Maternal Uterine Artery Adenoviral Vascular Endothelial Growth Factor (Ad.VEGF-A 165) Gene Therapy Normalises Fetal Brain Growth and Microglial Activation in Nutrient Restricted Pregnant Guinea Pigs

Hristova, MD; Krishnan, T; Rossi, CA; Nouza, J; White, A; Peebles, DM; Sebire, NJ; Zachary, IC; David, AL; Vaughan, OR

Abstract

Fetal growth restriction (FGR) is associated with uteroplacental insufficiency, and neurodevelopmental and structural brain deficits in the infant. It is currently untreatable. We hypothesised that treating the maternal uterine artery with vascular endothelial growth factor adenoviral gene therapy (Ad.VEGF-A(165)) normalises offspring brain weight and prevents brain injury in a guinea pig model of FGR. Pregnant guinea pigs were fed a restricted diet before and after conception and received Ad.VEGF-A(165) (1 x 10(10) viral particles, n = 18) or vehicle (n = 18), delivered to the external surface of the uterine arteries, in mid-pregnancy. Pregnant, ad libitum-fed controls received vehicle only (n = 10). Offspring brain weight and histological indices of brain injury were assessed at term and 5-months postnatally. At term, maternal nutrient restriction reduced fetal brain weight and increased microglial ramification in all brain regions but did not alter indices of cell death, astrogliosis or myelination. Ad.VEGF-A(165 )increased brain weight and reduced microglial ramification in fetuses of nutrient restricted dams. In adult offspring, maternal nutrient restriction did not alter brain weight or markers of brain injury, whilst Ad.VEGF-A(165) increased microglial ramification and astrogliosis in the hippocampus and thalamus, respectively. Ad.VEGF-A(165) did not affect cell death or myelination in the fetal or offspring brain. Ad.VEGF-A(165) normalises brain growth and markers of brain injury in guinea pig fetuses exposed to maternal nutrient restriction and may be a potential intervention to improve childhood neurodevelopmental outcomes in pregnancies complicated by FGR.

Citation

Hristova, M., Krishnan, T., Rossi, C., Nouza, J., White, A., Peebles, D., …Vaughan, O. (2024). Maternal Uterine Artery Adenoviral Vascular Endothelial Growth Factor (Ad.VEGF-A 165) Gene Therapy Normalises Fetal Brain Growth and Microglial Activation in Nutrient Restricted Pregnant Guinea Pigs. Reproductive Sciences, https://doi.org/10.1007/s43032-024-01604-w

• Journal Article Type: Article
• Acceptance Date: May 22, 2024
• Online Publication Date: Jun 21, 2024
• Publication Date: 2024
• Deposit Date: Jul 19, 2024
• Publicly Available Date: Jul 19, 2024
• Print ISSN: 1933-7191
• Publisher: Springer
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1007/s43032-024-01604-w
• Keywords: Placenta; Cerebral palsy; Pre-eclampsia; Ionized calcium binding adapter molecule 1 protein; Glial fibrillary astrocytic protein; FEED RESTRICTION; BLOOD-FLOW; CHILDHOOD NEURODEVELOPMENT; INCREASES; TERM; MODEL; PLACENTA