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Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury

Gene Therapy volume 14, pages 396–404 (2007)Cite this article

Abstract

Endothelial cell loss is a critical event in the pathological repair of the injured blood vessel. Impaired endothelial function results in reduced production of key vascular mediators such as nitric oxide (NO) within the vessel wall leading to enhanced smooth muscle cell proliferation and migration and ultimately intimal hyperplasia. The aim of the present study was to directly compare the effects of adenoviral-mediated gene delivery of two nitric oxide synthase (NOS) isoforms, eNOS and iNOS on endothelial regeneration and intimal hyperplasia following endothelial injury in the rabbit carotid artery. The right carotid arteries of male New Zealand white rabbits were denuded by passing a 3French Fogarty balloon catheter along the artery three times. In all, 1 × 109 PFU of adenoviral(Ad)eNOS, AdiNOS or Adβ-galactosidase (Adβ-Gal) was then delivered intraluminally and allowed to dwell for 20 min. Transgene expression was sought after 3 days by immunohistochemistry and at 7 days by quantitative reverse transcriptase PCR. The effect on intimal hyperplasia was sought using histological staining after 14 days. Evans blue staining was used to determine the effect on endothelial regeneration. eNOS and iNOS expression was detected in transduced arteries. Neointima/media ratios were significantly reduced in eNOS (0.07±0.044) and iNOS (0.087±0.086) transduced arteries compared with Adβ-Gal (0.332±0.14) transduced arteries (n=7). In addition, AdeNOS treatment (4.21±3.12% de-endothelialized area) enhanced endothelial regeneration compared to Adβ-Gal treatment (10.05±4.98), while treatment with AdiNOS (25.17±11.92) inhibited endothelial regeneration in the injured rabbit carotid artery (n=7–8). These results highlight the potential of NOS gene therapy, in particular, eNOS gene therapy as a potential therapeutic strategy for the prevention of restenosis after vascular injury.

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Acknowledgements

This work was funded by the Health Research Board of Ireland. We thank Tina Harte and Aoife Duffy for technical assistance. TOB is supported by a Centre for Science Engineering and Technology award from Science Foundation Ireland.

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Authors and Affiliations

  1. Regenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Sciences (NCBES), National University of Ireland, Galway (NUIG), Ireland

    R Cooney, S O Hynes, F Sharif, L Howard & T O'Brien

  2. Department of Medicine, University College Hospital and NUI Galway, Ireland

    R Cooney, S O Hynes, F Sharif, L Howard & T O'Brien

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  1. R Cooney
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  2. S O Hynes
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Correspondence to T O'Brien.

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Cooney, R., Hynes, S., Sharif, F. et al. Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury. Gene Ther 14, 396–404 (2007). https://doi.org/10.1038/sj.gt.3302882

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