Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep

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Abstract
Impaired materno-placental perfusion causes two important obstetric complications, fetal growth restriction and preeclampsia. This study investigated whether adenoviral vector-mediated overexpression of vascular endothelial growth factor (VEGF) in the uterine arteries (UtAs) increases uterine artery blood flow (UBF). First-generation adenovirus vectors (5 × 1011 particles) containing the VEGF gene (Ad.VEGF-A or -D) or the β-galactosidase reporter gene (Ad.lacZ) were injected into the UtAs of pregnant sheep (n=6) at 88–102 days of gestation (term=145 days). UBF was measured using Doppler sonography before, and 4–7 days after injection. Mean UBF increased significantly from 233±156 (s.d.) ml min−1 to 753±415 ml min−1 following Ad.VEGF-A injection (P=0.005, n=5); Ad.lacZ infection had no significant effect. Organ bath experiments on uterine arterial sections 4–7 days after injection showed that, compared with Ad.lacZ vessels, Ad.VEGF-A-transduced vessels had a reduced contractile response to phenylephrine (Emax 148±10.9 vs Emax 228.2±27.5, P50) values 9.11±0.01 vs 8.65±0.11, P<0.05). Injection of Ad.VEGF-A into the UtAs increases UBF by enhancing vasodilatation. This may provide the basis for therapy in pregnancies complicated by uteroplacental insufficiency.

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