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Biomaterials. 2019 Aug;212:28-38. doi: 10.1016/j.biomaterials.2019.05.011. Epub 2019 May 7.

Fas ligand and nitric oxide combination to control smooth muscle growth while sparing endothelium.

Author information

1
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Anesthesiology, Yale University, New Haven, CT 06519, USA. Electronic address: mehmet.kural@yale.edu.
2
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Anesthesiology, Yale University, New Haven, CT 06519, USA.
3
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Surgery, Yale University, New Haven, CT 06519, USA.
4
Department of Biomedical Engineering, Yale University, New Haven, CT 06519, USA.
5
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06519, USA.
6
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Anesthesiology, Yale University, New Haven, CT 06519, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06519, USA; Yale Stem Cell Center, New Haven, CT 06520, USA.

Abstract

Metallic stents cause vascular wall damage with subsequent smooth muscle cell (SMC) proliferation, neointimal hyperplasia, and treatment failure. To combat in-stent restenosis, drug-eluting stents (DES) delivering mTOR inhibitors such as sirolimus or everolimus have become standard for coronary stenting. However, the relatively non-specific action of mTOR inhibitors prevents efficient endothelium recovery and mandates dual antiplatelet therapy to prevent thrombosis. Unfortunately, long-term dual antiplatelet therapy leads to increased risk of bleeding/stroke and, paradoxically, myocardial infarction. Here, we took advantage of 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 endothelial cells (ECs) are relatively resistant to this pathway. 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. This differential effect was corroborated in ex vivo pig coronaries, where the neointimal formation was inhibited by the drug combination, but endothelial viability was retained. We also deployed FasL-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 close to the stent struts, even in the presence of flow rates mimicking those of native arteries. Thus, the FasL-NO donor-combination has a potential to prevent intimal hyperplasia and in-stent restenosis, without harming endothelial restoration, and hence may be a superior drug delivery strategy for DES.

KEYWORDS:

Bioreactor; Coronary; Fas ligand; Intimal hyperplasia; Nitric oxide; Stent

PMID:
31102854
PMCID:
PMC6567994
[Available on 2020-08-01]
DOI:
10.1016/j.biomaterials.2019.05.011

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