P197Local anti-angiogenic gene therapy reduces in-stent restenosis in a preclinical atherosclerotic triple-injury model

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Abstract

Background

In-stent restenosis (ISR) remains a key limitation to endovascular revascularization therapies. Strong cytotoxic drugs used in common drug eluting stents (DES) reduce ISR but hamper the healing of the vessel through re-endothelialization. The growth of vasa vasorum into the restenotic lesion from the adventitia has also been suggested as an accelerator for the process of ISR and Vascular Endothelial Growth Factor (VEGF) is the key mediator of angiogenesis. Our aim was to study the feasibility and therapeutic potential of local anti-angiogenic therapy in ISR utilizing soluble VEGF receptors that act as decoys and reduce the amount of free VEGF in the tissue

Methods

67 hyperlipidemic WHHL rabbit aortas were denuded with an embolectomy catheter. Six weeks later side branch free sections of the abdominal aorta were injected with 1.5x10e10 pfu adenovirus encoding soluble VEGF Receptor 1 (sVEGFR1), sVEGFR2, sVEGFR3 or control LacZ using Infiltrator drug delivery catheter. After gene transfer a bare metal stent (BMS) was implanted on same section at 1.1:1 ratio. Control angiographies and euthanasia were performed on d6, d14, d42 and d90 followed by tissue harvest. Histological analyses were performed with immunohistological techniques.

Results

Gene transfer efficacy was assessed at d6 with LacZ controls and found to be sufficient and localized mainly in the adventitial cells and abluminal parts of the media. There were no significant differences between the groups in the degree of restenosis at d14. At d42 sVEGFR1 group showed a 21.4% reduction and sVEGFR2 group a 36.3% reduction in restenosis compared to control. At d90 the reduction in the rate of restenosis persisted but was attenuated (10.9% and 25.7% reduction, sVEGFR1 and sVEGFR2 respectively). Treatment with sVEGFR1 and sVEGFR2 reduced proliferation in the neointima compared to LacZ control evaluated as proliferating, Ki-67 positive cell nuclei in mm2 of neointima. The proliferation was reduced at d14 by 55.2% and 63.6% and by 25.0% and 73.5% at d90 (sVEGFR1 and sVEGFR2, respectively) . The anti-angiogenic therapy did not hamper luminal re-endothelialization and there were no differences between the groups.

Conclusions

This study suggests that local anti-angiogenic gene delivery might be a useful therapy when battling ISR without depending on strong cytotoxic stent coatings. Although the peak expression after adenoviral gene therapy occurs at d6 and is faded by d14, we show positive results persisting three months after treatment.

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