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

David, A L and Torondel, B and Zachary, I and Wigley, V and Nader, K A and Mehta, V and Buckley, S M K and Cook, T and Boyd, M and Rodeck, C H and Martin, J and Peebles, D M (2008) Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep. Gene Therapy, 15 (19). pp. 1344-1350.

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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 X 10(11) particles) containing the VEGF gene (Ad. VEGF-A or-D) or the beta-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 (E-max 148 +/- 10.9 vs E-max 228.2 +/- 27.5, P<0.05) but increased relaxation with bradykinin (pD2 (-log EC50) 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.