Abstract 15515: Sexual Dimorphism in Cardiac Response to Intrauterine Growth Restriction (IUGR)
Background: Poor fetal nutrient availability predisposes to adult cardiovascular disease (CVD). We have developed a fetal baboon model of maternal undernutrition resulting in Intrauterine Growth Restriction (IUGR) in both male and female fetuses (Li, et al, J Endocrinol, 2013). MicroRNAs are small non-coding RNAs that regulate gene expression through mRNA degradation and translational repression.
Hypothesis: We hypothesized that IUGR is accompanied by cardiac dysfunction and dysregulation of cardiac miRNAs.
Methods: Six control pregnant baboons ate ad libitum, and six nutrient restricted pregnant baboons ate a globally reduced diet (70% of control feed) from 0.16 gestation (G) through pregnancy resulting in fetal IUGR compared to controls (p<0.05). No differences in heart weight were observed. Fetuses (3 males and 3 females per group) were euthanized at C-section at 0.9G. Cardiac sections were studied for morphological changes and fibrosis using H&E and Masson’s trichrome staining respectively. Total left ventricular RNA was isolated and miRNA array was performed.
Results: While no differences in myofiber orientation were observed, IUGR male but not female fetuses showed a reverse correlation between birth weight and accumulation of fibrotic tissue in the heart (r=-0.831, p=0.01). We next investigated the expression of the extracellular matrix proteins thrombospondin-1 (TSP-1) and connective tissue growth factor (CTGF). A reverse correlation between birth weight and cardiac TSP-1 levels (r=-0.77, p=0.03) was found in male but not female fetuses. No changes in CTGF were observed.
Sexual dimorphism was observed in fetal cardiac miRNA expression within both IUGR and control groups. In male IUGR group, the increase in levels of TSP-1 was associated with more than 50% reduction in expression of its targeting miRNA-19a, reduction in which has been implicated in CVD. Other CVD-related and differentially expressed miRNAs in male IUGR included miRNA-23b, 27b, 99b, 143, 181a, and 378-3p.
Summary: IUGR resulting from decreased maternal nutrition is associated with sexual dimorphism in cardiac structure and miRNA expression. If the changes observed in male IUGR fetuses persists postnatally they may program offspring for higher CVD risk later in life.
Author Disclosures: A. Maloyan: None. S. Muralimanoharan: None. M. Nijland: None. P.W. Nathanielsz: None.
- © 2014 by American Heart Association, Inc.