Effects of intrauterine growth restriction on lung liquid dynamics and lung development in fetal sheep

2001 ◽  
Vol 184 (2) ◽  
pp. 209-216 ◽  
Author(s):  
Megan L. Cock ◽  
Cheryl A. Albuquerque ◽  
Belinda J. Joyce ◽  
Stuart B. Hooper ◽  
Richard Harding
Keyword(s):  
Intrauterine Growth Restriction ◽  
Lung Development ◽  
Growth Restriction ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Lung Liquid ◽  
Liquid Dynamics

scholarly journals Intrauterine growth restriction decreases NF-κB signaling in fetal pulmonary artery endothelial cells of fetal sheep

2018 ◽  
Vol 315 (3) ◽  
pp. L348-L359 ◽  
Author(s):  
R. Blair Dodson ◽  
Kyle N. Powers ◽  
Jason Gien ◽  
Paul J. Rozance ◽  
Gregory Seedorf ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Intrauterine Growth Restriction ◽  
Lung Diseases ◽  
Growth Restriction ◽  
Mouse Lung ◽  
Similar Degree ◽  
Fetal Sheep ◽  
Vascular Growth ◽  
Intrauterine Growth ◽  
Pulmonary Artery Endothelial Cell

Intrauterine growth restriction (IUGR) in premature newborns increases the risk for bronchopulmonary dysplasia, a chronic lung disease characterized by disrupted pulmonary angiogenesis and alveolarization. We previously showed that experimental IUGR impairs angiogenesis; however, mechanisms that impair pulmonary artery endothelial cell (PAEC) function are uncertain. The NF-κB pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NF-κB-regulated proangiogenic targets in fetal PAEC. PAECs were isolated from the lungs of control fetal sheep and sheep with experimental IUGR from an established model of chronic placental insufficiency. Microarray analysis identified suppression of NF-κB signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4α1 and laminin α4, components of the basement membrane and putative NF-κB targets. In comparison with controls, immunostaining of active NF-κB complexes, NF-κB-DNA binding, baseline expression of NF-κB subunits p65 and p50, and LPS-mediated inducible activation of NF-κB signaling were decreased in IUGR PAEC. Although pharmacological NF-κB inhibition did not affect angiogenic function in IUGR PAEC, angiogenic function of control PAEC was reduced to a similar degree as that observed in IUGR PAEC. These data identify reductions in endothelial NF-κB signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NF-κB-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NF-κB activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR.

scholarly journals The effects of intrauterine growth restriction and antenatal glucocorticoids on ovine fetal lung development

2012 ◽  
Vol 71 (6) ◽  
pp. 689-696 ◽  
Author(s):  
Amy E. Sutherland ◽  
Kelly J. Crossley ◽  
Beth J. Allison ◽  
Graham Jenkin ◽  
Euan M. Wallace ◽  
...  
Keyword(s):  
Intrauterine Growth Restriction ◽  
Lung Development ◽  
Fetal Lung ◽  
Growth Restriction ◽  
Intrauterine Growth ◽  
Fetal Lung Development ◽  
Ovine Fetal

scholarly journals Increased Hepatic Glucose Production in Fetal Sheep With Intrauterine Growth Restriction Is Not Suppressed by Insulin

Diabetes ◽  
2012 ◽  
Vol 62 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Stephanie R. Thorn ◽  
Laura D. Brown ◽  
Paul J. Rozance ◽  
William W. Hay ◽  
Jacob E. Friedman
Keyword(s):  
Intrauterine Growth Restriction ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Growth Restriction ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Hepatic Glucose

Increased Stiffness of the Abdominal Aorta With Intrauterine Growth Restriction in the Near-Term Fetal Sheep

2012 ◽  
Author(s):  
Reuben Blair Dodson ◽  
Paul J. Rozance ◽  
Kendall S. Hunter ◽  
Virginia L. Ferguson
Keyword(s):  
Abdominal Aorta ◽  
Intrauterine Growth Restriction ◽  
Structural Changes ◽  
Epidemiological Studies ◽  
Growth Restriction ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Systemic Artery ◽  
Artery Stiffness ◽  
Near Term

Fetal intrauterine growth restriction (IUGR) results in increased placental resistance to blood flow, fetal hypertension and increased pulsatility [1]. These hemodynamic changes have been shown to lead to vascular remodeling in adolescents and adults [2, 3] but have received little study of its effect during this critical period of vascular formation. Epidemiological studies link IUGR to cardiovascular disease in adulthood [4], but the reason for this is not clearly understood. Here, we examine a large elastic artery for developmental alterations under hypertensive conditions. We hypothesize that fetal hypertension induces abdominal aorta (AA) stiffening in the fetal ovine model of IUGR and that the increased systemic artery stiffness is due to altered extracellular matrix (ECM) composition and structural changes.

scholarly journals Role of miR-29 in mediating offspring lung phenotype in a rodent model of intrauterine growth restriction

2018 ◽  
Vol 315 (5) ◽  
pp. R1017-R1026 ◽  
Author(s):  
Tsai-Der Chuang ◽  
Reiko Sakurai ◽  
Ming Gong ◽  
Omid Khorram ◽  
Virender K. Rehan
Keyword(s):  
Intrauterine Growth Restriction ◽  
Lung Development ◽  
Molecular Mechanisms ◽  
Vascular Tissue ◽  
Growth Restriction ◽  
Lung Fibroblasts ◽  
Intrauterine Growth ◽  
Maternal Undernutrition ◽  
Ecm Proteins

Considerable epidemiological and experimental evidence supports the concept that the adult chronic lung disease (CLD), is due, at least in part, to aberrations in early lung development in response to an abnormal intrauterine environment; however, the underlying molecular mechanisms remain unknown. We used a well-established rat model of maternal undernutrition (MUN) during pregnancy that results in offspring intrauterine growth restriction (IUGR) and adult CLD to test the hypothesis that in response to MUN, excess maternal glucocorticoids (GCs) program offspring lung development to a CLD phenotype by altering microRNA (miR)-29 expression, which is a key miR in regulating extracellular matrix (ECM) deposition during development and injury-repair. At postnatal day 21 and 5 mo, compared with the control offspring lung, MUN offspring lung miR-29 expression was significantly decreased in conjunction with an elevated expression of multiple downstream target ECM proteins [collagen (COL)1A1, COL3A1, COL4A5, and elastin], at both mRNA and protein levels. Importantly, MUN-induced changes in miR-29 and target gene expressions were at least partially blocked in the lungs of offspring of MUN dams treated with metyrapone, a selective GC synthesis inhibitor. Furthermore, dexamethasone treatment of cultured fetal rat lung fibroblasts significantly induced miR-29 expression along with the suppression of target ECM proteins. These data, along with the previously known role of miR-29 in regulating ECM deposition in vascular tissue in the MUN offspring, suggest miR-29 to be a common mechanistic denominator for the vascular and pulmonary phenotypes in the IUGR offspring, providing a novel potential therapeutic target.

scholarly journals Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction

2010 ◽  
Vol 298 (4) ◽  
pp. E770-E778 ◽  
Author(s):  
Rafael A. Leos ◽  
Miranda J. Anderson ◽  
Xiaochuan Chen ◽  
Juliana Pugmire ◽  
K. Arbor Anderson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Intrauterine Growth Restriction ◽  
Adrenergic Receptor ◽  
Plasma Insulin ◽  
Placental Insufficiency ◽  
Growth Restriction ◽  
Receptor Expression ◽  
Plasma Norepinephrine ◽  
Fetal Sheep ◽  
Intrauterine Growth

In this study, we examined chronic norepinephrine suppression of insulin secretion in sheep fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR). Glucose-stimulated insulin secretion (GSIS) was measured with a square-wave hyperglycemic clamp in the presence or absence of adrenergic receptor antagonists phentolamine (α) and propranolol (β). IUGR fetuses were hypoglycemic and hypoxemic and had lower GSIS responsiveness ( P ≤ 0.05) than control fetuses. IUGR fetuses also had elevated plasma norepinephrine (3,264 ± 614 vs. 570 ± 86 pg/ml; P ≤ 0.05) and epinephrine (164 ± 32 vs. 60 ± 12 pg/ml; P ≤ 0.05) concentrations. In control fetuses, adrenergic inhibition increased baseline plasma insulin concentrations (1.7-fold, P ≤ 0.05), whereas during hyperglycemia insulin was not different. A greater ( P ≤ 0.05) response to adrenergic inhibition was found in IUGR fetuses, and the average plasma insulin concentrations increased 4.9-fold at baseline and 7.1-fold with hyperglycemia. Unlike controls, basal plasma glucose concentrations fell ( P ≤ 0.05) with adrenergic antagonists. GSIS responsiveness, measured by the change in insulin, was higher (8.9-fold, P ≤ 0.05) in IUGR fetuses with adrenergic inhibition than controls (1.8-fold, not significant), showing that norepinephrine suppresses insulin secretion in IUGR fetuses. Strikingly, in IUGR fetuses, adrenergic inhibition resulted in a greater GSIS responsiveness, because β-cell mass was 56% lower and the maximal stimulatory insulin response tended ( P < 0.1) to be higher than controls. This persistent norepinephrine suppression appears to be partially explained by higher mRNA concentrations of adrenergic receptors α1D, α2A, and α2B in a cohort of fetuses that were naïve to the antagonists. Therefore, norepinephrine suppression of insulin secretion was maintained, in part, by upregulating adrenergic receptor expression, but the β-cells also appeared to compensate with enhanced GSIS. These findings may begin to explain why IUGR infants have a propensity for increased glucose requirements if norepinephrine is suddenly decreased after birth.

scholarly journals Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 2104-2115 ◽  
Author(s):  
Antoni R. Macko ◽  
Dustin T. Yates ◽  
Xiaochuan Chen ◽  
Leslie A. Shelton ◽  
Amy C. Kelly ◽  
...  
Keyword(s):  
Intrauterine Growth Restriction ◽  
Arterial Oxygen Tension ◽  
Placental Insufficiency ◽  
Growth Restriction ◽  
Arterial Oxygen ◽  
Plasma Norepinephrine ◽  
Β Cell ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Chronic Hypoxemia

Abstract In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on β-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.65 gestation. As expected, AD-IUGR fetuses had lower norepinephrine concentrations than intact-IUGR fetuses despite being hypoxemic and hypoglycemic. Placental insufficiency reduced fetal weights, but the severity of IUGR was less with AD. Although basal plasma insulin concentrations were lower in intact-IUGR and AD-IUGR fetuses compared with intact-controls, glucose-stimulated insulin concentrations were greater in AD-IUGR fetuses compared with intact-IUGR fetuses. Interestingly, AD-controls had lower glucose- and arginine-stimulated insulin concentrations than intact-controls, but AD-IUGR and AD-control insulin responses were not different. To investigate chronic hypoxemia in the IUGR fetus, arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction. Oxygenation of IUGR fetuses enhanced glucose-stimulated insulin concentrations 3.3-fold in intact-IUGR and 1.7-fold in AD-IUGR fetuses but did not lower norepinephrine and epinephrine concentrations. Together these findings show that chronic hypoxemia and hypercatecholaminemia have distinct but complementary roles in the suppression of β-cell responsiveness in IUGR fetuses.

scholarly journals Intrauterine growth restriction delays cardiomyocyte maturation and alters coronary artery function in the fetal sheep

2007 ◽  
Vol 578 (3) ◽  
pp. 871-881 ◽  
Author(s):  
Kristen J. Bubb ◽  
Megan L. Cock ◽  
M. Jane Black ◽  
Miodrag Dodic ◽  
Wee-Ming Boon ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Fetal Sheep ◽  
Intrauterine Growth
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