Recapitulation of Human Placental Insufficiency in a Novel Mouse Model :New Paradigm in Translational Research

Objective: To develop a mouse model of placental insufficiency (PI) that recapitulates important characteristics of the human PI. We tested the effects of selective reduction of placental blood flow by mesenteric uterine artery branch ligation (MUAL) reliably resulting in fetal growth restriction (FGR).Methods: At 18 days, timed mated C57BL/6J dams were divided into two groups: MUAL(n=18) ; and control-sham operated (n=18) with uterine horn fetal positions matched to each MUAL fetus. Pups were delivered on day 20, cross-fostered to surrogate CD-1 mothers for 4 weeks, and followed for 8 weeks. Outcome data included birth and placental weight, postnatal growth, placental volume determined by stereology, quantification of placental insulin-like growth factors-1(IGF-1) and IGF-2 and IGF binding proteins(IGFBP 2 and 6) by ELISA and gene expression by qPCR and GeneChip microarray analysis. RESULTS: Compared with control, MUAL caused significant decrease (11%) in mean birth weight (1.06 ± 0.13 g vs. 0.94 ± 0.13 g, p<0.001) but no difference in placental weight (0.08 ± 0.03 g vs. 0.07 ±0.03 g,p=0.6). At 4 weeks of age, mean body weights of MUAL pups were also significantly lower than sham. By 8 weeks, males but not females MUAL mice achieved equivalent mean body weight to control. Placental labyrinth depth, volume, and placental gene expression of IGF-1 and 2 were significantly reduced by MUAL. In contrast, placental protein level of IGFBP-2 and 6 were significantly elevated in the MUAL. Genomic expression analysis profiling demonstrates that MUAL pups significantly up-regulated the expression of 344 genes, many of which were associated with apoptosis and growth-regulation related pathways. CONCLUSION: This novel mouse animal model of FGR using selective mesenteric uterine artery ligation effectively recapitulates important characteristics of PI in humans. This is the first non-genetic mouse model of PI which offers its application in transgenic mice to better study the underlying mechanisms in PI.

Name thesis:degree_name

MS

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Medicine: Biostatistics (Environmental Health)

Grantor dc:publisher

University of Cincinnati

Year dc:date

2012

Author dc:creator

• Habli, Mounira A., M.D.

Contributors dc:contributor

• Pinney, Susan

• Surgery
• placental insufficiency
• Fetal growth restriction
• Insulin growth factor

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=ucin1338582019

OAI identifier oai:identifier

oai:etd.ohiolink.edu:ucin1338582019