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

Gene Therapy volume 15, pages 1344–1350 (2008)Cite this article

A Corrigendum to this article was published on 07 October 2008

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 × 1011 particles) containing the VEGF gene (Ad.VEGF-A or -D) or the β-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 (Emax 148±10.9 vs Emax 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.

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Acknowledgements

We are grateful to Ark Therapeutics for supply of reagents, Simon Waddington (Department of Haematology, Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School) for data analysis and statistical assistance, Helena Viita (Ark Therapeutics Oy, Kuopio, Finland) and Manfred Ramirez (Rayne Institute, University College London) for technical assistance; John Martin is Professor of Cardiovascular Science at British Heart Foundation. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.

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Author notes

  1. A L David and B Torondel: These authors contributed equally to this work.

Authors and Affiliations

  1. Prenatal Gene Therapy Group, Institute for Women's Health, Royal Free and University College London Medical School, London, UK

    A L David, V Wigley, K A Nader, V Mehta, C H Rodeck & D M Peebles

  2. Division of Medicine, Centre for Cardiovascular Biology and Medicine, BHF Laboratories, Royal Free and University College London Medical School, London, UK

    B Torondel, I Zachary & J Martin

  3. Department of Haematology, Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School, London, UK

    S M K Buckley

  4. Department of Pathology, Imperial College School of Medicine, London, UK

    T Cook

  5. Biological Services Unit, Royal Veterinary College, London, UK

    M Boyd

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Correspondence to A L David.

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David, A., Torondel, B., Zachary, I. et al. Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep. Gene Ther 15, 1344–1350 (2008). https://doi.org/10.1038/gt.2008.102

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