Intrauterine Growth Restriction Alters the Postnatal Development of the Rat Cerebellum

2017 ◽  
Vol 39 (1-4) ◽  
pp. 215-227 ◽  
Author(s):  
Annie R.A. McDougall ◽  
Vanny Wiradjaja ◽  
Aminath Azhan ◽  
Anqi Li ◽  
Nadia Hale ◽  
...  
Keyword(s):  
Intrauterine Growth Restriction ◽  
Molecular Mechanisms ◽  
Growth Restriction ◽  
Cerebellar Development ◽  
Mrna Levels ◽  
Fiber Density ◽  
Pregnant Rats ◽  
Intrauterine Growth ◽  
Protein Levels ◽  
Proliferative Zone

Intrauterine growth restriction (IUGR) is a major cause of antenatal brain injury. We aimed to characterize cerebellar deficits following IUGR and to investigate the potential underlying cellular and molecular mechanisms. At embryonic day 18, pregnant rats underwent either sham surgery (controls; n = 23) or bilateral uterine vessel ligation to restrict blood flow to fetuses (IUGR; n = 20). Offspring were collected at postnatal day 2 (P2), P7, and P35. Body weights were reduced at P2, P7, and P35 in IUGR offspring (p < 0.05) compared with controls. At P7, the width of the external granule layer (EGL) was 30% greater in IUGR than control rats (p < 0.05); there was no difference in the width of the proliferative zone or in the density of Ki67-positive cells in the EGL. Bergmann glia were disorganized at P7 and P35 in IUGR pups, and by P35, there was a 10% decrease in Bergmann glial fiber density (p < 0.05) compared with controls. At P7, trophoblast antigen-2 (Trop2) mRNA and protein levels in the cerebellum were decreased by 88 and 40%, respectively, and astrotactin 1 mRNA levels were increased by 20% in the IUGR rats (p < 0.05) compared with controls; there was no difference in ASTN1 protein. The expressions of other factors known to regulate cerebellar development (astrotactin 2, brain-derived neurotrophic factor, erb-b2 receptor tyrosine kinase 4, neuregulin 1, sonic hedgehog and somatostatin) were not different between IUGR and control rats at P7 or P35. These data suggest that damage to the migratory scaffold (Bergmann glial fibers) and alterations in the genes that influence migration (Trop2 and Astn1) may underlie the deficits in postnatal cerebellar development following IUGR.

Differential regulation of igf1 and igf1r mRNA levels in the two hepatic lobes following intrauterine growth restriction and its treatment with intra-amniotic insulin-like growth factor-1 in ovine fetuses

2010 ◽  
Vol 22 (8) ◽  
pp. 1188 ◽  
Author(s):  
Revati A. Darp ◽  
Hendrina A. de Boo ◽  
Hui Hui Phua ◽  
Mark H. Oliver ◽  
José G. B. Derraik ◽  
...  
Keyword(s):  
Growth Factor ◽  
Intrauterine Growth Restriction ◽  
Venous Blood ◽  
Growth Restriction ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Hepatic Lobe ◽  
Intrauterine Growth ◽  
The Right ◽  
Gut Maturation

Intrauterine growth restriction (IUGR) has life-long health implications, yet there is no effective prenatal treatment. Daily intra-amniotic administration of insulin-like growth factor (IGF)-1 to IUGR fetal sheep improves fetal gut maturation but suppresses hepatic igf1 gene expression. Fetal hepatic blood supply is regulated, in part, by shunting of oxygen- and nutrient-rich umbilical venous blood through the ductus venosus, with the left hepatic lobe predominantly supplied by umbilical venous blood and the right hepatic lobe predominantly supplied by the portal circulation. We hypothesised that: (1) once-weekly intra-amniotic IGF-1 treatment of IUGR would be effective in promoting gut maturation; and (2) IUGR and its treatment with intra-amniotic IGF-1 would differentially affect igf1 and igf1r mRNA expression in the two hepatic lobes. IUGR fetuses received 360 µg IGF-1 or saline intra-amniotically once weekly from 110 until 131 days gestation. Treatment of IUGR fetuses with IGF-1 reversed impaired gut growth. In unembolised, untreated control fetuses, igf1 mRNA levels were 19% lower in the right hepatic lobe than in the left; in IUGR fetuses, igf1 and igf1r mRNA levels were sixfold higher in the right lobe. IGF-1 treatment reduced igf1 and igf1r mRNA levels in both lobes compared with IUGR fetuses. Thus, weekly intra-amniotic IGF-1 treatment, a clinically feasible approach, reverses the impaired gut development seen in IUGR. Furthermore, igf1 and igf1r mRNA levels are differentially expressed in the two hepatic lobes and relative expression in the two lobes is altered by both IUGR and intra-amniotic IGF-1 treatment.

scholarly journals Reduced Placental 11β-Hydroxysteroid Dehydrogenase Type 2 mRNA Levels in Human Pregnancies Complicated by Intrauterine Growth Restriction: An Analysis of Possible Mechanisms

2001 ◽  
Vol 86 (10) ◽  
pp. 4979-4983 ◽  
Author(s):  
C. L. McTernan ◽  
N. Draper ◽  
H. Nicholson ◽  
S. M. Chalder ◽  
P. Driver ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Intrauterine Growth Restriction ◽  
Subsequent Development ◽  
Hydroxysteroid Dehydrogenase ◽  
Underlying Mechanism ◽  
Growth Restriction ◽  
Mrna Levels ◽  
Intrauterine Growth ◽  
Apparent Mineralocorticoid Excess

11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone. In the placenta 11β-HSD2 activity is thought to protect the fetus from the deleterious effects of maternal glucocorticoids. Patients with apparent mineralocorticoid excess owing to mutations in the 11β-HSD2 gene invariably have reduced birth weight, and we have recently shown reduced placental 11β-HSD2 activity in pregnancies complicated by intrauterine growth restriction. This is reflected in the literature by evidence of hypercortisolemia in the fetal circulation of small babies. In this study we have determined the levels of placental 11β-HSD2 mRNA expression across normal gestation (n = 86 placentae) and in pregnancies complicated by intrauterine growth restriction (n = 19) and evaluated the underlying mechanism for any aberrant 11β-HSD2 mRNA expression in intrauterine growth restriction. 11β-HSD2 mRNA expression increased more than 50-fold across gestation, peaking at term. Placental 11β-HSD2 mRNA levels were significantly decreased in intrauterine growth restriction pregnancies when compared with gestationally matched, appropriately grown placentae [e.g. at termΔ Ct (11β-hydroxysteroid dehydrogenase type 2/18S) 12.8 ± 0.8 (mean ± se) vs. 10.2 ± 0.2, respectively, P &lt; 0.001]. These differences were not attributable to changes in trophoblast mass in intrauterine growth restriction placentae, as assessed by parallel analyses of cytokeratin-8 mRNA expression. No mutations were found in the 11β-HSD2 gene in the intrauterine growth restriction cohort, and imprinting analysis revealed that the 11β-HSD2 gene was not imprinted. Although the underlying cause is unknown, 11β-HSD2 gene expression is reduced in intrauterine growth restriction pregnancies. These data highlight the important role of 11β-HSD2 in regulating fetal growth, a known factor in determining fetal morbidity but also the subsequent development of cardiovascular disease in adulthood.

scholarly journals Intralipid Infusion in Pregnant Rats Induces Plasma Angiogenic Imbalance, Inflammation, and Intrauterine Growth Restriction

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Jeremy W. Duncan ◽  
Matthew Bergeron ◽  
Jessica L. Bradshaw ◽  
Frank T. Spradley ◽  
Joey P. Granger
Keyword(s):  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Pregnant Rats ◽  
Intrauterine Growth

Abstract 130: Sphingosine-1-Phosphate Signaling Plays a Role in High Blood Pressure Programmed by Intrauterine Growth Restriction in Mouse

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Suttira Intapad
Keyword(s):  
Protein Expression ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Acute Administration ◽  
Mrna Levels ◽  
Male Control ◽  
Intrauterine Growth ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Intrauterine growth restriction (IUGR) is a risk factor for hypertension and cardiovascular (CV) disease in later life, but the underlying mechanisms remain unclear. The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) is critically involved in CV development in the fetus, and plays a significant role in the regulation of CV health in adulthood. S1P receptor (S1PR) type 1, 2 and 3 are widely expressed in CV system which S1PR1 has a protective role against kidney injury, while S1PR3 is involved in controlling BP. Yet, the contribution of S1P on BP in IUGR is unknown. In the present studies, we tested the hypothesis that IUGR alters renal S1P receptors expression during- and post-nephrogenesis, which contributes to high BP in male IUGR mouse. C57bl/6J mice underwent sham or reduced uterine perfusion (RUP) at day 13 of gestation with delivery at full term. IUGR offspring (from RUP dam) had a lower birth weight than control (p<0.05). Kidneys were isolated from 2 day old male pups or adult 24 week old male control and IUGR. S1PR3 protein expression was increased in 2 day old IUGR kidneys (2.4 fold vs control, N=3, p< 0.01). At 24 weeks of age, S1PR3 mRNA levels were increased (1.2 fold vs control, N=4, p< 0.05) whereas S1PR3 protein levels were decreased (0.75 fold vs control, N=4, p< 0.05) in IUGR kidneys. mRNA and protein expression levels of S1PR1 and S1PR2 were not different between control and IUGR kidneys. Finally, we assessed the role of S1PRs agonist on BP of IUGR. Male IUGR offspring had a significantly higher BP compared to male control via carotid catheter in the conscious state (control: 112.1±2.1, IUGR: 125.0±3.7 mmHg; N=7, P <0.05). Acute administration of FTY720 (1 mg/kgBW i.p, Fingomod), a S1P receptor type 1, 3 agonist did not significantly alter BP in control (106.0 ± 5.7 mmHg) but significantly decreased BP in IUGR (105.7±2.3 mmHg, p< 0.05). A dose response to FTY720 (10 mg/kgBW) decreased BP in both control (94.0±2.0 mmHg, p< 0.05) and IUGR (99.3±2.3 mmHg, p< 0.05). Together our data suggest that IUGR programs an alteration of renal S1PR3 expression in both during- and post-nephrogenesis thereby contributing to an increase in sensitivity to S1PRs agonist. Thus, S1P signaling is a putative mechanism underlying the hypertension of IUGR offspring.

scholarly journals Human Cytomegalovirus Infection Interferes with the Maintenance and Differentiation of Trophoblast Progenitor Cells of the Human Placenta

2015 ◽  
Vol 89 (9) ◽  
pp. 5134-5147 ◽  
Author(s):  
Takako Tabata ◽  
Matthew Petitt ◽  
Martin Zydek ◽  
June Fang-Hoover ◽  
Nicholas Larocque ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Human Cytomegalovirus ◽  
Intrauterine Growth Restriction ◽  
Molecular Mechanisms ◽  
Hcmv Infection ◽  
Congenital Infection ◽  
Growth Restriction ◽  
Chorionic Villi ◽  
Intrauterine Growth

ABSTRACTHuman cytomegalovirus (HCMV) is a major cause of birth defects that include severe neurological deficits, hearing and vision loss, and intrauterine growth restriction. Viral infection of the placenta leads to development of avascular villi, edema, and hypoxia associated with symptomatic congenital infection. Studies of primary cytotrophoblasts (CTBs) revealed that HCMV infection impedes terminal stages of differentiation and invasion by various molecular mechanisms. We recently discovered that HCMV arrests earlier stages involving development of human trophoblast progenitor cells (TBPCs), which give rise to the mature cell types of chorionic villi—syncytiotrophoblasts on the surfaces of floating villi and invasive CTBs that remodel the uterine vasculature. Here, we show that viral proteins are present in TBPCs of the chorion in cases of symptomatic congenital infection.In vitrostudies revealed that HCMV replicates in continuously self-renewing TBPC lines derived from the chorion and alters expression and subcellular localization of proteins required for cell cycle progression, pluripotency, and early differentiation. In addition, treatment with a human monoclonal antibody to HCMV glycoprotein B rescues differentiation capacity, and thus, TBPCs have potential utility for evaluation of the efficacies of novel antiviral antibodies in protecting and restoring placental development. Our results suggest that HCMV replicates in TBPCs in the chorionin vivo, interfering with the earliest steps in the growth of new villi, contributing to virus transmission and impairing compensatory development. In cases of congenital infection, reduced responsiveness of the placenta to hypoxia limits the transport of substances from maternal blood and contributes to fetal growth restriction.IMPORTANCEHuman cytomegalovirus (HCMV) is a leading cause of birth defects in the United States. Congenital infection can result in permanent neurological defects, mental retardation, hearing loss, visual impairment, and pregnancy complications, including intrauterine growth restriction, preterm delivery, and stillbirth. Currently, there is neither a vaccine nor any approved treatment for congenital HCMV infection during gestation. The molecular mechanisms underlying structural deficiencies in the placenta that undermine fetal development are poorly understood. Here we report that HCMV replicates in trophoblast progenitor cells (TBPCs)—precursors of the mature placental cells, syncytiotrophoblasts and cytotrophoblasts, in chorionic villi—in clinical cases of congenital infection. Virus replication in TBPCsin vitrodysregulates key proteins required for self-renewal and differentiation and inhibits normal division and development into mature placental cells. Our findings provide insights into the underlying molecular mechanisms by which HCMV replication interferes with placental maturation and transport functions.

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