Mouse Model Of Growth Restriction Research Articles

Male fetal sex affects uteroplacental angiogenesis in growth restriction mouse model†.

Abnormally increased angiotensin II activity related to maternal angiotensinogen (AGT) genetic variants, or aberrant receptor activation, is associated with small-for-gestational-age babies and abnormal uterine spiral artery remodeling in humans. Our group studies a murine AGT gene titration transgenic (TG; 3-copies of the AGT gene) model, which has a 20% increase in AGT expression mimicking a common human AGT genetic variant (A[-6]G) associated with intrauterine growth restriction (IUGR) and spiral artery pathology. We hypothesized that aberrant maternal AGT expression impacts pregnancy-induced uterine spiral artery angiogenesis in this mouse model leading to IUGR. We controlled for fetal sex and fetal genotype (e.g., only 2-copy wild-type [WT] progeny from WT and TG dams were included). Uteroplacental samples from WT and TG dams from early (days 6.5 and 8.5), mid (d12.5), and late (d16.5) gestation were studied to assess uterine natural killer (uNK) cell phenotypes, decidual metrial triangle angiogenic factors, placental growth and capillary density, placental transcriptomics, and placental nutrient transport. Spiral artery architecture was evaluated at day 16.5 by contrast-perfused three-dimensional microcomputed tomography (3D microCT). Our results suggest that uteroplacental angiogenesis is significantly reduced in TG dams at day 16.5. Males from TG dams are associated with significantly reduced uteroplacental angiogenesis from early to late gestation compared with their female littermates and WT controls. Angiogenesis was not different between fetal sexes from WT dams. We conclude that male fetal sex compounds the pathologic impact of maternal genotype in this mouse model of growth restriction.

Prenatal development of skull and brain in a mouse model of growth restriction

RESUMEN Los patrones de covariacion entre rasgos fenotipicos resultan de la accion de diversos procesos que se solapan durante el desarrollo. Los estudios experimentales constituyen la aproximacion mas adecuada para evaluar el efecto de procesos especificos en la generacion de tales patrones. El objetivo de este trabajo es analizar las interacciones entre rasgos morfologicos craneofaciales y cerebrales durante la vida prenatal tardia (18,5 dias posconcepcion) en ratones expuestos a desnutricion proteica materna. Se obtuvieron imagenes del craneo y cerebro a partir de microtomografia computada y se digitalizaron landmarks en 3D para cuantificar la forma y tamano con tecnicas de morfometria geometrica. Los resultados subrayan un efecto sistemico de la restriccion proteica en el tamano del craneo y el cerebro. La forma del craneo es parcialmente explicable por el tamano cerebral y los patrones de variacion en forma fueron solo en parte coincidentes con los reportados antes para otras edades, lo cual sugiere que las trayectorias alometricas a lo largo de la vida pre- y posnatal cambian su direccion. Los rasgos de forma del neurocraneo y el esqueleto facial covariaron fuertemente, aunque se encontro una asociacion debil entre la forma del craneo y del cerebro. Estos resultados concuerdan con estudios previos en ratones mutantes y revelan la relevancia de analizar la variacion fenotipica en distintas etapas. El presente estudio contribuye al conocimiento basico de las interacciones epigeneticas entre tejidos en crecimiento y tiene implicancias en el campo paleoantropologico en el que las inferencias acerca de la morfologia cerebral son usualmente derivadas del analisis del craneo. Palabras clave restriccion proteica materna; integracion fenotipica; modulos craneanos; micro-TC ABSTRACT Patterns of covariation result from the overlapping effect of several developmental processes. By perturbing certain specific developmental processes, experimental studies contribute to a better understanding of their particular effects on the generation of phenotype. The aim of this work was to analyze the interactions among morphological traits of the skull and the brain during late prenatal life (18.5 days postconception) in mice exposed to maternal protein undernutrition. Images from the skull and brain were obtained through micro-computed tomography and 3D landmark coordinates were digitized in order to quantify shape and size of both structures with geometric morphometric techniques. The results highlight a systemic effect of protein restriction on the size of the skull and the brain, which were both significantly reduced in the undernourished group compared to control group. Skull shape is partially explained by brain size, and patterns of shape variation were only partially coincident with previous reports for other ontogenetic stages, suggesting that allometric trajectories across pre- and postnatal ages change their directions. Within the skull, neurocranial and facial shape traits covaried strongly, while subtle covariation was found between the shape of the skull and the brain. These findings are in line with former studies in mutant mice and reveal the importance of carrying out analyses of phenotypic variation in a broad range of developmental stages. The present study contributes to the basic understanding of epigenetic relations among growing tissues and has direct implications for the field of paleoanthropology, where inferences about brain morphology are usually derived from skull remains. Key words maternal protein restriction; phenotypic integration; cranial modules; micro-CT

46: Insulin growth factor 1 gene therapy restores altered umbilical artery (UA) doppler indices in a mouse model of growth restriction (IUGR)

Previous work in our laboratory demonstrated that intra-placental gene therapy with adenoviral insulin growth factor 1(AdIGF1) corrects fetal weight in a surgical mouse model of intrauterine growth restriction. Doppler indices have not been evaluated. Aim of this study is to investigate the effect of intraplacental IGF-1 over-expression on fetal/placental hemodynamics by assessing pre & post treatment UA Doppler indices in a surgical mouse model of IUGR