluorescent-labelled human uterine microvascular endothelial cells and HTR8/SVNeo cells were co-cultured on Matrigel™ and treated with recombinant human PlGF (rhPlGF) (10ng/mL) and/or TNF-α (0.5ng/mL). Trophoblast integration into endothelial networks was reduced by added TNF-α (P=.006), as was rhPlGF concentration in conditioned media (P<.0001). Cell integration was not ameliorated by addition of rhPlGF (P>.9). Although TNF-α-induced EPE was not reversed with pre-emptive rmPlGF-2, a further trial of pre-emptive rhPlGF in vivo is required to determine whether the absence of effect of rhPlGF demonstrated in vitro precludes PlGF as a preventative therapy for pre-eclampsia.

The Effect of BML-111 in Preeclampsia Rat Model Induced by the Low Dose of Cadmium Chloride.

Aim This article determines the optimal time and dose of cadmium chloride (CdCl 2 ) injected to pregnant rat to establish experimental preeclampsia (PE) model. In addition, the therapeutic potential of BML-111, a lipoxin A4 analogue, in the CdCl 2 -induced PE model was also evaluated. Methods Peritoneal injection of two dose of CdCl 2 for successive 6 days was tested in the pregnant rats starting from various gestational days (GDs). During this process, the systolic blood pressure and the body weight of pregnant rats and neonatal rats were monitored. The pathological changes of the placenta and kidney were evaluated by hematoxylin and eosin staining. The phosphorylation of extracellular signal-regulated kinase 1/2 and signal transducer and activator of transcription 3 in the placentas was detected by Western blot, and the messenger ribonucleic acid expression of interleukin (IL)-6, tumor necrosis factor-α, and IL-10 in the placentas were detected by real-time polymerase chain reaction. BML-111 at the dose of 1 mg/kg/day was peritoneally injected into the rat after establishing the PE model to test its therapeutic potential. Results In the present study, we successfully established the PE model in pregnant rats by intraperitoneally injection of CdCl 2 at the dose of 0.125 mg/kg/day from GD 9 to 14. We recapitulated multiple features of clinical PE in CdCl 2 -induced rat, including high blood pressure, renal dysfunction, and inflammatory response in placenta. Furthermore, treatment with BML-111 significantly relieved multiple features in our PE rat model. Conclusions BML-111 has a potential therapeutic effect in pregnant rats with CdCl 2 -induced PE, which appears to be mediated through inhibition of inflammatory processes in the placenta.

L-NAME-induced Preeclampsia: correction of functional disorders of the hemostasis system with Resveratrol and Nicorandil

Introduction. Preeclampsia is a formidable disease of the second half of pregnancy, leading to severe complications, including disability and even death. Many authors have recognized the correlation between the severity of preeclampsia and the degree of disturbances in the hemostasis system. In this regard, the objective of this study was to assess inhibition of platelet aggregation and the possibility of its correction with resverаtrol and nicorandil.&#x0D; Materials and methods. The study was performed on 250 mature white Wistar female rats weighing 250–300 g. The platelet aggregation induced by ADP, collagen, ristomycin, adrenaline was determined, as well as PTT, TT, aPTT, fibrinogen, and the clotting time.&#x0D; Results and discussion. Introduction of resverаtrol and nicorandil resulted in a decrease in thrombocyte aggregation capacity from 53.8 ± 2.60% to 22.1 ± 1.25% and 37.1 ± 1.79%, respectively, when using ADP as an inducer. The clotting time was from 841 ± 42 s up to 1135 ± 33 s and 1034 ± 26 s, respectively. In addition, there was an increase intemporal parameters of plasma-coagulation hemostasis and a decrease in plasma fibrinogen content. The use of gliben-clamide resulted in partial cancellation of the positive effects of resverаtrol and nicorandil, with an increase in platelet aggregation to 28.9 ± 1.8% and 43.9 ± 1.2% when using ADP as an inducer and a decrease in the thrombosis time to 988 ± 26 s and 950 ± 22 s, respectively.&#x0D; Conclusion. In animals with experimental preeclampsia, there were disturbances in the hemostasis system, comparable to those in the clinical situation. The use of resverаtrol and nicorandil leads to a pronounced correction of hemostasis parameters. The positive effects of the studied pharmacological agents are mediated by several mechanisms, including K+ATP channels.K+ATP channels.&#x0D;

Synthesis of Nomega-Nitro-l-arginine methyl ester modified reduced graphene oxide nanosheets and their protective action on experimental preeclampsia in mice

The purpose of this study is to synthesize Nomega-Nitro-L-arginine methyl ester (L-NAME) adsorbed reduced graphene oxide (RGO) sheets and demonstrate their protective impact on the detrimental effect detected in investigational pre-eclampsia, a prerequisite where increase in oxidative stress and decreased Nitric Oxide (NO) production were present. The synthesized graphene sheets were studies by using various characterization techniques. Later, a prerequisite similar to pre-eclampsia has been induced through chronic inhibition of NO fabrication using a 60 mg/kg/day L-NAME, orally in pregnant mice. We observed arterial pressure increase, a decrease of alive fetus toward the end of pregnancy and insulin resistance increase in pregnant L-NAME mice and no much difference was detected in pregnant L-NAME-RGO mice. We also observed an arterial pressure increase in normal L-NAME mice. In this paper, we determined a protective impact of RGO in investigational pre-eclampsia.

96. Effect of preventative treatment with placental growth factor-2 on experimental preeclampsia induced by TNF-α in pregnant mice

Introduction Placental growth factor (PlGF) is deficient in women with preeclampsia and treatment of experimental preeclampsia (EPE) with parenteral PlGF has been successful in animal models. Abnormal placentation is thought to be the initiating event in the pathogenesis of preeclampsia and this process may be mediated by PlGF. Objective To evaluate the effect of preventative treatment with PlGF-2 in pregnant mice with EPE induced by tumour necrosis factor- α (TNF- α ) infusion. Methods C57/BL6 mice were treated with daily PlGF-2 (100 ng/kg) or control (phosphate buffered saline 100 uL) intraperitoneally from gestational day (gd) 10 onward. Mice were allocated to one of 3 experimental arms: 1) Animals (n = 5 per group) were euthanised on gd13 to assess the effect of PlGF-2 in early pregnancy; 2) Animals (n = 5 per group) had EPE induced by continuous TNF- α (500 ng/kg/day) infusion. These animals had continuous blood pressure (BP) measurement by radiotelemetry device inserted a minimum 10 days prior to timed mating; 3) Animals (n = 3 per group) had EPE induced as above and live placenta magnetic resonance imaging (MRI) in an 11.74 Tesla spectrometer on gd17. Animals in arm 2 and 3 were euthanized at gd17 and blood, urine and tissue samples were collected. Data was analysed with GraphPad Prism 7. Results PlGF-2 animals euthanised at gd13 demonstrated increased placenta PlGF (p = 0.01) and toll like receptor-3 (TLR-3) (p = 0.03) mRNA expression as compared with controls. In animals with EPE there was no difference in BP (p = 0.7) or proteinuria (p > 0.9) between control and PLGF-2 treated animals. There was no difference in T2 labyrinthine/junctional zone ratio in mouse placentas imaged (p = 0.9). Discussion Preventative treatment with PlGF-2 altered expression of PlGF and TLR-3 but did not ameliorate features of EPE or placental perfusion as assessed by live MRI.

110. Preeclamptic plasma affects gene expression in human endothelial cells and vascular smooth muscle cells

Introduction One of the main preeclampsia features is maternal vascular dysfunction. In rat experimental preeclampsia we have previously shown that this includes changes in vascular gene expression (Lip et al. Sci. Rep. 7, 14807(2017)). Objective We tested whether vascular gene expression in experimental preeclampsia can be induced by incubation of human endothelial and vascular smooth muscle cells with preeclamptic plasma in vitro. Methods Human umbilical vein endothelial cells (HUVEC) and human aortic vascular smooth muscle cells (VSMC) were incubated with 15% plasma from early-onset preeclamptic (n = 5), healthy pregnant (n = 5) or non-pregnant women (n = 5) for 24 h. RNA was isolated from the cells and RT-RT-PCR was performed to determine gene expression. We measured top dysregulated vascular genes in experimental preeclampsia (KCNA6, ESM1 for HUVEC and TTN, ACTC1, CHRNA3 for VSMC). Additionally, we measured expression of genes which might be altered in the vasculature during preeclampsia (NOS3, EDN1, PTGIS, CXCL8 for HUVEC and MYL6, MYL9, ACTG2 and ACTA2 for VSMC). Results Stimulation of HUVEC with preeclamptic plasma induced upregulation of KCNA6, ESM1 and CXCL8 compared to healthy pregnant plasma, while expression of NOS3, EDN1 and PTGIS was not affected. Stimulation of VSMC with preeclamptic plasma induced upregulation of ACTC1 compared to healthy pregnant plasma and upregulation of CHRNA3, MYL6, ACTG2 and ACTA2 compared to plasma from non-pregnant women, while expression of TTN and MYL9 was not affected. Discussion Using gene expression array data from the vasculature of a preeclamptic rat model, we selected potential targets to be upregulated in endothelial cells and vascular smooth muscle cells by preeclamptic plasma. The upregulation of genes by preeclamptic plasma may suggest that these gene are upregulated in vivo in preeclamptic women inducing vascular dysfunction in this condition. We next aim to determine which factors in the circulation of preeclamptic women induce these effects.

Increased salt sensitivity in offspring of pregnancies complicated by experimental preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy known to increase the risk of cardiovascular disease in mothers and offspring. Offspring exposed to a suboptimal intrauterine environment may experience altered fetal programming and subsequent long-term cardiovascular changes. This study investigated changes in the vascular response in offspring from experimental preeclampsia (EPE) induced by uterine artery ligation, in the absence of fetal growth restriction, compared to normal baboon pregnancies (controls), following a high salt diet challenge. After 1week of standard diet (containing <1% salt), animals were fed a high salt diet (6%) for 2weeks. Systolic and diastolic blood pressure (SBP, DBP), aldosterone, renin and creatinine clearance were evaluated in EPE (n=6, 50% male) and control (n=6, 50% male) offspring. A repeated measures analysis was performed, and P<0.05 was considered significant. At baseline, there were no differences between the groups in any parameter (EPE, mean age and weight 3.2±1.2years, 6.8±1.0kg, respectively; Control, 2.9±0.8years, 7.1±1.5kg). After salt loading the EPE group had significantly higher SBP (92±5mmHg) compared to the control group (83±4mmHg, P=0.03). Aldosterone concentration was higher in the EPE group despite the same salt excretion and no difference in renal function. Salt sensitivity may differ in offspring from hypertensive pregnancies due to fetal programming. This could have long-term consequences for cardiovascular health of EPE offspring and further research is required to determine the exact pathological mechanisms.

Innate immune cells in the placental bed in healthy pregnancy and preeclampsia

Immune cells in the placental bed are important for adequate development of the placental bed. The most prominent immune cells in the placental bed early in pregnancy are uterine natural killer cells (uNK) cells and macrophages. Also dendritic cells and mast cells can be found in the early placental bed. These cells not only have an immune regulatory function, but are also involved in the regulation of trophoblast invasion, angiogenesis and spiral artery remodeling. In preeclampsia, one of the major complications of pregnancy, decreased trophoblast invasion and spiral artery remodeling has been found. This is associated with decreased numbers of uNK cells, increased numbers of macrophages around the spiral arteries and similar or increased numbers of dendritic cells in the placental bed. In this review, we discuss the current insights in the functions of uNK cells, macrophages, dendritic cells and mast cells in the placental bed in humans during healthy pregnancy and during preeclampsia. As animal models are instrumental in understanding the role of immune cells in the placental bed, we also review studies on the function and phenotype of these innate immune cells in experimental preeclampsia. A better understanding of the dynamics and functional changes of these immune cells in the placental bed may eventually lead to new therapeutic targets for preeclampsia.

Evaluation of DNA Damage in Experimental Preeclampsia by Comet Assay.

Experimental preeclampsia induced by substitution of drinking water with 1.8% NaCl during pregnancy was associated with an increase in the level of DNA damage in fetal brain and placenta measured by DNA comet assay by 35.7 and 27.8 times, respectively, in comparison with physiological pregnancy.

Angiotensin II responsiveness after preeclampsia: translational data from an experimental rat model and early-onset human preeclampsia.

Formerly preeclamptic women have an increased risk for cardiovascular and renal disease later in life. It is unknown which mechanisms contribute to this increased risk and whether this is induced by preeclampsia or by prepregnancy factors. We hypothesized that the increased risk for cardiovascular disease is partly due to an increased angiotensin II (ang II) responsiveness postpartum and that preeclampsia itself is involved in inducing this increased ang II responsiveness. In never-pregnant, formerly healthy pregnant rats and rats with former experimental preeclampsia [experimental preeclampsia model induced by low-dose endotoxin infusion on day 14 of pregnancy; endotoxin-infused pregnant rats (EP-rats)], ang II responsiveness was studied by measuring changes in blood pressure (BP) and proteinuria after chronic ang II infusion with osmotic minipumps (200 ng/kg per min). In addition, we measured BP and responses to ang II (0.3, 1.0 and 3.0 ng/kg per min) in 18 formerly early-onset preeclamptic, without comorbidities, and 18 formerly healthy pregnant women (controls). In rats, a significantly higher systolic BP at termination was observed in formerly EP-rats vs. never-pregnant rats after ang II infusion (159.5 ± 29.5 vs. 136.7 ± 16.8; P = 0.049). In response to ang II, there was a significant increase in proteinuria in formerly EP-rats vs. healthy pregnant and never-pregnant rats (P < 0.01 for both). In humans, 1.0 ng/kg per min ang II showed a trend towards an increased mean arterial BP response in formerly preeclamptic women vs. controls (P = 0.057). Our data show an increased ang II responsiveness following (experimental) preeclampsia and support a role for preeclampsia itself in altered ang II responsiveness postpartum.

Experimental preeclampsia in rats affects vascular gene expression patterns

Normal pregnancy requires adaptations of the maternal vasculature. During preeclampsia these adaptations are not well established, which may be related to maternal hypertension and proteinuria. The effects of preeclampsia on the maternal vasculature are not yet fully understood. We aimed to evaluate gene expression in aortas of pregnant rats with experimental preeclampsia using a genome wide microarray. Aortas were isolated from pregnant Wistar outbred rats with low-dose LPS-induced preeclampsia (ExpPE), healthy pregnant (Pr), non-pregnant and low-dose LPS-infused non-pregnant rats. Gene expression was measured by microarray and validated by real-time quantitative PCR. Gene Set Enrichment Analysis was performed to compare the groups. Functional analysis of the aorta was done by isotonic contraction measurements while stimulating aortic rings with potassium chloride. 526 genes were differentially expressed, and positive enrichment of “potassium channels”, “striated muscle contraction”, and “neuronal system” gene sets were found in ExpPE vs. Pr. The potassium chloride-induced contractile response of ExpPE aortic rings was significantly decreased compared to this response in Pr animals. Our data suggest that potassium channels, neuronal system and (striated) muscle contraction in the aorta may play a role in the pathophysiology of experimental preeclampsia. Whether these changes are also present in preeclamptic women needs further investigation.

Differential responses of mesenteric arterial bed to vasoactive substances in L-NAME-induced preeclampsia: Role of oxidative stress and endothelial dysfunction

ABSTRACTTo investigate the systemic and placental oxidant status as well as vascular function in experimental preeclampsia (PE) induced by nitro-L-arginine methyl ester (L-NAME). Fetal parameters and maternal blood pressure, proteinuria, mesenteric arterial bed (MAB) reactivity, and systemic and placental oxidative stress were compared between four groups: pregnant rats receiving L-NAME (60 mg/kg/day, orally) (P + L-NAME) or vehicle (P) from days 13 to 20 of pregnancy and nonpregnant rats receiving L-NAME (NP + L-NAME) or vehicle (NP) during 7 days. L-NAME administration during pregnancy induced some hallmarks of PE, such as hypertension and proteinuria. The P + L-NAME group presented lower weight gain and placental mass as well as reduced number and weight of live fetuses than P group. The vasodilator effect induced by acetylcholine (ACh) and angiotensin II (Ang II) was lower in the perfused MAB from NP + L-NAME and P + L-NAME than in control groups. Otherwise, the nitroglycerine-induced vasodilation and the phenylephrine- and Ang II-induced vasoconstriction were higher in MAB from NP + L-NAME and P + L-NAME groups than in the respective controls. Systemic and placental oxidative damage, assessed by malondialdehyde and carbonyl levels, was increased and activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced in P + L-NAME and NP + L-NAME groups compared to controls. The present data suggest that the oxidative stress and reduced bioavailability of nitric oxide may contribute to attenuation of vasodilator responses to ACh and Ang II, and hyperreactivity to Ang II in the mesentery of preeclamptic rat, which may contribute to the increased peripheral vascular resistance and BP, as well as intrauterine growth restriction in L-NAME-induced PE.