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

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.

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Glucose Replacement to Euglycemia Causes Hypoxia, Acidosis, and Decreased Insulin Secretion in Fetal Sheep With Intrauterine Growth Restriction

Pediatric Research ◽

10.1203/pdr.0b013e318189358c ◽

2009 ◽

Vol 65 (1) ◽

pp. 72-78 ◽

Cited By ~ 26

Author(s):

Paul J Rozance ◽

Sean W Limesand ◽

James S Barry ◽

Laura D Brown ◽

William W Hay

Keyword(s):

Insulin Secretion ◽

Intrauterine Growth Restriction ◽

Growth Restriction ◽

Fetal Sheep ◽

Intrauterine Growth

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

Diabetes ◽

10.2337/db11-1727 ◽

2012 ◽

Vol 62 (1) ◽

pp. 65-73 ◽

Cited By ~ 44

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

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

American Journal of Obstetrics and Gynecology ◽

10.1067/mob.2001.108858 ◽

2001 ◽

Vol 184 (2) ◽

pp. 209-216 ◽

Cited By ~ 66

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

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Altered Placental and Fetal Expression of IGFs and IGF-Binding Proteins Associated With Intrauterine Growth Restriction in Fetal Sheep During Early and Mid-Pregnancy

Pediatric Research ◽

10.1203/01.pdr.0000242364.78002.71 ◽

2006 ◽

Vol 60 (5) ◽

pp. 507-512 ◽

Cited By ~ 36

Author(s):

Barbra de Vrijer ◽

Meredith L Davidsen ◽

Randall B Wilkening ◽

Russell V Anthony ◽

Timothy R H Regnault

Keyword(s):

Intrauterine Growth Restriction ◽

Binding Proteins ◽

Growth Restriction ◽

Igf Binding Proteins ◽

Fetal Sheep ◽

Intrauterine Growth ◽

Igf Binding

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

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80634 ◽

2012 ◽

Cited By ~ 1

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.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00494.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. E770-E778 ◽

Cited By ~ 53

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.

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Structural coronary artery remodelling in the rabbit fetus as a result of intrauterine growth restriction

PLoS ONE ◽

10.1371/journal.pone.0218192 ◽

2019 ◽

Vol 14 (6) ◽

pp. e0218192 ◽

Cited By ~ 1

Author(s):

Patricia Garcia-Canadilla ◽

Tom de Vries ◽

Anna Gonzalez-Tendero ◽

Anne Bonnin ◽

Eduard Gratacos ◽

...

Keyword(s):

Coronary Artery ◽

Intrauterine Growth Restriction ◽

Growth Restriction ◽

Intrauterine Growth ◽

Rabbit Fetus

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

Endocrinology ◽

10.1210/en.2015-1850 ◽

2016 ◽

Vol 157 (5) ◽

pp. 2104-2115 ◽

Cited By ~ 21

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.

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Lower oxygen consumption and Complex I activity in mitochondria isolated from skeletal muscle of fetal sheep with intrauterine growth restriction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00057.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. E67-E80

Author(s):

Alexander L. Pendleton ◽

Andrew T. Antolic ◽

Amy C. Kelly ◽

Melissa A. Davis ◽

Leticia E. Camacho ◽

...

Keyword(s):

Skeletal Muscle ◽

Oxygen Consumption ◽

Intrauterine Growth Restriction ◽

Complex I ◽

Tca Cycle ◽

Growth Restriction ◽

Fetal Sheep ◽

Intrauterine Growth ◽

Tca Cycle Enzymes ◽

Complex I Activity

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower hindlimb oxygen consumption rates (OCRs), indicating depressed mitochondrial oxidative phosphorylation capacity in their skeletal muscle. We hypothesized that OCRs are lower in skeletal muscle mitochondria from IUGR fetuses, due to reduced electron transport chain (ETC) activity and lower abundances of tricarboxylic acid (TCA) cycle enzymes. IUGR sheep fetuses ( n = 12) were created with mid-gestation maternal hyperthermia and compared with control fetuses ( n = 12). At 132 ± 1 days of gestation, biceps femoris muscles were collected, and the mitochondria were isolated. Mitochondria from IUGR muscle have 47% lower State 3 (Complex I-dependent) OCRs than controls, whereas State 4 (proton leak) OCRs were not different between groups. Furthermore, Complex I, but not Complex II or IV, enzymatic activity was lower in IUGR fetuses compared with controls. Proteomic analysis ( n = 6/group) identified 160 differentially expressed proteins between groups, with 107 upregulated and 53 downregulated mitochondria proteins in IUGR fetuses compared with controls. Although no differences were identified in ETC subunit protein abundances, abundances of key TCA cycle enzymes [isocitrate dehydrogenase (NAD+) 3 noncatalytic subunit β (IDH3B), succinate-CoA ligase ADP-forming subunit-β (SUCLA2), and oxoglutarate dehydrogenase (OGDH)] were lower in IUGR mitochondria. IUGR mitochondria had a greater abundance of a hypoxia-inducible protein, NADH dehydrogenase 1α subcomplex 4-like 2, which is known to incorporate into Complex I and lower Complex I-mediated NADH oxidation. Our findings show that mitochondria from IUGR skeletal muscle adapt to hypoxemia and hypoglycemia by lowering Complex I activity and TCA cycle enzyme concentrations, which together, act to lower OCR and NADH production/oxidation in IUGR skeletal muscle.

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