Abstract 03: Ablation Of Endothelial Dysfunction Improves Blood Pressure And Fetal Growth Restriction In A Mouse Model Of Preeclampsia-like Hyperleptinemia

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Derrian Wright ◽  
Simone Kennard ◽  
Galina Antonova ◽  
Iris Z Jaffe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Fold Change ◽  
Growth Restriction ◽  
Mesenteric Arteries ◽  
Pregnant Mice ◽  
Placental Efficiency

Placental ischemia, an initiating event of preeclampsia (PE), increases plasma leptin levels. We recently developed a model of midgestation (gestation day (GD)11-18) leptin infusion mimicking the midgestation rise in leptin levels of PE patients. Our previous work demonstrates that deletion of endothelial mineralocorticoid receptors (ECMR) improves markers of vascular dysfunction in leptin-infused female mice. We hypothesized vascular function improvement with ECMR deletion ablates hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR +/+ (WT) and ECMR -/- (KO) mice were infused with vehicle or leptin by osmotic pump (lep, 0.9mg/kg/day, s.c.) on GD11-18 while implanted with radiotelemeters for conscious blood pressure (BP) measurement and wire myography of thoracic aorta and 2 nd order mesenteric arteries at GD18 (*=P<0.05). Leptin infusion did not decrease maternal weight in any groups. Leptin decreased pup weight (0.86±0.04g WT vs 0.52±0.11 WT+lep*) and placental efficiency (pup/placenta ratio) (9.7±0.7 WT vs 7.9±0.6 WT+lep*) in WT pregnant mice. ECMR deletion prevented leptin-mediated decreases in pup weight (0.91±0.06g KO vs 1.0±0.07 KO+lep) and placental efficiency (9.6±0.5 KO vs 9.4±1.2 KO+lep). Mean arterial pressure (BP) increased in leptin-infused WT (102±3mmHg WT vs 120±12 WT+lep*), but not KO (107±2 KO vs 106±8 KO+lep), mice from GD11-18. Leptin infusion reduced acetylcholine-mediated relaxation in both aorta and mesenteric arteries of WT* and constriction to KCl in mesenteric arteries in WT*, but not KO, pregnant mice (2-way ANOVA, repeated measures). Leptin increased plasma endothelin-1 (ET-1, 1.1±0.3 pg/ml WT vs 4.4±1.8 WT+lep*), placental mRNA expression of prepro-ET-1 (1.9±0.3-fold change from WT*) and ET-1 converting enzyme-1 (1.6±0.3-fold change from WT*) in pregnant WT mice. Leptin infusion also increased adrenal aldosterone-synthase protein (1.4±0.4 WT ratio/β actin vs 3.2±0.3 WT+lep*) and angiotensin II type 1 receptor b (3.5±0.8-fold change from WT*) mRNA in pregnant mice. Collectively, these data indicate that leptin infusion induces hypertension and fetal growth restriction in pregnant mice due to vascular dysfunction and increased ECMR activation in pregnant mice.

scholarly journals Cigarette exposure induces changes in maternal vascular function in a pregnant mouse model

2010 ◽  
Vol 298 (5) ◽  
pp. R1249-R1256 ◽  
Author(s):  
Robin E. Gandley ◽  
Arun Jeyabalan ◽  
Ketaki Desai ◽  
Stacy McGonigal ◽  
Jennifer Rohland ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cigarette Smoke ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Smoke Exposure ◽  
Renal Arteries ◽  
Growth Restriction ◽  
Whole Body ◽  
Cigarette Smoke Exposure ◽  
Pregnant Mice

Smoking is associated with multiple adverse pregnancy outcomes, including fetal growth restriction. The objective of this study was to determine whether cigarette smoke exposure during pregnancy in a mouse model affects the functional properties of maternal uterine, mesenteric, and renal arteries as a possible mechanism for growth restriction. C57Bl/CJ mice were exposed to whole body sidestream smoke for 4 h/day. Smoke particle exposure was increased from day 4 of gestation until late pregnancy ( day 16–19), with mean total suspended particle levels of 63 mg/m3, representative of moderate-to-heavy smoking in humans. Uterine, mesenteric, and renal arteries from late-pregnant and virgin mice were isolated and studied in a pressure-arteriograph system ( n = 23). Plasma cotinine was measured by ELISA. Fetal weights were significantly reduced in smoke-exposed compared with control fetuses (0.88 ± 0.1 vs. 1.0 ± 0.08 g, P < 0.02), while litter sizes were not different. Endothelium-mediated relaxation responses to methacholine were significantly impaired in both the uterine and mesenteric vasculature of pregnant mice exposed to cigarette smoke during gestation. This difference was not apparent in isolated renal arteries from pregnant mice exposed to cigarette smoke; however, relaxation was significantly reduced in renal arteries from smoke-exposed virgin mice. In conclusion, we found that passive cigarette smoke exposure is associated with impaired vascular relaxation of uterine and mesenteric arteries in pregnant mice. Functional maternal vascular perturbations during pregnancy, specifically impaired peripheral and uterine vasodilation, may contribute to a mechanism by which smoking results in fetal growth restriction.

scholarly journals Nano Zinc Oxide Induced Fetal Mice Growth Restriction, Based on Oxide Stress and Endoplasmic Reticulum Stress

Nanomaterials ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 259 ◽  
Author(s):  
Bolu Chen ◽  
Wuding Hong ◽  
Pengfei Yang ◽  
Yizhou Tang ◽  
Yu Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Reproductive Toxicity ◽  
Growth Restriction ◽  
Oral Exposure ◽  
Zno Nps ◽  
Pregnant Mice ◽  
Oxide Stress

ZnO NPs have been assessed to show adverse effects on reproductive organs, but the molecular mechanisms of reproductive toxicity have not been sufficiently studied. In this research, the dosage effects from the oral exposure of ZnO NPs (30 nm) to pregnant mice in gestation day 10.5 to 17.5 was analyzed. Pregnant mice exposed to ZnO NPs induced dam injury, mice fetal growth restriction, and the fetus number decreased. The pathological evaluation showed that ZnO NPs exposure caused placental spongiotrophoblast area decease and structural damage. The RT-qPCR and immunocytochemistry data indicated that ZnO NPs could induce placenta oxide stress, endoplasmic reticulum stress responses, apoptosis, and altered placental function. These findings indicated that ZnO NPs could induce dam injury and fetal growth restriction. Reproductive toxicity of ZnO NPs may be due to placental injury and function alteration caused by apoptosis, oxide stress, and endoplasmic reticulum stress after ZnO NPs exposure.

scholarly journals Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction-Like Symptoms in Pregnant Mice

2017 ◽  
Vol 31 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Kento Yoshikawa ◽  
Takashi Umekawa ◽  
Shintaro Maki ◽  
Michiko Kubo ◽  
Masafumi Nii ◽  
...  
Keyword(s):  
Methyl Ester ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Growth Restriction ◽  
Pregnant Mice

scholarly journals Prenatal Use of Sildenafil in Fetal Growth Restriction and Its Effect on Neonatal Tissue Oxygenation—A Retrospective Analysis of Hemodynamic Data From Participants of the Dutch STRIDER Trial

2020 ◽  
Vol 8 ◽  
Author(s):  
Fieke Terstappen ◽  
Anne E. Richter ◽  
A. Titia Lely ◽  
Freek E. Hoebeek ◽  
Ayten Elvan-Taspinar ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Placebo Group ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Neonatal Intensive Care ◽  
Near Infrared ◽  
Cerebral Oxygenation ◽  
Growth Restriction ◽  
Tissue Oxygen Saturation

Objective: Sildenafil is under investigation as a potential agent to improve uteroplacental perfusion in fetal growth restriction (FGR). However, the STRIDER RCT was halted after interim analysis due to futility and higher rates of persistent pulmonary hypertension and mortality in sildenafil-exposed neonates. This hypothesis-generating study within the Dutch STRIDER trial sought to understand what happened to these neonates by studying their regional tissue oxygen saturation (rSO2) within the first 72 h after birth.Methods: Pregnant women with FGR received 25 mg placebo or sildenafil thrice daily within the Dutch STRIDER trial. We retrospectively analyzed the cerebral and renal rSO2 monitored with near-infrared spectroscopy (NIRS) in a subset of neonates admitted to two participating neonatal intensive care units, in which NIRS is part of standard care. Secondarily, blood pressure and heart rate were analyzed to aid interpretation. Differences in oxygenation levels and interaction with time (slope) between placebo- and sildenafil-exposed groups were tested using mixed effects analyses with multiple comparisons tests.Results: Cerebral rSO2 levels were not different between treatment groups (79 vs. 77%; both n = 14) with comparable slopes. Sildenafil-exposed infants (n = 5) showed lower renal rSO2 than placebo-exposed infants (n = 6) during several time intervals on day one and two. At 69–72 h, however, the sildenafil group showed higher renal rSO2 than the placebo group. Initially, diastolic blood pressure was higher and heart rate lower in the sildenafil than the placebo group, which changed during day two.Conclusions: Although limited by sample size, our data suggest that prenatal sildenafil alters renal but not cerebral oxygenation in FGR neonates during the first 72 post-natal hours. The observed changes in renal oxygenation could reflect a vasoconstrictive rebound from sildenafil. Similar changes observed in accompanying vital parameters support this hypothesis.

Metallothionein-I- and -II-deficient mice display increased susceptibility to cadmium-induced fetal growth restriction

2013 ◽  
Vol 305 (6) ◽  
pp. E727-E735 ◽  
Author(s):  
Johanna Selvaratnam ◽  
Haiyan Guan ◽  
James Koropatnick ◽  
Kaiping Yang
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cadmium Exposure ◽  
Growth Restriction ◽  
Glut1 Expression ◽  
Pregnant Mice ◽  
Underlying Mechanisms

Maternal cadmium exposure induces fetal growth restriction (FGR), but the underlying mechanisms remain largely unknown. The placenta is the main organ known to protect the fetus from environmental toxins such as cadmium. In this study, we examine the role of the two key placental factors in cadmium-induced FGR. The first is placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is known to protect the fetus from exposure to high cortisol levels and subsequently FGR, and the second the cadmium binding/sequestering proteins metallotheionein (MT)-I and -II. Using the MT-I/II −/− mouse model, pregnant mice were administered cadmium, following which pups and placentas were collected and examined. MT-I/II−/− pups exposed to cadmium were significantly growth restricted, but neither placental weight nor 11β-HSD2 was altered. Although cadmium administration did not result in any visible structural changes in the placenta, increased apoptosis was detected in MT-I/II−/− placentas following cadmium exposure, with a significant increase in levels of both p53 and caspase 3 proteins. Additionally, glucose transporter (GLUT1) was significantly reduced in MT-I/II−/− placentas of pups exposed to cadmium, whereas zinc transporter (ZnT-1) remained unaltered. Taken together, these results demonstrate that MT-I/II−/− mice are more vulnerable to cadmium-induced FGR. The present data also suggest that increased apoptosis and reduced GLUT1 expression in the placenta contribute to the molecular mechanisms underlying cadmium-induced FGR.

Maternal administration of Sildenafil Citrate alters fetal vascular function in a mouse model of fetal growth restriction

Placenta ◽  
2013 ◽  
Vol 34 (9) ◽  
pp. A22
Author(s):  
Lewis Renshall ◽  
Elizabeth Cowley ◽  
Susan Greenwood ◽  
Mark Dilworth ◽  
Mark Wareing
Keyword(s):  
Mouse Model ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Vascular Function ◽  
Growth Restriction ◽  
Sildenafil Citrate ◽  
Maternal Administration

scholarly journals eNOS knockout mouse as a model of fetal growth restriction with an impaired uterine artery function and placental transport phenotype

2012 ◽  
Vol 303 (1) ◽  
pp. R86-R93 ◽  
Author(s):  
Laura C. Kusinski ◽  
Joanna L. Stanley ◽  
Mark R. Dilworth ◽  
Cassandra J. Hirt ◽  
Irene J. Andersson ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Vascular Function ◽  
Uterine Artery ◽  
Nutrient Transport ◽  
Growth Restriction ◽  
Growth Potential ◽  
Abdominal Circumference ◽  
Maternal Undernutrition ◽  
Endothelial Nitric Oxide

Fetal growth restriction (FGR) is the inability of a fetus to reach its genetically predetermined growth potential. In the absence of a genetic anomaly or maternal undernutrition, FGR is attributable to “placental insufficiency”: inappropriate maternal/fetal blood flow, reduced nutrient transport or morphological abnormalities of the placenta (e.g., altered barrier thickness). It is not known whether these diverse factors act singly, or in combination, having additive effects that may lead to greater FGR severity. We suggest that multiplicity of such dysfunction might underlie the diverse FGR phenotypes seen in humans. Pregnant endothelial nitric oxide synthase knockout (eNOS−/−) dams exhibit dysregulated vascular adaptations to pregnancy, and eNOS−/− fetuses of such dams display FGR. We investigated the hypothesis that both altered vascular function and placental nutrient transport contribute to the FGR phenotype. eNOS−/− dams were hypertensive prior to and during pregnancy and at embryonic day (E) 18.5 were proteinuric. Isolated uterine artery constriction was significantly increased, and endothelium-dependent relaxation significantly reduced, compared with wild-type (WT) mice. eNOS−/− fetal weight and abdominal circumference were significantly reduced compared with WT. Unidirectional maternofetal 14C-methylaminoisobutyric acid (MeAIB) clearance and sodium-dependent 14C-MeAIB uptake into mouse placental vesicles were both significantly lower in eNOS−/− fetuses, indicating diminished placental nutrient transport. eNOS−/− mouse placentas demonstrated increased hypoxia at E17.5, with elevated superoxide compared with WT. We propose that aberrant uterine artery reactivity in eNOS−/− mice promotes placental hypoxia with free radical formation, reducing placental nutrient transport capacity and fetal growth. We further postulate that this mouse model demonstrates “uteroplacental hypoxia,” providing a new framework for understanding the etiology of FGR in human pregnancy.

scholarly journals Investigation of interleukin-2-mediated changes in blood pressure, fetal growth restriction, and innate immune activation in normal pregnant rats and in a preclinical rat model of preeclampsia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mark W. Cunningham ◽  
Lorena M. Amaral ◽  
Nathan E. Campbell ◽  
Denise C. Cornelius ◽  
Tarek Ibrahim ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Nk Cells ◽  
Fetal Growth ◽  
Rat Model ◽  
Fetal Growth Restriction ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Growth Restriction ◽  
High Dose ◽  
Fetal Survival

AbstractTwo important clinical features of preeclampsia (PE) are hypertension and fetal growth restriction. The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE exhibits both of these features. Moreover, RUPP and PE women have elevated vasoconstrictor peptide endothelin-1 (ET-1) and inflammation. Interleukin-2 (IL-2) is a cytokine that regulates NK cell activity and is elevated in miscarriage, PE, and RUPP rats. The objective of this study was to examine a role for IL-2 in NK cell activation, fetal growth restriction, and hypertension during pregnancy by either infusion of IL-2 or blockade of IL-2 (basiliximab) in normal pregnant (NP) and RUPP rats. On gestational day 14, NP and RUPP rats received low (LD), middle (MD), or high dose (HD) IL-2 (0.05, 0.10, or 0.20 ng/ml) IP or basiliximab (0.07 mg per rat) by IV infusion. On day 19, blood pressure (MAP), pup weights, and blood were collected. Basiliximab had no effect on blood pressure, however, significantly lowered NK cells and may have worsened overall fetal survival in RUPP rats. However, IL-2 LD (102 ± 4 mmHg) and IL-2 HD (105 ± 6 mmHg) significantly lowered blood pressure, ET-1, and activated NK cells compared to control RUPPs (124 ± 3 mmHg, p < 0.05). Importantly, IL-2 in RUPP rats significantly reduced fetal weight and survival. These data indicate that although maternal benefits may have occurred with low dose IL-2 infusion, negative effects were seen in the fetus. Moreover, inhibition of IL-2 signaling did not have favorable outcome for the mother or fetus.

scholarly journals Maternal circulating miRNAs that predict infant FASD outcomes influence placental maturation

2019 ◽  
Vol 2 (2) ◽  
pp. e201800252 ◽  
Author(s):  
Alexander M Tseng ◽  
Amanda H Mahnke ◽  
Alan B Wells ◽  
Nihal A Salem ◽  
Andrea M Allan ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Epithelial Mesenchymal Transition ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Growth Restriction ◽  
Circulating Mirnas ◽  
Placental Development ◽  
Mesenchymal Transition ◽  
Pregnant Mice

Prenatal alcohol exposure (PAE), like other pregnancy complications, can result in placental insufficiency and fetal growth restriction, although the linking causal mechanisms are unclear. We previously identified 11 gestationally elevated maternal circulating miRNAs (HEamiRNAs) that predicted infant growth deficits following PAE. Here, we investigated whether theseHEamiRNAs contribute to the pathology of PAE, by inhibiting trophoblast epithelial–mesenchymal transition (EMT), a pathway critical for placental development. We now report for the first time that PAE inhibits expression of placental pro-EMT pathway members in both rodents and primates, and thatHEamiRNAs collectively, but not individually, mediate placental EMT inhibition.HEamiRNAs collectively, but not individually, also inhibited cell proliferation and the EMT pathway in cultured trophoblasts, while inducing cell stress, and following trophoblast syncytialization, aberrant endocrine maturation. Moreover, a single intravascular administration of the pooled murine-expressedHEamiRNAs, to pregnant mice, decreased placental and fetal growth and inhibited the expression of pro-EMT transcripts in the placenta. Our data suggest thatHEamiRNAs collectively interfere with placental development, contributing to the pathology of PAE, and perhaps also, to other causes of fetal growth restriction.

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