Maternal Therapy with Ad.VEGF-A₁₆₅Increases 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-A or Ad.LacZ (1 × 10vp) 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-A-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-A-treated dams was higher compared with Ad.LacZ-treated dams. Maternal uterine artery Ad.VEGF-A increases fetal growth velocity and term fetal weight in growth-restricted guinea-pig pregnancy.

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

“…Applying an adenoviral vascular endothelial growth factor vectors in combination with pluronic gel led to local transgenic vascular endothelial growth factor protein expression in transduced arteries, altered vascular reactivity and increased fetal growth in global maternal nutrient restriction FGR pregnancies (Swanson et al . ). In addition, atrial natriuretic peptide infusion selectively increased blood flow to placentas of FGR fetuses while placental blood flow of normal‐sized fetuses remained unchanged (Jansson, ).…”

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

“…The medical plausibility for maternal VEGF gene therapy is based on the observation that reduced uterine blood flow is a key pathology in placental insufficiency, and that manipulation of VEGF expression can improve uterine blood flow, increase uterine artery relaxation and endothelial nitric oxide synthase production, and increase local angiogenesis . In preclinical animal models we have previously shown that local maternal VEGF gene transfer to the utero–placental circulation using adenovirus vectors increases uterine blood flow, attenuates constriction of the uterine arteries and increases angiogenesis; these changes result in improved growth of severely growth restricted fetuses …”

“…56,57 In preclinical animal models we have previously shown that local maternal VEGF gene transfer to the utero-placental circulation using adenovirus vectors increases uterine blood flow, attenuates constriction of the uterine arteries and increases angiogenesis; 58 these changes result in improved growth of severely growth restricted fetuses. [59][60][61][62]…”

Treating the dysfunctional placenta

“…The use of pluronic gel was the most successful in every way: success rate of administration, maternal and fetal survival and transduction efficiency with no spread to maternal or fetal tissues. Using this method of administration, Swanson et al (2016) investigated whether Ad.VEGF would improve fetal growth in an undernutrition model of guinea pig FGR, comparing to similar animals treated with adenovirus encoding a reporter gene, beta-galactosidase (Ad.LacZ). They found a very small (3%) higher fetal weight in the Ad.VEGF-treated pups at term (60–64 days) with no effect on litter size.…”