Yiu, Patrick; (1999) Nitric oxide in vascular injury : A study using nitric oxide synthase knockout mice & adenoviral gene transfer in rabbit carotid vein grafts. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Following coronary artery bypass surgery, 26% of vein grafts stenose in 1 year and 50% by 10 years. Insufficient nitric oxide (NO) production in veins may predispose grafts to stenosis by neointimal formation. A mouse model of angioplasty was developed to study the neointimal response between nitric oxide synthase (NOS) knockout mice and their strain controls. Both endothelial (eNOS) and inducible (iNOS) isoform knockouts were compared. Subsequently, NOS plasmids tagged with the green fluorescent protein marker was constructed and ligated into a third generation adenoviral vector (Av3). Adenoviral mediated transfer of NOS was studied in cell cultures and in isolated rabbit veins. Transgene expression was evaluated by GFP chemiluminesence, immunohistochemistry, nitrite/nitrate assay and by NO dependant relaxation in vascular rings. Optimal conditions required for gene transfer were established in rabbit and human vein organ cultures using Av3 containing the β-galactosidase marker gene (LacZ). Finally, rabbit jugular veins were transfected in vivo with the Av3-LacZ or the Av3 containing NOS and then anastomosed into the carotid artery as a reversed interposition vein graft. Control arterial vein grafting was also performed without vector or with Av3-null (viral vector with no insert). Grafts were harvested for detection of transgene expression (3 days to 4 weeks) and for morphometry (4 weeks). In the light of the project's findings, the implications of nitric oxide on vascular injury and vein grafting are discussed; as well as the potential for vein grafts to be therapeutic targets for adenoviral gene transfer in the future.

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