Model Of Fetal Growth Restriction Research Articles

Akt Activation and Inhibition of Cytochrome C Release: Mechanistic Insights into Leptin-promoted Survival of Type II Alveolar Epithelial Cells.

Fetal growth restriction (FGR) increases the risk of perinatal death, partly due to defects in lung development. Leptin, a polypeptide hormone, is involved in fetal lung development. We previously demonstrated that treatment with exogenous leptin during gestation significantly promotes fetal lung maturity in the rat model of FGR. In this study, to delineate the molecular pathways through which leptin may enhance fetal lung development, we investigated the impact of leptin treatment on the survival of type II alveolar epithelial cells (AECs), essential leptin-responsive cells involved in lung development, in a rat model of FGR. The rat model of FGR was induced in pregnant Sprague-Dawley rats by partial uterine artery and vein ligation. In vivo and in vitro analyses of fetal lung tissues and freshly-isolated cultured AECs, respectively, showed that leptin protects type II AECs from hypoxia-induced apoptosis. Further molecular studies revealed the role of Akt activation in the leptin-mediated promotion of survival of type II AECs. The data also showed that the anti-apoptotic effects of leptin are dependent on phosphoinositol 3-kinase (PI3K) activation, and involve the down-regulation of caspases 3 and 9, upregulation of pro-survival proteins Bcl-2, and p-Bad, and inhibition of the release of cytochrome c from mitochondria. Taken together, our data suggested that leptin enhances the maturity of fetal lungs by mediating the regulation of caspase-3 and -9 during hypoxia-induced apoptosis of type II AECs and provide support for the potential of leptin as a therapeutic agent for promoting lung development in FGR.

Animal models of fetal growth restriction: Considerations for translational medicine

Fetal growth restriction (FGR) is the failure of a fetus to reach its full genetic growth potential. It occurs in up to 8% of pregnancies, and after premature birth is the second leading cause of infant mortality and morbidity. There is no treatment currently available for FGR. Its primary cause, when not attributable to structural or genetic defects of the fetus, is ‘placental insufficiency’. This broad definition covers the inability of the fetus to acquire sufficient nutrients and oxygen, and is influenced by a number of factors including altered maternal or fetal blood flow, reduced nutrient transport or changes in the placenta such as increased barrier thickness inhibiting nutrient transfer. For those researchers studying FGR and developing new therapies, choosing an animal model is a crucial consideration. It is vital to clearly frame the question being asked, as this will impact the factor influencing fetal nutrient delivery in the model, and will also affect the applicability of the results to the human condition. This review examines the range of in vivo models of FGR available for those engaged in translational research.

Expression of lung surfactant proteins SP-B and SP-C and their modulating factors in fetal lung of FGR rats.

This study investigated the expression of lung surfactant proteins SP-B and SP-C, and their modulating factors TTF-1 and PLAGL2 in the fetal lung of rats with fetal growth restriction (FGR). The rat FGR model was established by prenatal hypoxia in the first stage of pregnancy, 180 rats for experiment served as hypoxia group, and 197 healthy rats served as normal control group. The FGR incidence in hypoxia was compared with that in normal control group. The histological changes in the fetal lung were observed under the light microscope and electronic microscope in two groups. The SP-B, SP-C, TTF-1 and PLAGL2 proteins were determined in the fetal lung of two groups immunohistochemically. The expression levels of SP-B, SP-C, TTF-1 and PLAGL2 protein and mRNA in the fetal lung of two groups were detected by using Western blotting and RT-PCR respectively. The FGR rat model was successfully established by using hypoxia. Pathologically the fetal lung developed slowly, and the expression levels of SP-B, SP-C, TTF-1 and PLAGL2 protein and mRNA in the fetal lung were significantly reduced in hypoxia group as compared with those in normal control group. It was suggested that maternal hypoxia in the first stage of pregnancy could induce FGR, and reduce the expression of SP-B and SP-C, resulting in the disorder of fetal lung development and maturation.

The transformation of the utero-placental interface in early pregnancy: Functional insights from computational modeling

The transformation of the utero-placental interface in early pregnancy: Functional insights from computational modeling

In vitro assessment of mouse fetal abdominal aortic vascular function.

Fetal growth restriction (FGR) affects 3–8% of human pregnancies. Mouse models have provided important etiological data on FGR; they permit the assessment of treatment strategies on the physiological function of both mother and her developing offspring. Our study aimed to 1) develop a method to assess vascular function in fetal mice and 2) as a proof of principle ascertain whether a high dose of sildenafil citrate (SC; Viagra) administered to the pregnant dam affected fetal vascular reactivity. We developed a wire myography methodology for evaluation of fetal vascular function in vitro using the placenta-specific insulin-like growth factor II (Igf2) knockout mouse (P0; a model of FGR). Vascular function was determined in abdominal aortas isolated from P0 and wild-type (WT) fetuses at embryonic day (E) 18.5 of gestation. A subset of dams received SC 0.8 mg/ml via drinking water from E12.5; data were compared with water-only controls. Using wire myography, we found that fetal aortic rings exhibited significant agonist-induced contraction, and endothelium-dependent and endothelium-independent relaxation. Sex-specific alterations in reactivity were noted in both strains. Maternal treatment with SC significantly attenuated endothelium-dependent and endothelium-independent relaxation of fetal aortic rings. Mouse fetal abdominal aortas reproducibly respond to vasoactive agents. Study of these vessels in mouse genetic models of pregnancy complications may 1) help to delineate early signs of abnormal vascular reactivity and 2) inform whether treatments given to the mother during pregnancy may impact upon fetal vascular function.

10.6 Influence of prenatal adenovirus-VEGF gene therapy on mRNA expression of angiogenic related genes in fetal and postnatal ovine intestine

Maternal uterine artery adenovirus VEGF (Ad. VEGF-A165) gene therapy has increased pre- and early postnatal growth velocity in an overnourished adolescent ovine model of fetal growth restriction. Our objective was...

PFM.01 Influence of prenatal adenovirus-VEGF gene therapy on mRNA expression of angiogenic related genes in fetal and postnatal ovine intestine

Maternal uterine artery adenovirus VEGF (Ad. VEGF-A165) gene therapy has increased pre- and early postnatal growth velocity in an overnourished adolescent ovine model of fetal growth restriction. Our objective was...

Inflammation-induced fetal growth restriction in rats is associated with altered placental morphometrics

IntroductionEvidence links alterations in placental shape and size to fetal growth restriction (FGR). Here we determined whether alterations in placental morphometrics are linked to FGR induced by abnormal maternal inflammation. MethodsWe used an inflammation-induced model of FGR in which pregnant rats receive lipopolysaccharide (LPS) on gestational days (GD) 13.5–16.5. Fetal weights were matched to various parameters of placental morphometrics including weight, area, minor and major axes lengths and thickness. ResultsCompared with saline administration, LPS administration was associated with altered placental morphometrics, including reduced placental weight, decreased placental area and a trend towards reduced placental thickness. When data were dichotomized as FGR or normal-sized fetuses within treatment groups, a significant increase in the placental-weight-to-fetal-weight ratio and placental thickness was observed only in the saline-associated FGR subgroup. Multivariable linear regression revealed that the lengths of the major and minor placental axes were predictors of fetal weight, regardless of treatment modality. Subgroup regression analysis by treatment revealed that the lengths of the major and minor placental axes were predictors of fetal weight in the saline-treatment group while only the minor placental axis was a predictor of fetal weight in the LPS cohort. Finally, placental area and the length of the minor placental axis were correlated with implantation site location only in the saline-treatment group. Discussion/conclusionThese findings indicate that inflammation-induced FGR is associated with alterations in placental morphometrics. Our data reveal that the mechanisms leading to inflammation-induced FGR may be different from the mechanisms leading to idiopathic FGR.

Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

Fetal growth restriction (FGR) occurs in ∼8% of pregnancies and is a major cause of perinatal mortality and morbidity. There is no effective treatment. FGR is characterized by reduced uterine blood flow (UBF). In normal sheep pregnancies, local uterine artery (UtA) adenovirus (Ad)-mediated overexpression of vascular endothelial growth factor (VEGF) increases UBF. Herein we evaluated Ad.VEGF therapy in the overnourished adolescent ewe, an experimental paradigm in which reduced UBF from midgestation correlates with reduced lamb birthweight near term. Singleton pregnancies were established using embryo transfer in adolescent ewes subsequently offered a high intake (n=45) or control intake (n=12) of a complete diet to generate FGR or normal fetoplacental growth, respectively. High-intake ewes were randomized midgestation to receive bilateral UtA injections of 5×10¹¹ particles Ad.VEGF-A165 (n=18), control vector Ad.LacZ (n=14), or control saline (n=13). Fetal growth/well-being were evaluated using serial ultrasound. UBF was monitored using indwelling flowprobes until necropsy at 0.9 gestation. Vasorelaxation, neovascularization within the perivascular adventitia, and placental mRNA expression of angiogenic factors/receptors were examined using organ bath analysis, anti-vWF immunohistochemistry, and qRT-PCR, respectively. Ad.VEGF significantly increased ultrasonographic fetal growth velocity at 3-4 weeks postinjection (p=0.016-0.047). At 0.9 gestation fewer fetuses were markedly growth-restricted (birthweight >2SD below contemporaneous control-intake mean) after Ad.VEGF therapy. There was also evidence of mitigated fetal brain sparing (lower biparietal diameter-to-abdominal circumference and brain-to-liver weight ratios). No effects were observed on UBF or neovascularization; however, Ad.VEGF-transduced vessels demonstrated strikingly enhanced vasorelaxation. Placental efficiency (fetal-to-placental weight ratio) and FLT1/KDR mRNA expression were increased in the maternal but not fetal placental compartments, suggesting downstream effects on placental function. Ad.VEGF gene therapy improves fetal growth in a sheep model of FGR, although the precise mechanism of action remains unclear.

Liver mTOR Controls IGF-I Bioavailability by Regulation of Protein Kinase CK2 and IGFBP-1 Phosphorylation in Fetal Growth Restriction

Fetal growth restriction (FGR) increases the risk for perinatal complications and predisposes the infant to diabetes and cardiovascular disease later in life. No treatment for FGR is available, and the underlying pathophysiology remains poorly understood. Increased IGFBP-1 phosphorylation has been implicated as an important mechanism by which fetal growth is reduced. However, to what extent circulating IGFBP-1 is phosphorylated in FGR is unknown, and the molecular mechanisms linking FGR to IGFBP-1 phosphorylation have not been established. We used umbilical cord plasma of appropriate for gestational age (AGA) and growth-restricted human fetuses and determined IGFBP-1 and IGF-I concentrations (ELISA) and site-specific IGFBP-1 phosphorylation (Western blotting using IGFBP-1 phospho-site specific antibodies). In addition, we used a baboon model of FGR produced by 30% maternal nutrient restriction and determined mammalian target of rapamycin (mTOR)C1 activity, CK2 expression/activity, IGFBP-1 expression and phosphorylation, and IGF-I levels in baboon fetal liver by Western blot, enzymatic assay, and ELISA. HepG2 cells and primary fetal baboon hepatocytes were used to explore mechanistic links between mTORC1 signaling and IGFBP-1 phosphorylation. IGFBP-1 was hyperphosphorylated at Ser101, Ser119, and Ser169 in umbilical plasma of human FGR fetuses. IGFBP-1 was also hyperphosphorylated at Ser101, Ser119, and Ser169 in the liver of growth-restricted baboon fetus. mTOR signaling was markedly inhibited, whereas expression and activity of CK2 was increased in growth-restricted baboon fetal liver in vivo. Using HepG2 cells and primary fetal baboon hepatocytes, we established a mechanistic link between mTOR inhibition, CK2 activation, IGFBP-1 hyperphosphorylation, and decreased IGF-I-induced IGF-I receptor autophosphorylation. We provide clear evidence for IGFBP-1 hyperphosphorylation in FGR and identified an mTOR and CK2-mediated mechanism for regulation of IGF-I bioavailability. Our findings are consistent with the model that inhibition of mTOR in the fetal liver, resulting in increased CK2 activity and IGFBP-1 hyperphosphorylation, constitutes a novel mechanistic link between nutrient deprivation and restricted fetal growth.

Sildenafil Citrate Increases Fetal Weight in a Mouse Model of Fetal Growth Restriction with a Normal Vascular Phenotype

Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5th centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5th centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. 14C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR.

Recapitulation of characteristics of human placental vascular insufficiency in a novel mouse model

ObjectiveWe tested the effects of selective reduction of placental blood flow by mesenteric uterine artery branch ligation (MUAL) resulting in fetal growth restriction (FGR). MethodsTimed mated C57BL/6J Day(D) 18 dams were divided into two groups: MUAL (n = 18); and control-sham (n = 18). Pups were delivered on D20, cross-fostered to surrogate CD-1 mothers for 4 weeks, and followed for 8 weeks. Outcome data included birth and placental weight, postnatal growth, placental volume determined by stereology, quantification of placental insulin-like growth factors-1(IGF-1) and IGF-2 and IGF binding proteins(IGFBP 2 and 6) by ELISA and gene expression by qPCR and GeneChip microarray analysis. ResultsCompared with control, MUAL had an 11% reduction in mean birth weight (1.06 ± 0.13 g vs. 0.94 ± 0.13 g, p < 0.001) but no difference in placental weight. At 4 weeks of age, mean body weights of MUAL pups were significantly lower than sham. By 8 weeks, males but not females MUAL mice achieved equivalent mean body weight to control. Placental labyrinth depth, volume, and placental gene expression of IGF-1 and 2 were significantly reduced by MUAL. In contrast, placental protein level of IGFBP-2 and 6 were significantly elevated in the MUAL. Genomic expression analysis demonstrated that MUAL pups significantly up-regulated genes that were associated with apoptosis and growth pathways. ConclusionThis novel mouse animal model of FGR using selective ligation recapitulates multiple characteristics of placental vascular insufficiency (PI) in humans. This is the first non-genetic mouse model of PI which offers its application in transgenic mice to better study the underlying mechanisms in PI. CondensationA new mouse model of placental vascular insufficiency by selective ligation of mesenteric uterine artery branch recapitulates multiple findings observed in human placental vascular insufficiency.

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

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

Leptin Promotes Fetal Lung Maturity and Upregulates SP-A Expression in Pulmonary Alveoli Type-II Epithelial Cells Involving TTF-1 Activation

The placental hormone leptin has important functions in fetal and neonatal growth, and prevents depressed respiration in leptin-deficient mice. The effect of leptin on respiratory distress suffered by low birth weight and premature infants has been studied. However, it is unclear how leptin enhances lung maturity in the fetus and ameliorates neonatal respiratory distress. In the present study, we found that antenatal treatment with leptin for 2 d significantly enhanced the relative alveolus area and improved the maturity of fetal lungs in a rat model of fetal growth restriction (FGR). Mean birth weight and lung wet weight were higher in the leptin-treated group than in the PBS-treated group, indicating promotion of fetal growth. Leptin upregulated the intracellular expression and extracellular secretion of surfactant protein (SP) A in type-II alveolar epithelial cells (AECs) in vivo and in vitro. Dual positive effects of leptin were found on protein expression and transcriptional activity of thyroid transcription factor-1 (TTF-1), a nuclear transcription essential for branching morphogenesis of the lung and expression of SP-A in type-II AECs. Knockdown of TTF-1 by RNA interference indicated that TTF-1 may play a vital role in leptin-induced SP-A expression. These results suggest that leptin may have great therapeutic potential for the treatment of FGR, and leptin-mediated SP-A induction and lung maturity of the fetus are TTF-1 dependent.

Fetal growth restriction alters hippocampal 17-beta estradiol and estrogen receptor alpha levels in the newborn male rat

Fetal growth restriction (FGR) is associated with impaired neurodevelopmental outcomes in affected newborns. The pathogenesis of FGR-associated neurodevelopmental impairment implicates abnormal hippocampal function. The steroid hormone estrogen and its receptor, estrogen receptor alpha (ERα), are involved in the normal programming of hippocampal development and structure. However, the impact of FGR on hippocampal estrogen and hippocampal ERα is not well characterized. We hypothesized that FGR will reduce hippocampal and serum levels of 17-beta estradiol and its receptor, ERα, in the newborn rat hippocampus. We further hypothesize that FGR will reduce hippocampal ERα levels in a region-specific manner. To test our hypotheses, we used the well characterized rat model of FGR induced by uteroplacental-insufficiency in the pregnant Sprague-Dawley rat. Hippocampi and serum were obtained from FGR and control day 0 rat pups and examined for hippocampal 17-beta estradiol, serum 17-beta estradiol, and ERα mRNA and protein levels. Immunohistochemistry was performed to examine region-specific ERα staining. FGR decreased hippocampal 17-beta estradiol levels in the hippocampi of male newborn rats but not females. Serum 17-beta estradiol levels were not affected by FGR in either gender. FGR decreased hippocampal ERα mRNA levels in males but not females. Hippocampal ERα protein levels by Western blotting were not affected by FGR. However, FGR decreased apparent ERα staining in the cornu ammonis (CA)1, CA3, and dentate gyrus regions in the hippocampi of male newborn rats but not females. We conclude that FGR affects the programming of hippocampal estrogen and hippocampal ERα levels in the newborn rat in a gender-specific manner.

1.3 DNA Methylation of Somatotropic Axis Genes in Relation to Postnatal Growth and Metabolism Following Ad.VEGF Treatment of Growth-Restricted Sheep Fetuses

IntroductionWe previously showed that adenovirus (Ad) mediated overexpression of vascular endothelial growth factor (VEGF) in the uteroplacental circulation increases fetal growth velocity in the overnourished adolescent sheep paradigm of fetal...

Antenatal taurine supplementation reduces cerebral cell apoptosis in fetal rats with growth restriction

Objective To explore the effect of antenatal taurine supplementation on cerebral apoptosis and the expression of glial cell line-derived neurotrophic factor (GDNF) and caspase-3 in fetal rats with fetal growth restriction (FGR).Methods Fifteen pregnant Sprague-Dawley rats were randomly divided into three groups:control group,FGR model group (model group) and FGR with antenatal taurine supplementation group (taurine group).Taurine was added into the diet of taurine group at a dose of 300 mg/(kg · d) from the 12th day of gestation until natural delivery.Two appropriate for gestational age (AGA) newborn rats were randomly selected from each mother in control group and two FGR fetal rats were randomly selected from each mother both in model and taurine groups.Apoptosis of neural cells in the brain was detected by terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL).Changes in protein expression of GDNF and caspase-3 were detected by immunohistochemistry.Levene method,one-way ANOVA and SNK-test,or Kruskal Wallis rank sum test and Tamhane’ s test were applied for statistical analysis.Results (1)The total amounts of fetal rats in control group,model group and taurine group were 65,60 and 59.The mean body weight of fetal rats were (6.36±0.44) g,(4.55 ± 0.45) g and (5.11±0.67) g,respectively.All fetal rats developed FGR in model group,while 76.3％(45/59) of fetal rats were FGR in taurine group.Therefore,FGR model was successfully established.(2) In control group,there were few expression of TUNEL positive cells in cerebral cortex.A large amount of TUNEL positive cells were found in the cortex,hippocampal and white matter area in model group,but less positive cells were identified in taurine group than in model group.The amount of apoptotic brain cells in the three groups were (0.46 ± 0.11),(14.76 ± 3.42) and (6.78 ± 1.93),respectively(H=429.80,P=0.000).(3)There were only small amount of GDNF positive cells in cerebral cortex in control group and more in model group.The amount of GDNF positive cells was further increased in taurine group.The amount of GDNF positive cells in cerebral cortex in the three groups were (93.56± 6.73),(120.36± 6.23)and(139.56± 5.28),respectively (H=715.17,P=0.000).(4) Few caspase-3 positive cells were found in cerebral cortex in control group.A large amount of positive cells were found in model group and less positive cells were found in taurine group,which was still more than those in control group.The amounts of caspase-3 positive cells in the three groups were (7.50±2.31),(151.32±24.43)and(37.28±11.21),respectively (F=132.54,P=0.000).Conclusions The number of apoptotic neural cells in brain tissue of baby rats with FGR were significantly increased,which can be significantly alleviated by maternal antenatal taurine supplementation through upregulation of GDNF and downregulation of caspase-3 expression. Key words: Fetal growth retardation; Taurine; Apoptosis; Glial cell line-derived neurotrophic factor; Caspase 3

Liver phosphatidylinosital 3-kinase/protein kinase B pathway is involved in the decrease of insulin sensitivity in rats with fetal growth restriction

Objective To investigate the effect of liver phosphatidylinosital 3-kinase/protein kinase B (PI3-K/AKT) pathway on the decrease of insulin sensitivity in fetal growth restriction (FGR) rats.Methods Twenty pregnant female rats were randomly divided into two groups one day after conception:normal-protein group and low protein group (n=10,respectively).Rats in low-protein group was given low protein diet (8.00％ protein) during pregnancy to build FGR model,while normal-protein group was given normal protein diet (20.00％ protein).On day 3,7,14,30,60 and 90 after birth,fasting blood samples of 8 male FGR offsprings from low-protein group and 8 normal offsprings from normal-protein group were collected to measure fasting plasma glucose and insulin level.Then insulin resistance index and insulin sensitivity index were calculated to determine insulin sensitivity.On day 7,14,30,60 and 90 after birth,liver tissue of 8 male FGR and normal offsprings were collected,insulin receptor substrate 1,2 (IRS1/IRS2)and glucose transporter 4 (GLUT4) mRNA expression were measured by real-time fluorescence polymerase chain reaction and the protein expressions of IRS1,PI3-K (subunit p110β),and AKT and phosphorylated AKT (pAKT) were measured by Western blot.The relationships between the expression changes of key molecules of PI3-K/AKT pathway and insulin sensitivity were analyzed by correlation and multiple linear regression method.Results (1) Mean birth weight of baby rats in low-protein group was significantly lower than that of normal-protein group [(4.92±0.36) g vs (6.43±0.59) g,t=14.73,P＜0.05].The incidence of FGR in low-protein group was 88.2％ (97/110); and for male offsprings,it was 94.1 ％ (48/51).(2) Compared to normal offsprings,fasting plasma glucose levels of male FGR offsprings were significantly higher from the age of 60 days to 90 days.Insulin levels and insulin resistance index were significantly higher and insulin sensitivity index was lower from the age of 30 days to 90 days,P＜0.05 respectively.(3) Compared to normal offsprings,IRS1 (0.45 ± 0.02 vs 0.68± 0.03,t=16.633,P＜0.05) and IRS2 mRNA (0.34±0.10 vs 0.70±0.19,t=4.864,P＜0.05) expressions in FGR offsprings were lower from day 7 after birth to day 90 (0.48±0.03 vs 0.59±0.05,t=5.237,P＜0.05; 0.49±0.20 vs 0.70±0.11,t=2.253,P＜0.05).There were no differences in expressions of GIUT4 mRNA and AKT protein between two groups (P＞ 0.05).IRS1,PI3-K and pAKT protein expressions of FGR offsprings decreased significantly from day 14 (0.22±0.05 vs 0.52±0.11,t=7.024,P＜0.05; 0.46±0.03 vs 0.97±0.08,t=17.508,P＜0.05; 0.62±0.10 vs 0.89±0.08,t=6.100,P＜0.05) to day 90 (1.11±0.08 vs 1.32±0.14,t=3.714,P＜0.05; 0.63±0.07 vs 1.00±0.19,t=5.206,P＜0.05;0.28±0.03 vs 0.45±0.10,t=4.880,P＜0.05).(4) The pAKT protein expression level of FGR rats was positively correlated with insulin sensitivity index (r=0.704,P＜0.05) ; while negatively correlated to the level of fasting plasma glucose (r=-0.609,P＜0.05),fasting insulin (r=-0.561,P＜0.05) and insulin resistance index (r =0.577,P＜ 0.05).Conclusions The changes of some key molecules' expressions of PI3-K/AKT pathway in liver might be involved in the insulin resistance in FGR rats. Key words: Fetal growth retardation; Insulin resistance; 1-Phosphatidylinositol 3-kinase; Protooncogene proteins c-akt; Liver; Disease models,animal

Crossing mice deficient in eNOS with placental-specific Igf2 knockout mice: A new model of fetal growth restriction

We tested the hypothesis that crossing two mouse models of fetal growth restriction (FGR) of differing phenotype would induce more severe FGR than either model alone. Female endothelial nitric oxide synthase knockout mice (eNOS−/−) were mated with placental-specific Igf2 knockout males (P0). Resultant fetuses were no more growth restricted than those with P0 deletion alone. However, P0 deletion attenuated the reduced placental system A amino acid transporter activity previously observed in eNOS−/− mice. Manipulating maternal and fetal genotypes provides a means to compare maternal and fetal regulation of fetal growth.

Effect of the Anti-Oxidant Tempol on Fetal Growth in a Mouse Model of Fetal Growth Restriction1

Fetal growth restriction (FGR) greatly increases the risk of perinatal morbidity and mortality and is associated with increased uterine artery resistance and levels of oxidative stress. There are currently no available treatments for this condition. The hypothesis that the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (Tempol) would improve uterine artery function and rescue fetal growth was tested in a mouse model of FGR, using the endothelial nitric oxide synthase knockout mouse (Nos3(-/-)). Pregnant Nos3(-/-) and control C57BL/6J mice were treated with the superoxide dismutase-mimetic Tempol (1 mmol/L) or vehicle from Gestational Day 12.5 to 18.5. Tempol treatment significantly increased pup weight (P < 0.05) and crown-rump length (P < 0.01) in C57BL/6J and Nos3(-/-) mice. Uterine artery resistance was increased in Nos3(-/-) mice (P < 0.05); Tempol significantly increased end diastolic velocity in Nos3(-/-) mice (P < 0.05). Superoxide production in uterine arteries did not differ between C57BL/6J and Nos3(-/-) mice but was significantly increased in placentas from Nos3(-/-) mice (P < 0.05). This was not reduced by Tempol treatment. Placental System A activity was reduced in Nos3(-/-) mice (P < 0.01); this was not improved by treatment with Tempol. Treatment of Nos3(-/-) mice with Tempol, however, was associated with reduced vascular density in the placental bed (P < 0.05). This study demonstrated that treatment with the antioxidant Tempol is able to improve fetal growth in a mouse model of FGR. This was associated with an increase in uterine artery blood flow velocity but not an improvement in uterine artery function or placental System A activity.