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Long-term increase in uterine blood flow is achieved by local overexpression of VEGF-A165 in the uterine arteries of pregnant sheep

Gene Therapy volume 19, pages 925–935 (2012)Cite this article

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Abstract

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-A165 (VEGF-A165) 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 × 1011 particles) encoding the VEGF-A165 gene (Ad.VEGF-A165) 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-A165 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 (Emax 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-A165 transduction. Local overexpression of VEGF-A165 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.

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Acknowledgements

This study was partly funded by University College London Hospital (UCLH) Charities. VM is supported by a Dorothy Hodgkin Postgraduate Award from the UK Medical Research Council and UCLH Charities. We thank Tom Bellamy, Marie Buitendyk, Beth Laverick, Laura Milross, Gemma Petts, Neil Smith, Berrin Tezcan, Panicos Shangaris and Simon Waddington for their assistance. JM is British Heart Foundation Professor of Cardiovascular Science. Work in IZ's group is funded by the 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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  1. V Mehta and K N Abi-Nader: These two authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Women's Health, University College London, London, UK

    V Mehta, K N Abi-Nader, D M Peebles, E Benjamin, V Wigley, E Filippi, S W Shaw & A L David

  2. Division of Medicine, Centre for Cardiovascular Biology and Medicine, University College London, London, UK

    B Torondel, J Martin & I Zachary

  3. BSU, Royal Veterinary College, London, UK

    M Boyd

  4. Ark Therapeutics Ltd, London, UK

    J Martin

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Correspondence to V Mehta or K N Abi-Nader.

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This work was funded in part by Ark Therapeutics Ltd, London. The adenovirus vectors were supplied free of charge by Ark Therapeutics Oy, Kuopio, Finland. JM is Chief Scientific Officer, Ark Therapeutics Ltd. IZ is a consultant for Ark Therapeutics Ltd.

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Mehta, V., Abi-Nader, K., Peebles, D. et al. Long-term increase in uterine blood flow is achieved by local overexpression of VEGF-A165 in the uterine arteries of pregnant sheep. Gene Ther 19, 925–935 (2012). https://doi.org/10.1038/gt.2011.158

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