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Prenatal AD.VEGF gene therapy increases fetal growth velocity and alters uterine artery vascular reactivity in the absence of a measurable effect on uterine blood flow in a sheep model of fetal growth restriction
  1. DJ Carr1,2,
  2. RP Aitken2,
  3. JS Milne2,
  4. V Mehta1,3,
  5. DM Peebles1,
  6. JF Martin3,4,
  7. IC Zachary3,
  8. JM Wallace2,
  9. AL David1
  1. 1UCL Institute for Women's Health, University College London, London, United Kingdom
  2. 2Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
  3. 3Centre for Cardiovascular Medicine and Biology, University College London, London, United Kingdom
  4. 4Ark Therapeutics Ltd, London, United Kingdom

Abstract

Introduction Adenovirus (Ad) mediated over-expression of vascular endothelial growth factor (VEGF) in the uterine artery (UtA) enhances pre- and postnatal growth in growth-restricted sheep fetuses (Carr 2011a/2011b). Herein effects on uterine blood flow (UBF), vascular reactivity and UtA remodelling were investigated.

Methods Singleton pregnancies were established by embryo transfer in 57 adolescent ewes subsequently overnourished to restrict placental/fetal growth or fed a control diet. At 89±1.5d gestation, overnourished ewes were randomised to receive Ad.VEGF-A165 (n=18), Ad.LacZ (n=14) or saline (n=13) injected into each UtA. Controls received saline (n=12). Flowprobes were fitted around the UtA supplying the gravid horn. Fetal biometry/wellbeing was assessed blind by weekly ultrasound. UBF was monitored until necropsy at 131±1.6d. In 24 animals, three branches of UtA from both the gravid and non-gravid horns were challenged in an organ bath with phenylephrine and bradykinin to assess vessel contractility and relaxation, respectively. Adventitial vessels were immunostained with anti-vWF and counted. Intima:media ratios (IMR) were also calculated.

Results Fetal abdominal circumference measurements were greater in Ad.VEGF-A165 versus Ad.LacZ/saline groups at 112±0.1d and 119±0.1d gestation (p=<0.001–0.047) but Ad.VEGF-A165 had no measurable effect on UBF or UtA adventitial vessel number. IMR was greater in Ad.VEGF-A165 versus Ad.LacZ+saline groups in the main gravid UtA branch (p=0.016). Bradykinin-induced relaxation was increased in Ad.VEGF-A165 versus Ad.LacZ/saline/control groups in the second gravid UtA branch (p=0.001–0.032).

Conclusion Ad.VEGF-A165 increased fetal growth velocity without apparent changes in UBF. There was evidence of enhanced vasodilatation and increased IMR but no neovascularisation in UtAs treated with Ad.VEGF-A165.

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