Peri- and Postnatal Effects of Prenatal Adenoviral VEGF Gene Therapy in Growth-Restricted Sheep.
Uterine artery (UtA) adenovirus (Ad) vector-mediated overexpression of vascular endothelial growth factor (VEGF) enhances uterine blood flow in normal sheep pregnancy and increases fetal growth in the overnourished adolescent sheep model of fetal growth restriction (FGR). Herein, we examined its impact on gestation length, neonatal survival, early postnatal growth and metabolism. Singleton-bearing ewes were evenly allocated to receive Ad.VEGF-A165 (5 × 10(10) particles/ml, 10 ml, n = 17) or saline (10 ml, n = 16) injected into each UtA at laparotomy (0.6 gestation). Fetal growth was serially monitored (blind) by ultrasound until delivery. Lambs were weighed and blood was sampled weekly and a glucose tolerance test performed (68-day postnatal age). Hepatic DNA/RNA was extracted at necropsy (83-day postnatal age) to examine methylation status of eight somatotropic axis genes. IGF1 mRNA and protein expression were measured by RT-PCR and radioimmunoassay, respectively. All pregnancies remained viable following Ad.VEGF-A165 treatment. Fetal abdominal circumference and renal volume were greater in the Ad.VEGF-A165 group compared with the saline group at 21/28 days (P ≤ 0.04) postinjection. At delivery, gestation length (P = 0.07), lamb birthweight (P = 0.08), umbilical girth (P = 0.06), and plasma glucose (P = 0.09) tended to be greater in Ad.VEGF-A165-treated lambs. Levels of neonatal intervention required to ensure survival was equivalent between groups. Absolute postnatal growth rate (P = 0.02), insulin area under the curve (P = 0.04) and carcass weight at necropsy (P = 0.04) were increased by Ad.VEGF-A165 treatment. There was no impact on markers of insulin sensitivity or methylation/expression of key genes involved in somatic growth. Ad.VEGF-A165 gene therapy increased fetal growth in a sheep FGR model, and lambs continued to thrive during the neonatal and early postnatal period.
Prenatal Cell and Gene Therapy Group, University College London Institute for Women's Health, University College London, London, United Kingdom Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, United Kingdom davidcarr@doctors.org.uk.
David J
DJ
Carr
Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, United Kingdom.
Jacqueline M
JM
Wallace
Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, United Kingdom.
Raymond P
RP
Aitken
Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, United Kingdom.
John S
JS
Milne
Centre of Cardiovascular Biology and Medicine, University College London, London, United Kingdom.
John F
JF
Martin
Centre of Cardiovascular Biology and Medicine, University College London, London, United Kingdom.
Ian C
IC
Zachary
Prenatal Cell and Gene Therapy Group, University College London Institute for Women's Health, University College London, London, United Kingdom National Institute for Health Research University College London Hospitals Biomedical Research Centre, Maple House, London, United Kingdom.
Donald M
DM
Peebles
Prenatal Cell and Gene Therapy Group, University College London Institute for Women's Health, University College London, London, United Kingdom National Institute for Health Research University College London Hospitals Biomedical Research Centre, Maple House, London, United Kingdom.
Anna L
AL
David
D000256:Adenoviridae; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001823:Body Composition; D019175:DNA Methylation; D005260:Female; D047109:Fetal Development; D005317:Fetal Growth Retardation / Q000628:therapy*; D015316:Genetic Therapy; D005951:Glucose Tolerance Test; D011247:Pregnancy; D011256:Pregnancy Outcome; D012756:Sheep; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A
gene therapy; intrauterine growth restriction (IUGR); metabolism; sheep; vascular endothelial growth factor