Vascular stent with immobilized anti-inflammatory chemerin 15 peptides mitigates neointimal hyperplasia and accelerates vascular healing.

Endovascular stenting is a safer alternative to open surgery for use in treating cerebral arterial stenosis and significantly reduces the recurrence of ischemic stroke, but the widely used bare-metal stents (BMSs) often result in in-stent restenosis (ISR). Although evidence suggests that drug-eluting stents are superior to BMSs in the short term, their long-term performances remain unknown. Herein, we propose a potential vascular stent modified by immobilizing clickable chemerin 15 (C15) peptides on the stent surface to suppress coagulation and restenosis. Various characterization techniques and an animal model were used to evaluate the surface properties of the modified stents and their effects on endothelial injury, platelet adhesion, and inflammation. The C15-immobilized stent could prevent restenosis by minimizing endothelial injury, promoting physiological healing, restraining the platelet-leukocyte-related inflammatory response, and inhibiting vascular smooth muscle cell proliferation and migration. Furthermore, in vivo studies demonstrated that the C15-immobilized stent mitigated inflammation, suppressed neointimal hyperplasia, and accelerated endothelial restoration. The use of surface-modified, anti-inflammatory, endothelium-friendly stents may be of benefit to patients with arterial stenosis. STATEMENT OF SIGNIFICANCE: Endovascular stenting is increasingly used for cerebral arterial stenosis treatment, aiming to prevent and treat ischemic stroke. But an important accompanying complication is in-stent restenosis (ISR). Persistent inflammation has been established as a hallmark of ISR and anti-inflammation strategies in stent modification proved effective. Chemerin 15, an inflammatory resolution mediator with 15-aa peptide, was active at picomolar through cell surface receptor, no need to permeate cell membrane and involved in resolution of inflammation by inhibiting inflammatory cells adhesion, modulating macrophage polarization into protective phenotype, and reducing inflammatory factors release. The implications of this study are that C15 immobilized stent favors inflammation resolution and rapid re-endothelialization, and exhibits an inhibitory role of restenosis. As such, it helps the decreased incidence of ISR.

Gas station in blood vessels: An endothelium mimicking, self-sustainable nitric oxide fueling stent coating for prevention of thrombosis and restenosis.

Stenting is the primary treatment for vascular obstruction-related cardiovascular diseases, but it inevitably causes endothelial injury which may lead to severe thrombosis and restenosis. Maintaining nitric oxide (NO, a vasoactive mediator) production and grafting endothelial glycocalyx such as heparin (Hep) onto the surface of cardiovascular stents could effectively reconstruct the damaged endothelium. However, insufficient endogenous NO donors may impede NO catalytic generation and fail to sustain cardiovascular homeostasis. Here, a dopamine-copper (DA-Cu) network-based coating armed with NO precursor L-arginine (Arg) and Hep (DA-Cu-Arg-Hep) is prepared using an organic solvent-free dipping technique to form a nanometer-thin coating onto the cardiovascular stents. The DA-Cu network adheres tightly to the surface of stents and confers excellent NO catalytic activity in the presence of endogenous NO donors. The immobilized Arg functions as a NO fuel to generate NO via endothelial nitric oxide synthase (eNOS), while Hep works as eNOS booster to increase the level of eNOS to decompose Arg into NO, ensuring a sufficient supply of NO even when endogenous donors are insufficient. The synergistic interaction between Cu and Arg is analogous to a gas station to fuel NO production to compensate for the insufficient endogenous NO donor in vivo. Consequently, it promotes the reconstruction of natural endothelium, inhibits smooth muscle cell (SMC) migration, and suppresses cascading platelet adhesion, preventing stent thrombosis and restenosis. We anticipate that our DA-Cu-Arg-Hep coating will improve the quality of life of cardiovascular patients through improved surgical follow-up, increased safety, and decreased medication, as well as revitalize the stenting industry through durable designs.