Sex Differences in Cerebrum miRNAs, Mitochondrial Translation Elongation Factor, Electron Transport Chain Proteins, and Blood Pressure in Adult IUGR Rats

Introduction: Fetuses that do not grow to normal weight in utero, also known as intrauterine growth restriction (IUGR), have an increased risk of developing hypertension (HTN) in adulthood, especially males. The sex difference in blood pressure may be due to cerebral mitochondrial dysfunction and oxidative stress. Epigenetic changes, such as miRNA, can alter mitochondrial development, structure, and function to increase oxidative stress. The purpose of this study is to observe the changes in differentially expressed miRNAs and blood pressure of male (M) and female (F) IUGR rats. We hypothesize that adult IUGR rats, particularly males, will display high blood pressure (HBP) and increased expression of miRNAs that influence cerebrum mitochondrial function, electron transport chain (ETC) proteins, and oxidative stress. Methods: To perform these experiments, IUGR and control (CON) M and F Sprague Dawley rats were evaluated at 16-18 weeks (adulthood). CON pups were produced from normal pregnant dams, and IUGR pups were generated from placental ischemic dams. Results: Results show that IUGR M have HBP (136±2 vs 120±7 mmHg, p=0.0488) compared to CON M, while IUGR F exhibit no difference in blood pressure vs CON F. Using Ingenuity Pathway Analysis (IPA), we identified 11 differentially expressed miRNAs in IUGR vs CON rats. Nine miRNAs that were differentially expressed in IUGR M vs CON M, six miRNAs in IUGR F vs CON F, and four shared downregulated miRNAs in IUGR rats from both sexes. miRNA let-7d-3p was uniquely upregulated in IUGR M vs CON M and had a 1.2-fold increase in expression between IUGR M vs CON M (1.2±0.2 vs 1.0±0.1-fold-change, ns ) with qPCR. GFM-1, the gene for mitochondrial elongation factor G1 that is predicted to be regulated by let-7d-3p, increased in IUGR F vs CON F (114±2 vs 100±4 IU/Protein/CON%, p=0.013) and did not change in M. ETC proteins were unchanged in M, but complexes 3 (110±4 vs 100±2 IU/Protein/CON%, p=0.068) and 4 (121.1±4.3 vs 100±5.5 IU/Protein/CON%, p=0.013) were elevated in IUGR F vs CON F. There were no alterations in oxidative stress for F, but a ~50% increase in H 2 O 2 concentration in IUGR M vs CON M (3.3±0.9 vs 1.8±0.4 nmol H 2 O 2 /mg Protein, p=0.1254). Conclusion: In summary, IUGR M have HBP and an increase in let-7d-3p expression in the cerebrum. We predict that the increase in let-7d-3p inhibited the compensatory increase in GFM-1 and ETC proteins that are needed to prevent cerebrum oxidative stress and HBP in IUGR M. However, unchanged let-7d-3p in IUGR F vs CON F, allowed for the increase in GFM-1 and ETC proteins to inhibit cerebrum mitochondrial dysfunction, oxidative stress, and HBP. Findings from this study will provide insights into the pathway linking epigenetic changes to mitochondrial dysfunction, oxidative stress, and HTN in adults born IUGR. Neurobiology of Aging and Alzheimer’s Disease Training Program (NIH T32AG020494), start-up (Cunningham), and AHA Career Development (AHA 18CDA34110264, Cunningham) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.