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• W1489566313 abstract "Impaired uterine blood flow (UBF) leads to fetal growth restriction (FGR),one of the most challenging obstetric complications. FGR is associated withstillbirth, long-term neurological impairment and adult onset cardiovasculardisease; there is no treatment currently available.Previously, it was shown that sustained local over-expression of VascularEndothelial Growth Factor (VEGF) in the uterine arteries (UAs) of pregnantsheep using an adenoviral vector results in increased UBF as measured byDoppler sonography, reduced vascular contractility and increased vascularrelaxation 4-7 days after administration. The aim of this thesis is to examine thelong-term effects on UBF, UA vascular reactivity, and the possible mechanism ofaction.Telemetric transit-time flow probes were implanted around the UAs ofmid-gestation pregnant sheep (n=10), and a telemetric blood-pressure sensitivecatheter was inserted in the maternal (n=5) or fetal (n=4) carotid arteries. Afterobtaining baseline values for 7 days, we injected adenovirus vectors (5x1011particles) encoding the VEGF-A165 gene (Ad.VEGF) into one UA, and a reporterβ-galactosidase gene (Ad.LacZ), contra-laterally. UBF and maternalhaemodynamics were measured daily until term, when the UAs were harvestedand their vascular reactivity studied. There was a significant increase in UBF inthe Ad.VEGF transduced side (36.53% v/s 20.08%, p=0.02), a reduction in UAcontractility but no difference in relaxation. A significantly greater number ofadventitial blood vessels were observed in the Ad.VEGF treated UA. There wereno significant changes in maternal or fetal blood pressure post-injection. Similareffects were observed with injection of an adenovirus encoding another memberof the VEGF gene family, VEGF-DΔNΔC (n=5). Endothelial cells (ECs) were isolated from the UAs of control midgestationpregnant sheep, cultured and infected with Ad.VEGF or Ad.LacZvector. Protein extracted from UAECs infected ex vivo was assayed for eNOS andphosphorylated eNOS (Ser1177) levels by Western blotting. eNOS and phosphoeNOSlevels increased with rising Ad.VEGF concentrations in UAECs; Ad.LacZvector transduction had no effect.Local over-expression of VEGF effects a long-term increase in UBF byupregulation of eNOS, with neovascularization of the adventitia and reduced UAcontractility. These changes may benefit pregnancies complicated by severe FGR.With clinical translation in mind, the last section of this thesis describes theoptimization of a technique of gene targeting to the utero-placental circulation ofgrowth-restricted guinea pigs, using a thermo-sensitive pluronic gel. Havingoptimized this technique, VEGF over-expression in the uteroplacental circulationis now being tested in this animal model of FGR." @default.
• W1489566313 created "2016-06-24" @default.
• W1489566313 creator A5015463830 @default.
• W1489566313 date "2011-12-28" @default.
• W1489566313 modified "2023-09-24" @default.
• W1489566313 title "The effects of VEGF overexpression on the utero-placentalcirculation" @default.
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