Clearance of senescent vascular smooth muscle cells retards aging-related restenosis following bioresorbable scaffolds implantation

Abstract

In contrast to bioinert metal stents, the degradation of bioresorbable scaffolds (BRS) induces complex mechanical changes and accumulation of degradation products, potentially leading to adverse events following implantation into stenotic arteries. Atherosclerosis (AS) is a typical age-related disease, plaque formation and changes in vascular mechanical properties can significantly affect the process of restenosis and vascular repair after BRS implantation. The aging of vascular smooth muscle cells (VSMCs) is earlier than that of endothelial cells (ECs) and plays a decisive role in the mechanical properties of blood vessels. This study investigated the impact of senescent VSMCs (s-VSMCs) on the effectiveness of 3-D printed poly-l-lactide BRS implanted in the aged abdominal aortas of Sprague-Dawley rats over a 6-month period. Synthetic phenotype switch of s-VSMCs contribute to aging-related in-stent restenosis (ISR) and hinder neointima recovery, by reducing positive remodeling and impeding the neointima recovery of ECs. Further analysis indicated that the regulation of ECs was influenced by mechanoresponsive miRNAs and increased stiffness induced by s-VSMCs. To effectively eliminate s-VSMCs and accelerate vascular repair, two types of senolytic-coated BRS were developed and tested with ABT-263 and young plasma-derived exosomes. These results highlight the critical role of s-VSMCs in increasing aging-related ISR and delaying intima recovery following BRS implantation. The senolytic coatings, with their ability to clear senescent cells, promoted vascular repair. This study offers valuable insights for potential mechanisms responsible for the elevated ISR risks associated with BRS in aged aortas and the development of advanced BRS coatings.