Chronic intrauterine hypoxia interferes with aortic development in the late gestation ovine fetus

This study explored arterial remodelling in fetuses growth restricted by hypoxia. Chronically catheterized fetal sheep were made moderately or severely hypoxic by placental embolization for 15 days starting at gestational age 116-118 (term ∼147 days). Cross-sections of the aorta were analysed for collagen and elastin content using histological procedures, while immunofluorescence was applied to measure markers of vascular smooth muscle cell (VSMC) type. In frozen aortae quantitative PCR was used to measure mRNA levels of extracellular matrix (ECM) precursor proteins as well as molecular regulators of developmental and pathological remodelling. Relative to Control (n= 6), aortic wall thickness was increased by 23% in the Moderate group (n= 5) and 33% (P \u3c 0.01) in the Severe group (n= 5). Relative to Control, the Severe group exhibited a 5-fold increase in total collagen content (P \u3c 0.01) that paralleled increases in mRNA levels of procollagen I (P \u3c 0.05) and III and transforming growth factor β (TGF-β 1) (P \u3c 0.05). The percentage area stained for α-actin was inversely related to fetal arterial oxygen saturation (P \u3c 0.05) and total α-actin content was 45% higher in the Moderate group and 65% (P \u3c 0.05) higher in the Severe group, compared to Control. A 12% and 39% (P \u3c 0.05) reduction in relative elastic fibre content was observed in Moderate and Severe fetuses, respectively. mRNA levels of the elastolytic enzyme, matrix metalloproteinase-2 (MMP-2) were inversely correlated with fetal arterial oxygen saturation (P \u3c 0.05) (Fig. 7) and mRNA levels of its activator, membrane-type MMP (MTI-MMP), were elevated in the Severe group (P \u3c 0.05). Marked neointima formation was apparent in Severe fetuses (P \u3c 0.05) concomitant with an increase in E-selectin mRNA expression (P \u3c 0.05). Thus, aberrant aortic formation in utero mediated by molecular regulators of arterial growth occurs in response to chronic hypoxaemia. © 2011 The Authors. Journal compilation © 2011 The Physiological Society

Fetal sex impacts birth to placental weight ratio and umbilical cord oxygen values with implications for regulatory mechanisms

Background: We determined the effect of fetal sex on birth/placental weight and umbilical vein and artery oxygen values with implications for placental efficiency and regulatory mechanisms underlying fetal–placental growth differences. Methods: A hospital database was used to obtain birth/placental weight, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA \u3e 34 weeks (N = 69,836). Oxygen saturation was calculated from the cord PO2 and pH data, while fractional O2 extraction was calculated from the oxygen saturation data. The effect of fetal sex on birth/placental weight, cord PO2, O2 saturation, and fractional O2 extraction was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. Results: Birth/placental weights were lower in females indicating decreased placental efficiency. Umbilical vein oxygen values were higher in females attributed to increased uterine blood flow, while artery oxygen values were lower in females attributed to decreased hemoglobin and umbilical blood flow, and increased oxygen consumption. Fetal O2 extraction was increased in females confirming increased O2 consumption relative to delivery. Conclusions: Sex-related differences in uterine/umbilical blood flows, placental development, and fetal O2 consumption can be linked to the differences observed in cord oxygen. The lower umbilical artery oxygen in females as a measure of systemic oxygenation signaling growth could account for their decreased birth weights, while slower development in female placentae could account for their lower placental weights, which could be differentially effected contributing to their lower birth/placental weights

Maternal nutrient restriction in guinea pigs as an animal model for studying growth-restricted offspring with postnatal catch-up growth

We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs with fetal growth restriction (FGR) on offspring body and organ weights, hypothesizing that FGR-MNR animals will show catch-up growth but with organ-specific differences. Guinea pig sows were fed ad libitum (Control) or 70% of the control diet from 4 weeks preconception, switching to 90% at midpregnancy (MNR). Control newborns \u3e95 g [appropriate for gestational age (AGA); n = 37] and MNR newborns \u3c85 g (FGR; n = 37) were monitored until neonatal (~25 days) or adult (~110 days) necropsy. Birth weights and body/organ weights at necropsy were used to calculate absolute and fractional growth rates (FRs). FGR-MNR birth weights were decreased ~32% compared with the AGA-Controls. FGR-MNR neonatal whole body FRs were increased ~36% compared with Controls indicating catch-up growth, with values negatively correlated to birth weights indicating the degree of FGR leads to greater catch-up growth. However, the increase in organ FRs in the FGR-MNR neonates compared with Controls was variable, being similar for the brain and kidneys indicating comparable catch-up growth to that of the whole body and twofold increased for the liver but negligible for the heart indicating markedly increased and absent catch-up growth, respectively. While FGR-MNR body and organ weights were unchanged from the AGA-Controls by adulthood, whole body growth rates were increased. These findings confirm early catch-up growth in FGR-MNR guinea pigs but with organ-specific differences and enhanced growth rates by adulthood, which are likely to have implications for structural alterations and disease risk in later life

Maternal nutrient restriction in Guinea pigs leads to fetal growth restriction with evidence for chronic hypoxia

BackgroundWe determined whether maternal nutrient restriction (MNR) in Guinea pigs leading to fetal growth restriction (FGR) impacts markers for tissue hypoxia, implicating a mechanistic role for chronic hypoxia.MethodsGuinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1), a marker of tissue hypoxia, was injected into pregnant sows. Fetuses were then necropsied and liver, kidney, and placental tissues were processed for erythropoietin (EPO), EPO-receptor (EPOR), and vascular endothelial growth factor (VEGF) protein levels, and for HP-1 immunoreactivity (IR).ResultsFGR-MNR fetuses were 36% smaller with asymmetrical growth restriction compared to controls. EPO and VEGF protein levels were increased in the female FGR-MNR fetuses, providing support for hypoxic stimulus and linkage to increased erythropoiesis, but not in the male FGR-MNR fetuses, possibly reflecting a weaker link between oxygenation and erythropoiesis. HP-1 IR was increased in the liver and kidneys of both male and female FGR-MNR fetuses as an index of local tissue hypoxia, but with no changes in the placenta.ConclusionChronic hypoxia is likely to be an important signaling mechanism for the decreased fetal growth seen with maternal undernutrition and appears to be post-placental in nature

Neutrinos in Non-linear Structure Formation - The Effect on Halo Properties

We use N-body simulations to find the effect of neutrino masses on halo properties, and investigate how the density profiles of both the neutrino and the dark matter components change as a function of the neutrino mass. We compare our neutrino density profiles with results from the N-one-body method and find good agreement. We also show and explain why the Tremaine-Gunn bound for the neutrinos is not saturated. Finally we study how the halo mass function changes as a function of the neutrino mass and compare our results with the Sheth-Tormen semi-analytic formulae. Our results are important for surveys which aim at probing cosmological parameters using clusters, as well as future experiments aiming at measuring the cosmic neutrino background directly.Comment: 20 pages, 8 figure

Differential and synergistic effects of low birth weight and western diet on skeletal muscle vasculature, mitochondrial lipid metabolism and insulin signaling in male guinea pigs

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar “Western” diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose-tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male “lean” offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism, as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high-fat/high-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism, promoting mitochondrial overload

The lifelong impact of fetal growth restriction on cardiac development

Background: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. Methods: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. Results: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR–FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR–FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR–FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. Conclusions: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual\u27s risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig\u27s potential to enhance clinical therapeutic innovation to improve human health. (Figure presented.)

Inflation, cold dark matter, and the central density problem

A problem with high central densities in dark halos has arisen in the context of LCDM cosmologies with scale-invariant initial power spectra. Although n=1 is often justified by appealing to the inflation scenario, inflationary models with mild deviations from scale-invariance are not uncommon and models with significant running of the spectral index are plausible. Even mild deviations from scale-invariance can be important because halo collapse times and densities depend on the relative amount of small-scale power. We choose several popular models of inflation and work out the ramifications for galaxy central densities. For each model, we calculate its COBE-normalized power spectrum and deduce the implied halo densities using a semi-analytic method calibrated against N-body simulations. We compare our predictions to a sample of dark matter-dominated galaxies using a non-parametric measure of the density. While standard n=1, LCDM halos are overdense by a factor of 6, several of our example inflation+CDM models predict halo densities well within the range preferred by observations. We also show how the presence of massive (0.5 eV) neutrinos may help to alleviate the central density problem even with n=1. We conclude that galaxy central densities may not be as problematic for the CDM paradigm as is sometimes assumed: rather than telling us something about the nature of the dark matter, galaxy rotation curves may be telling us something about inflation and/or neutrinos. An important test of this idea will be an eventual consensus on the value of sigma_8, the rms overdensity on the scale 8 h^-1 Mpc. Our successful models have values of sigma_8 approximately 0.75, which is within the range of recent determinations. Finally, models with n>1 (or sigma_8 > 1) are highly disfavored.Comment: 13 pages, 6 figures. Minor changes made to reflect referee's Comments, error in Eq. (18) corrected, references updated and corrected, conclusions unchanged. Version accepted for publication in Phys. Rev. D, scheduled for 15 August 200

Observing the First Stars and Black Holes

The high sensitivity of JWST will open a new window on the end of the cosmological dark ages. Small stellar clusters, with a stellar mass of several 10^6 M_sun, and low-mass black holes (BHs), with a mass of several 10^5 M_sun should be directly detectable out to redshift z=10, and individual supernovae (SNe) and gamma ray burst (GRB) afterglows are bright enough to be visible beyond this redshift. Dense primordial gas, in the process of collapsing from large scales to form protogalaxies, may also be possible to image through diffuse recombination line emission, possibly even before stars or BHs are formed. In this article, I discuss the key physical processes that are expected to have determined the sizes of the first star-clusters and black holes, and the prospect of studying these objects by direct detections with JWST and with other instruments. The direct light emitted by the very first stellar clusters and intermediate-mass black holes at z>10 will likely fall below JWST's detection threshold. However, JWST could reveal a decline at the faint-end of the high-redshift luminosity function, and thereby shed light on radiative and other feedback effects that operate at these early epochs. JWST will also have the sensitivity to detect individual SNe from beyond z=10. In a dedicated survey lasting for several weeks, thousands of SNe could be detected at z>6, with a redshift distribution extending to the formation of the very first stars at z>15. Using these SNe as tracers may be the only method to map out the earliest stages of the cosmic star-formation history. Finally, we point out that studying the earliest objects at high redshift will also offer a new window on the primordial power spectrum, on 100 times smaller scales than probed by current large-scale structure data.Comment: Invited contribution to "Astrophysics in the Next Decade: JWST and Concurrent Facilities", Astrophysics & Space Science Library, Eds. H. Thronson, A. Tielens, M. Stiavelli, Springer: Dordrecht (2008