Long-term increase in uterine blood flow is achieved by local overexpression of VEGF-A 165 in the uterine arteries of pregnant sheep

摘要

Increasing uterine artery blood flow (UABF) may benefit fetal growth restriction where impaired uteroplacental perfusion prevails. Based on previous short-term results, we examined the long-term effects of adenovirus vector-mediated overexpression of vascular endothelial growth factor-A 165 (VEGF-A 165) in the uterine artery (UtA). Transit-time flow probes were implanted around both UtAs of mid-gestation pregnant sheep (n=11) to measure UABF. A carotid artery catheter was inserted to measure maternal or fetal hemodynamics. Baseline UABF was measured over 3 days, before injection of adenovirus vector (5 × 10 11 particles) encoding the VEGF-A 165 gene (Ad.VEGF-A 165) into one UtA and a reporter Β-galactosidase gene (Ad.LacZ) contralaterally. UABF was then measured daily until term. At 4 weeks post injection, the increase in UABF was significantly higher in Ad.VEGF-A 165 compared with Ad.LacZ-transduced UtAs (36.53% vs 20.08%, P=0.02). There was no significant effect on maternal and fetal blood pressure. Organ bath studies showed significantly lesser vasoconstriction (E max 154.1 vs 184.7, P0.001), whereas immunohistochemistry demonstrated a significantly increased number of adventitial blood vessels (140 vs 91, n=26, P0.05) following Ad.VEGF-A 165 transduction. Local overexpression of VEGF-A 165 in the UtAs of pregnant mid-gestation sheep leads to a sustained long-term increase in UABF, which may be explained by neovascularization and altered vascular reactivity.