Maternal Therapy with Ad.VEGF-A165 Increases Fetal Weight at Term in a Guinea-Pig Model of Fetal Growth Restriction

Abstract

In a model of growth-restricted sheep pregnancy, it was previously demonstrated that transient uterine artery VEGF overexpression can improve fetal growth. This approach was tested in guinea-pig pregnancies, where placental physiology is more similar to humans. Fetal growth restriction (FGR) was attained through peri-conceptual nutrient restriction in virgin guinea pigs. Ad.VEGF-A₁₆₅ or Ad.LacZ (1 × 10¹⁰vp) was applied at mid-gestation via laparotomy, delivered externally to the uterine circulation with thermosensitive gel. At short-term (3-8 days post surgery) or at term gestation, pups were weighed, and tissues were sampled for vector spread analysis, VEGF expression, and its downstream effects. Fetal weight at term was increased (88.01 ± 13.36 g; n = 26) in Ad.VEGF-A₁₆₅-treated animals compared with Ad.LacZ-treated animals (85.52 ± 13.00 g; n = 19; p = 0.028). The brain, liver, and lung weight and crown rump length were significantly larger in short-term analyses, as well as VEGF expression in transduced tissues. At term, molecular analyses confirmed the presence of VEGF transgene in target tissues but not in fetal samples. Tissue histology analysis and blood biochemistry/hematological examination were comparable with controls. Uterine artery relaxation in Ad.VEGF-A₁₆₅-treated dams was higher compared with Ad.LacZ-treated dams. Maternal uterine artery Ad.VEGF-A₁₆₅ increases fetal growth velocity and term fetal weight in growth-restricted guinea-pig pregnancy.

Keywords: adenovirus VEGF; fetal growth restriction; guinea pig; maternal gene therapy; placental insufficiency.