Abstract 378: Global MicroRNA Evaluation of The Brains and Aortas of a Prenatal Stress Murine Model With Vulnerable Plaque Show Sexual Dimorphism

Introduction and Hypothesis Stress is a major cardiovascular risk factor. Preliminary studies in our lab demonstrated that prenatal stress in a murine model is associated with accelerated atherosclerosis and a vulnerable plaque phenotype at 20 weeks of age. Here, we hypothesized that prenatal stress is associated with global microRNA (miRNA) changes, possibly gender specific, and we sought to determine them by seeking such changes in two different tissues (brain and aorta) in both sexes.

Methods Pregnant mixed background female mice were divided into stressed (chronic cold stress for the last 17 days of gestation) and non-stressed groups. Prenatally stressed and non-prenatally stressed offspring had urine corticosteroid levels measured at six weeks to see the effects of stress. At eight weeks the offspring were sacrificed and global miRNA levels were measured using the Affymetrix 2.0 miRNA chip on the brains and aorta.

Results Urine corticosteroid levels were decreased in both genders at six weeks (p≤0.01), which has been shown in previous severe stress murine models. These were more significant in males (p=0.006) than in females (p=0.01). In eight-week-old males, there were 84 miRNAs in the brain that were dysregulated between prenatally stressed and non-stressed (p<0.05). The top miRNAs in males by p-value were miR-26, miR-21, and miR-346. Females that were eight weeks old had 89 dysregulated miRNAs (p<0.005) in the brain with miR-154 and miR-331 as the top miRNAs by p-value. Analysis of the aortas revealed 74 and 92 dysregulated miRNAs (p<0.05) with miR-326 and miR-15 as the top hits in males and females by p-value, respectively. Of interest, these top miRNAs have, in prior published studies, been implicated in playing a role in ischemia, ischemic preconditioning, stress and endothelial degeneration.

Conclusions Prenatal stress leads to variety of miRNA changes that persist into at least the eighth postnatal week of life. These alterations in miRNA levels may contribute to the development of a vulnerable plaque phenotype that we have shown to be present at 20 weeks of age in a previous study. Prenatal stress also appears to exert gender specific effects, a finding that may provide insight into gender differences in cardiovascular outcomes.