Abstract 755: Fas Ligand- and Nitric Oxide-Releasing Stent

Abstract

To restore blood flow in stenotic vessels such as coronary arteries, metallic vascular stents are often used. However, stent deployment under high pressure leads to vascular wall and smooth muscle (SMC) damage, with compensatory thrombosis, inflammation, and neointimal proliferation of SMCs. These events result in vessel re-occlusion and treatment failure. In an effort to prevent intimal hyperplasia and treatment failure, drug-eluting stents were developed roughly 15 years ago. These stents release global inhibitors of proliferation (eg. “mTOR inhibitors”) which stop the growth of SMC as well as vascular endothelial cells (EC). Despite being widely used, drug-eluting stents mandate long-term treatment with potent anticoagulants. This is because mTOR inhibitors prevent re-endothelialization of the stent surface, leaving the clot-inducing metal exposed to the bloodstream. Yet, long-term dual antiplatelet therapy leads to increased risk of bleeding/stroke and myocardial infarction. Here, we leveraged the fact that nitric oxide (NO) increases Fas receptors on the SMC surface. Fas forms a death-inducing complex upon binding to Fas ligand (FasL), while ECs are relatively resistant to this pathway (Figure 1). Selected doses of FasL and NO donor synergistically increased SMC apoptosis and inhibited SMC growth more potently than did everolimus or sirolimus, while having no significant effect on EC viability and proliferation. We verified this differential effect in an ex vivo pig coronary artery model, where the intimal thickening was inhibited by the drug combination, but endothelial viability was retained. We also deployed FasL and NO donor-releasing ethylene-vinyl acetate copolymer (EVAc)-coated stents into pig coronary arteries, and cultured them in perfusion bioreactors for one week. FasL and NO donor, released from the stent coating, killed SMCs in the proximity of the stent struts, even in the presence of flow rates mimicking those of native arteries. Therefore, the FasL-NO donor-combination has the potential to prevent intimal hyperplasia and in-stent restenosis, without harming endothelial restoration, and hence may be a superior drug delivery strategy for drug-eluting stents.