Mitochondrial respiration is lower in the intrauterine growth-restricted fetal sheep heart.

Fetuses affected by intrauterine growth restriction have an increased risk of developing heart disease and failure in adulthood. Compared with controls, late gestation intrauterine growth-restricted (IUGR) fetal sheep have fewer binucleated cardiomyocytes, reflecting a more immature heart, which may reduce mitochondrial capacity to oxidize substrates. We hypothesized that the late gestation IUGR fetal heart has a lower capacity for mitochondrial oxidative phosphorylation.

IGF-1 infusion increases growth in fetal sheep when euinsulinemia is maintained.

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential.

Chronic Fetal Leucine Infusion Increases Rate of Leucine Oxidation but Not of Protein Synthesis in Late Gestation Fetal Sheep.

Background: Leucine increases protein synthesis rates in postnatal animals and adults. Whether supplemental leucine has similar effects in the fetus has not been determined.

Objective: To determine the effect of a chronic leucine infusion on whole-body leucine oxidation and protein metabolic rates, muscle mass, and regulators of muscle protein synthesis in late gestation fetal sheep.

A Two-Week Insulin Infusion in Intrauterine Growth Restricted Fetal Sheep at 75% Gestation Increases Skeletal Myoblast Replication but Did Not Restore Muscle Mass or Increase Fiber Number.

Intrauterine growth restricted (IUGR) fetuses are born with lower skeletal muscle mass, fewer proliferating myoblasts, and fewer myofibers compared to normally growing fetuses. Plasma concentrations of insulin, a myogenic growth factor, are lower in IUGR fetuses. We hypothesized that a two-week insulin infusion at 75% gestation would increase myoblast proliferation and fiber number in IUGR fetal sheep.

Lower citrate synthase activity, mitochondrial complex expression, and fewer oxidative myofibers characterize skeletal muscle from growth-restricted fetal sheep.

Skeletal muscle from the late gestation sheep fetus with intrauterine growth restriction (IUGR) has evidence of reduced oxidative metabolism. Using a sheep model of placental insufficiency and IUGR, we tested the hypothesis that by late gestation, IUGR fetal skeletal muscle has reduced capacity for oxidative phosphorylation because of intrinsic deficits in mitochondrial respiration. We measured mitochondrial respiration in permeabilized muscle fibers from biceps femoris (BF) and soleus (SOL) from control and IUGR fetal sheep.

Fetal Sex Does Not Impact Placental Blood Flow or Placental Amino Acid Transfer in Late Gestation Pregnant Sheep With or Without Placental Insufficiency.

Pregnant sheep have been used to model complications of human pregnancies including placental insufficiency and intrauterine growth restriction. Some of the hallmarks of placental insufficiency are slower uterine and umbilical blood flow rates, impaired placental transport of oxygen and amino acids, and lower fetal arterial concentrations of anabolic growth factors. An impact of fetal sex on these outcomes has not been identified in either human or sheep pregnancies.

Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect.

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses.

IGF-1 infusion to fetal sheep increases organ growth but not by stimulating nutrient transfer to the fetus.

Insulin-like growth factor-1 (IGF-1) is an important fetal growth factor. However, the role of fetal IGF-1 in increasing placental blood flow, nutrient transfer, and nutrient availability to support fetal growth and protein accretion is not well understood. Catheterized fetuses from late gestation pregnant sheep received an intravenous infusion of LR3 IGF-1 (LR3 IGF-1; = 8) or saline (SAL; = 8) for 1 wk.

Coronary vascular growth matches IGF-1-stimulated cardiac growth in fetal sheep.

As loss of contractile function in heart disease could often be mitigated by increased cardiomyocyte number, expansion of cardiomyocyte endowment paired with increased vascular supply is a desirable therapeutic goal. Insulin-like growth factor 1 (IGF-1) administration increases fetal cardiomyocyte proliferation and heart mass, but how fetal IGF-1 treatment affects coronary growth and function is unknown. Near-term fetal sheep underwent surgical instrumentation and were studied from 127 to 134 d gestation (term = 147 d), receiving either IGF-1 LR3 or vehicle.

Rates of myogenesis and myofiber numbers are reduced in late gestation IUGR fetal sheep.

Intrauterine growth-restricted (IUGR) fetuses are born with reduced skeletal muscle mass. We hypothesized that reduced rates of myogenesis would contribute to fewer and smaller myofibers in IUGR fetal hindlimb muscle compared to the normally growing fetus. We tested this hypothesis in IUGR fetal sheep with progressive placental insufficiency produced by exposing pregnant ewes to elevated ambient temperatures from 38 to 116 days gestation (dGA; term = 147 dGA).

Skeletal muscle amino acid uptake is lower and alanine production is greater in late gestation intrauterine growth-restricted fetal sheep hindlimb.

In a sheep model of intrauterine growth restriction (IUGR) produced from placental insufficiency, late gestation fetuses had smaller skeletal muscle mass, myofiber area, and slower muscle protein accretion rates compared with normally growing fetuses. We hypothesized that IUGR fetal muscle develops adaptations that divert amino acids (AAs) from protein accretion and activate pathways that conserve substrates for other organs. We placed hindlimb arterial and venous catheters into late gestation IUGR ( = 10) and control (CON, = 8) fetal sheep and included an external iliac artery flow probe to measure hindlimb AA uptake rates.

Ketamine Reduces Inflammation Pathways in the Hypothalamus and Hippocampus Following Transient Hypoxia in the Late-Gestation Fetal Sheep.

The physiological response to hypoxia in the fetus has been extensively studied with regard to redistribution of fetal combined ventricular output and sparing of oxygen delivery to fetal brain and heart. Previously, we have shown that the fetal brain is capable of mounting changes in gene expression that are consistent with tissue inflammation. The present study was designed to use transcriptomics and systems biology modeling to test the hypothesis that ketamine reduces or prevents the upregulation of inflammation-related pathways in hypothalamus and hippocampus after transient hypoxic hypoxia.

A 1 week IGF-1 infusion decreases arterial insulin concentrations but increases pancreatic insulin content and islet vascularity in fetal sheep.

Fetal insulin is critical for regulation of growth. Insulin concentrations are partly determined by the amount of β-cells present and their insulin content. Insulin-like growth factor-1 (IGF-1) is a fetal anabolic growth factor which also impacts β-cell mass in models of β-cell injury and diabetes.

Effects of ketamine on the fetal transcriptomic response to umbilical cord occlusion: comparison with hypoxic hypoxia in the cerebral cortex.

Key Points: The cerebral response to fetal asphyxia is characterized by an upregulation of nucleic acid and chromatin modification processes, as well as a downregulation of metabolic processes at 1 h post-umbilical cord occlusion (UCO). Twenty-four hours post UCO, there was an upregulation of metabolic processes and protein modifications. UCO did not alter bacterial gene expression levels, nor did it produce a robust inflammatory response compared to maternal hypoxia.

Post-hypoxia Invasion of the fetal brain by multidrug resistant Staphylococcus.

Herein we describe an association between activation of inflammatory pathways following transient hypoxia and the appearance of the multidrug resistant bacteria Staphylococcus simulans in the fetal brain. Reduction of maternal arterial oxygen tension by 50% over 30 min resulted in a subseiuent significant over-expression of genes associated with immune responses 24 h later in the fetal brain. The activated genes were consistent with stimulation by bacterial lipopolysaccharide; an influx of macrophages and appearance of live bacteria were found in these fetal brains.

Ketamine modulates fetal hemodynamic and endocrine responses to umbilical cord occlusion.

Umbilical cord occlusion (UCO) is a hypoxic insult that has been used to model birth asphyxia and umbilical cord compression in utero. UCO triggers vigorous neural and endocrine responses that include increased plasma ACTH and cortisol concentrations, increased blood pressure (BP), and decreased heart rate (HR). We have previously reported that ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, can modify the fetal hemodynamic and ACTH responses to ventilatory hypoxia and cerebral ischemia-reperfusion.

Genomic Effect of Triclosan on the Fetal Hypothalamus: Evidence for Altered Neuropeptide Regulation.

Triclosan (TCS), an antibacterial compound commonly added to personal care products, could be an endocrine disruptor at low doses. Although TCS has been shown to alter fetal physiology, its effects in the developing fetal brain are unknown. We hypothesize that exposure to TCS during fetal life could affect fetal hypothalamic gene expression.

Ketamine decreases inflammatory and immune pathways after transient hypoxia in late gestation fetal cerebral cortex.

Transient hypoxia in pregnancy stimulates a physiological reflex response that redistributes blood flow and defends oxygen delivery to the fetal brain. We designed the present experiment to test the hypotheses that transient hypoxia produces damage of the cerebral cortex and that ketamine, an antagonist ofNMDAreceptors and a known anti-inflammatory agent, reduces the damage. Late gestation, chronically catheterized fetal sheep were subjected to a 30-min period of ventilatory hypoxia that decreased fetal PaO2from 17 ± 1 to 10 ± 1 mmHg, or normoxia (PaO217 ± 1 mmHg), with or without pretreatment (10 min before hypoxia/normoxia) with ketamine (3 mg/kg, i.

Transcriptomics Modeling of the Late-Gestation Fetal Pituitary Response to Transient Hypoxia.

Background: The late-gestation fetal sheep responds to hypoxia with physiological, neuroendocrine, and cellular responses that aid in fetal survival. The response of the fetus to hypoxia represents a coordinated effort to maximize oxygen transfer from the mother and minimize wasteful oxygen consumption by the fetus. While there have been many studies aimed at investigating the coordinated physiological and endocrine responses to hypoxia, and while immunohistochemical or in situ hybridization studies have revealed pathways supporting the endocrine function of the pituitary, there is little known about the coordinated cellular response of the pituitary to the hypoxia.

Ketamine suppresses hypoxia-induced inflammatory responses in the late-gestation ovine fetal kidney cortex.

Acute fetal hypoxia is a form of fetal stress that stimulates renal vasoconstriction and ischaemia as a consequence of the physiological redistribution of combined ventricular output. Because of the potential ischaemia-reperfusion injury to the kidney, we hypothesized that it would respond to hypoxia with an increase in the expression of inflammatory genes, and that ketamine (an N-methyl-D-aspartate receptor antagonist) would reduce or block this response. Hypoxia was induced for 30 min in chronically catheterized fetal sheep (125 ± 3 days), with or without ketamine (3 mg kg(-1)) administered intravenously to the fetus 10 min prior to hypoxia.

Ketamine Attenuates the ACTH Response to Hypoxia in Late-Gestation Ovine Fetus.

Background: Ketamine, a noncompetitive N-Methyl-D-aspartate (NMDA) receptor antagonist, is a commonly used dissociative anesthetic in neonatology. We have proposed that ketamine reduces fetal stress responsiveness to stimuli that involve reduced oxygen supply to the fetal brain. Previously, we have shown that ketamine inhibits plasma ACTH levels in late-gestation fetal sheep subjected to brachiocephalic artery occlusion (BCO), an ischemic hypoxia model that might activate some of the same direct and reflex responses as hypoxia.

A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation.

Background: Heterozygous human mutations of NKX2-5 are highly penetrant and associated with varied congenital heart defects. The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy between human and mouse genetics.

Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment.

Estradiol (E2) is a well-known modulator of fetal neuroendocrine activity and has been proposed as a critical endocrine signal readying the fetus for birth and postnatal life. To investigate the modulatory role of E2 on fetal stress responsiveness and the response of the fetal brain to asphyxic stress, we subjected chronically catheterized fetal sheep to a transient (10 min) brachiocephalic artery occlusion (BCO) or sham occlusion. Half of the fetuses received subcutaneous pellets that increased plasma E2 concentrations within the physiological range.

Genomics of the fetal hypothalamic cellular response to transient hypoxia: endocrine, immune, and metabolic responses.

Fetuses respond to transient hypoxia (a common stressor in utero) with cellular responses that are appropriate for promoting survival of the fetus. The present experiment was performed to identify the acute genomic responses of the fetal hypothalamus to transient hypoxia. Three fetal sheep were exposed to 30 min of hypoxia and hypothalamic mRNA extracted from samples collected 30 min after return to normoxia.

Myosin light chain phosphorylation is critical for adaptation to cardiac stress.

Background: Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress.