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

• Published in: Gene therapy Vol. 19; no. 9; pp. 925 - 935
• Main Authors: Mehta, V, Abi-Nader, K N, Peebles, D M, Benjamin, E, Wigley, V, Torondel, B, Filippi, E, Shaw, S W, Boyd, M, Martin, J, Zachary, I, David, A L
• Format: Journal Article
• Language: English
• Published: 01.09.2012
• Subjects: Adenovirus; beta -Galactosidase; Blood pressure; Blood vessels; Carotid artery; Catheters; Expression vectors; Fetuses; Gene therapy; Hemodynamics; Immunohistochemistry; Long-term effects; Perfusion; Pregnancy; Probes; Uterus; vascularization; Vasoconstriction
• ISSN: 0969-7128
• DOI: 10.1038/gt.2011.158

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 sub(165) (VEGF-A sub(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 x 10 super(11) particles) encoding the VEGF-A sub(165) gene (Ad.VEGF-A sub(165)) into one UtA and a reporter beta -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 sub(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 sub(max) 154.1 vs 184.7, P<0.001), whereas immunohistochemistry demonstrated a significantly increased number of adventitial blood vessels (140 vs 91, n=26, P<0.05) following Ad.VEGF-A sub(165) transduction. Local overexpression of VEGF-A sub(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.