scholarly journals Increased arterial stiffness and extracellular matrix reorganization in intrauterine growth–restricted fetal sheep

2012 ◽  
Vol 73 (2) ◽  
pp. 147-154 ◽  
Author(s):  
Reuben Blair Dodson ◽  
Paul J. Rozance ◽  
Bradley S. Fleenor ◽  
Carson C. Petrash ◽  
Lauren G. Shoemaker ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Arterial Stiffness ◽  
Fetal Sheep ◽  
Intrauterine Growth

Intrauterine growth restriction delays surfactant protein maturation in the sheep fetus

2010 ◽  
Vol 298 (4) ◽  
pp. L575-L583 ◽  
Author(s):  
Sandra Orgeig ◽  
Tamara A. Crittenden ◽  
Ceilidh Marchant ◽  
I. Caroline McMillen ◽  
Janna L. Morrison
Keyword(s):  
Mrna Expression ◽  
Plasma Cortisol ◽  
Surfactant Protein ◽  
Cortisol Concentration ◽  
Plasma Catecholamine ◽  
Fetal Sheep ◽  
C Protein ◽  
Intrauterine Growth ◽  
Plasma Cortisol Concentration ◽  
The Impact

Pulmonary surfactant is synthesized by type II alveolar epithelial cells to regulate the surface tension at the air-liquid interface of the air-breathing lung. Developmental maturation of the surfactant system is controlled by many factors including oxygen, glucose, catecholamines, and cortisol. The intrauterine growth-restricted (IUGR) fetus is hypoxemic and hypoglycemic, with elevated plasma catecholamine and cortisol concentrations. The impact of IUGR on surfactant maturation is unclear. Here we investigate the expression of surfactant protein (SP) A, B, and C in lung tissue of fetal sheep at 133 and 141 days of gestation (term 150 ± 3 days) from control and carunclectomized Merino ewes. Placentally restricted (PR) fetuses had a body weight <2 SD from the mean of control fetuses and a mean gestational PaO2<17 mmHg. PR fetuses had reduced absolute, but not relative, lung weight, decreased plasma glucose concentration, and increased plasma cortisol concentration. Lung SP-A, -B, and -C protein and mRNA expression was reduced in PR compared with control fetuses at both ages. SP-B and -C but not SP-A mRNA expression and SP-A but not SP-B or -C protein expression increased with gestational age. Mean gestational PaO2was positively correlated with SP-A, -B, and -C protein and SP-B and -C mRNA expression in the younger cohort. SP-A and -B gene expression was inversely related to plasma cortisol concentration. Placental restriction, leading to chronic hypoxemia and hypercortisolemia in the carunclectomy model, results in significant inhibition of surfactant maturation. These data suggest that IUGR fetuses are at significant risk of lung complications, especially if born prematurely.

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 Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction

2015 ◽  
Vol 309 (8) ◽  
pp. R920-R928 ◽  
Author(s):  
Laura D. Brown ◽  
Paul J. Rozance ◽  
Jennifer L. Bruce ◽  
Jacob E. Friedman ◽  
William W. Hay ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Glucose Oxidation ◽  
Fetal Liver ◽  
Lactate Production ◽  
Glucose Production ◽  
Limited Capacity ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Insulin Clamp

Intrauterine growth-restricted (IUGR) fetal sheep, produced by placental insufficiency, have lower oxygen concentrations, higher lactate concentrations, and increased hepatic glucose production that is resistant to suppression by insulin. We hypothesized that increased lactate production in the IUGR fetus results from reduced glucose oxidation, during basal and maximal insulin-stimulated conditions, and is used to support glucose production. To test this, studies were performed in late-gestation control (CON) and IUGR fetal sheep under basal and hyperinsulinemic-clamp conditions. The basal glucose oxidation rate was similar and increased by 30–40% during insulin clamp in CON and IUGR fetuses ( P < 0.005). However, the fraction of glucose oxidized was 15% lower in IUGR fetuses during basal and insulin-clamp periods ( P = 0.05). IUGR fetuses also had four-fold higher lactate concentrations ( P < 0.001) and lower lactate uptake rates ( P < 0.05). In IUGR fetal muscle and liver, mRNA expression of pyruvate dehydrogenase kinase ( PDK4), an inhibitor of glucose oxidation, was increased over fourfold. In IUGR fetal liver, but not skeletal muscle, mRNA expression of lactate dehydrogenase A ( LDHA) was increased nearly fivefold. Hepatic expression of the gluconeogenic genes, phosphoenolpyruvate carboxykinase ( PCK)1, and PCK2, was correlated with expression of PDK4 and LDHA. Collectively, these in vivo and tissue data support limited capacity for glucose oxidation in the IUGR fetus via increased PDK4 in skeletal muscle and liver. We speculate that lactate production also is increased, which may supply carbon for glucose production in the IUGR fetal liver.

scholarly journals Prolonged amino acid infusion into intrauterine growth-restricted fetal sheep increases leucine oxidation rates

2018 ◽  
Vol 315 (6) ◽  
pp. E1143-E1153 ◽  
Author(s):  
Sandra G. Wai ◽  
Paul J. Rozance ◽  
Stephanie R. Wesolowski ◽  
William W. Hay ◽  
Laura D. Brown
Keyword(s):  
Amino Acid ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Fetal Sheep ◽  
Acid Infusion ◽  
Amino Acid Infusion ◽  
Intrauterine Growth ◽  
Leucine Oxidation ◽  
Fetal Plasma ◽  
Oxidation Rates

Overcoming impaired growth in an intrauterine growth-restricted (IUGR) fetus has potential to improve neonatal morbidity, long-term growth, and metabolic health outcomes. The extent to which fetal anabolic capacity persists as the IUGR condition progresses is not known. We subjected fetal sheep to chronic placental insufficiency and tested whether prolonged amino acid infusion would increase protein accretion in these IUGR fetuses. IUGR fetal sheep were infused for 10 days with either mixed amino acids providing ~2 g·kg−1·day−1 (IUGR-AA) or saline (IUGR-Sal) during late gestation. At the end of the infusion, fetal plasma leucine, isoleucine, lysine, methionine, and arginine concentrations were higher in the IUGR-AA than IUGR-Sal group ( P < 0.05). Fetal plasma glucose, oxygen, insulin, IGF-1, cortisol, and norepinephrine concentrations were similar between IUGR groups, but glucagon concentrations were fourfold higher in the IUGR-AA group ( P < 0.05). Net umbilical amino acid uptake rate did not differ between IUGR groups; thus the total amino acid delivery rate (net umbilical amino acid uptake + infusion rate) was higher in the IUGR-AA than IUGR-Sal group (30 ± 4 vs. 19 ± 1 μmol·kg−1·min−1, P < 0.05). Net umbilical glucose, lactate, and oxygen uptake rates were similar between IUGR groups. Fetal leucine oxidation rate, measured using a leucine tracer, was higher in the IUGR-AA than IUGR-Sal group (2.5 ± 0.3 vs. 1.7 ± 0.3 μmol·kg−1·min−1, P < 0.05). Fetal protein accretion rate was not statistically different between the IUGR groups (1.6 ± 0.4 and 0.8 ± 0.3 μmol·kg−1·min−1 in IUGR-AA and IUGR-Sal, respectively) due to variability in response to amino acids. Prolonged amino acid infusion into IUGR fetal sheep increased leucine oxidation rates with variable anabolic response.

scholarly journals Differential effects of intrauterine growth restriction and a hypersinsulinemic-isoglycemic clamp on metabolic pathways and insulin action in the fetal liver

2019 ◽  
Vol 316 (5) ◽  
pp. R427-R440 ◽  
Author(s):  
Amanda K. Jones ◽  
Laura D. Brown ◽  
Paul J. Rozance ◽  
Natalie J. Serkova ◽  
William W. Hay ◽  
...  
Keyword(s):  
Amino Acid ◽  
Signaling Pathways ◽  
Cholesterol Synthesis ◽  
Fetal Liver ◽  
Energy State ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Insulin Clamp

Intrauterine growth-restricted (IUGR) fetal sheep have increased hepatic glucose production (HGP) that is resistant to suppression during a hyperinsulinemic-isoglycemic clamp (insulin clamp). We hypothesized that the IUGR fetal liver would have activation of metabolic and signaling pathways that support HGP and inhibition of insulin-signaling pathways. To test this, we used transcriptomic profiling with liver samples from control (CON) and IUGR fetuses receiving saline or an insulin clamp. The IUGR liver had upregulation of genes associated with gluconeogenesis/glycolysis, transcription factor regulation, and cytokine responses and downregulation of genes associated with cholesterol synthesis, amino acid degradation, and detoxification pathways. During the insulin clamp, genes associated with cholesterol synthesis and innate immune response were upregulated in CON and IUGR. There were 20-fold more genes differentially expressed during the insulin clamp in IUGR versus CON. These genes were associated with proteasome activation and decreased amino acid and lipid catabolism. We found increased TRB3, JUN, MYC, and SGK1 expression and decreased PTPRD expression as molecular targets for increased HGP in IUGR. As candidate genes for resistance to insulin’s suppression of HGP, expression of JUN, MYC, and SGK1 increased more during the insulin clamp in CON compared with IUGR. Metabolites were measured with 1H-nuclear magnetic resonance and support increased amino acid concentrations, decreased mitochondria activity and energy state, and increased cell stress in the IUGR liver. These results demonstrate a robust response, beyond suppression of HGP, during the insulin clamp and coordinate responses in glucose, amino acid, and lipid metabolism in the IUGR fetus.

Antenatal glucocorticoids reduce growth in appropriately grown and growth-restricted ovine fetuses in a sex-specific manner

2012 ◽  
Vol 24 (5) ◽  
pp. 753 ◽  
Author(s):  
Suzanne L. Miller ◽  
Amy E. Sutherland ◽  
Veena G. Supramaniam ◽  
David W. Walker ◽  
Graham Jenkin ◽  
...  
Keyword(s):  
Umbilical Artery ◽  
Specific Effect ◽  
Single Umbilical Artery ◽  
Artery Ligation ◽  
Fetal Sheep ◽  
Control Male ◽  
Male And Female ◽  
Intrauterine Growth ◽  
Specific Manner ◽  
Maternal Administration

Antenatal glucocorticoids are administered to mature the fetal lungs before preterm birth. Glucocorticoids also have non-pulmonary effects, including reducing fetal body and brain growth. The present study examined whether glucocorticoid administration has a sex-specific effect on growth in appropriately grown (control) and intrauterine growth-restricted (IUGR) fetal sheep. IUGR was induced at 0.7 gestation in fetal sheep by single umbilical artery ligation. On Days 5 and 6 after surgery, IUGR or control fetuses were exposed to the synthetic glucocorticoid betamethasone (BM; 11.4 mg) or saline via intramuscular maternal administration. On Day 7, a postmortem was conducted to determine fetal sex and weight. Compared with control fetuses, the birthweight of male and female IUGR fetuses was significantly reduced (by 18.5 ± 4.4% (P = 0.002) and 21.7 ± 6.0% (P = 0.001), respectively). Maternal administration of BM significantly reduced bodyweight in both control and IUGR fetuses (by 11.3 ± 2.8% and 20.5 ± 3.6% in control male and female fetuses, respectively; and by 22.9 ± 3.1% and 38.3 ± 3.4% in IUGR male and female fetuses, respectively; P < 0.001 for all, versus control + saline) fetuses. In control and IUGR animals the degree of growth restriction was greater in females than males (P < 0.05) following administration of BM. These data suggest that antenatal glucocorticoids reduce fetal growth in a sex-specific manner, with females more growth restricted than males.

scholarly journals Impact of diet on the persistence of early vascular remodeling and stiffening induced by intrauterine growth restriction and a maternal high-fat diet

2019 ◽  
Vol 317 (2) ◽  
pp. H424-H433 ◽  
Author(s):  
Thomas A. Miller ◽  
R. Blair Dodson ◽  
Anastasiya Mankouski ◽  
Kyle N. Powers ◽  
Yueqin Yang ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
High Fat Diet ◽  
Intrauterine Growth Restriction ◽  
Vascular Remodeling ◽  
Structural Changes ◽  
Growth Restriction ◽  
Female Rats ◽  
High Fat ◽  
Regular Diet ◽  
Intrauterine Growth

Intrauterine growth restriction (IUGR) and maternal high-fat diet (HFD) independently predispose offspring to hypertension. In a rat model, IUGR more so than maternal HFD increases arterial stiffness with vascular remodeling as early as postnatal day (PND) 21. The trajectory of such early vascular changes remains unknown. We hypothesized that IUGR would increase blood pressure (BP), arterial stiffness, and markers of ongoing detrimental vascular remodeling in adult rats exposed to a maternal HFD regardless of weaning diet. Adult female rats were fed either a regular diet (RD) or an HFD before mating through lactation. IUGR was induced by uterine artery ligation. Offspring were weaned to either a RD or HFD through PND 60. For both control and IUGR rats, this design resulted in the following three diet groups: offspring from RD dams weaned to a RD and offspring from HFD dams weaned to a RD or to an HFD (IHH). In both males and females, only IHH increased systolic BP, but IUGR and HFD both alone and in combination increased arterial stiffness. Aortas contained fewer but thicker elastin bands in IHH rats and IUGR offspring from dams fed an HFD and weaned to a regular diet. IHH increased aortic lysl oxidase protein. In summary, the PND 21 rat mediators of vascular remodeling from IUGR and maternal HFD normalize by PND 60 while changes in elastin and arterial stiffness persist. We speculate that the longer-term risk of hypertension from dietary mediators is augmented by underlying IUGR-induced structural changes to the extracellular matrix. NEW & NOTEWORTHY We report that a combined insult of intrauterine growth restriction and maternal high-fat diet increases the risk of early cardiovascular pathology both independently and in conjunction with a continued high-fat diet in offspring.

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