Injury and cyclic stretch induce vein graft failure: effective treatment with zinc oxide-loaded electrospun polycaprolactone external stent

Abstract The great saphenous vein (GSV) is widely used in vascular surgery, especially for coronary artery bypass grafting (CABG). However, surgical injury and arterial (high) cyclic stretch induce vascular dysfunction in vein grafts. Here, we found that surgical injury induces vascular dysfunctions. Upon adhering to injured vessels, platelets release platelet-derived microvesicles, which serve as potent and persistent mediators of vascular dysfunction. RNA sequencing analysis revealed that zinc ion deficiency plays a vital role in vascular dysfunction. Of note, platelet membrane cloaked Zn-MOF nanoparticles (ZIF-8) alleviate injury-induced vascular dysfunction. To counteract the vascular dysfunction caused by surgical injury and high cyclic stretch in vein grafts, we developed an electrospun polycaprolactone (PCL) external stent loaded with zinc oxide (ZnO) (PCL–ZnO stent). Electrospun PCL external stents containing varying ZnO concentrations (0 wt%, 1 wt%, 3 wt% or 5 wt% ZnO) were fabricated and implanted around vein grafts. Vascular remodeling was assessed by histology, immunofluorescence and RNA sequencing. Moderate ZnO loading (3 wt%) suppressed neointimal hyperplasia to preserve appropriate venous arterialization as confirmed by hematoxylin and eosin (H&E) staining and increased expression of smooth muscle cell phenotypic markers including α-SMA and Calponin. RNA-seq data verified that Zn2+ mediates the regulation of genes involved in proliferation, inflammation and metabolism. Gene set enrichment analysis of RNA-seq data from PCL-3 wt% ZnO-treated vein grafts at 2 weeks revealed significant upregulation of gene sets associated with lipid biosynthesis and cholesterol homeostasis. Pathway enrichment analysis of differential metabolites identified significant perturbations in purine metabolism, amino sugar/nucleotide sugar metabolism, galactose metabolism, and glycerophospholipid metabolism. These results indicated that moderate ZnO incorporation (3 wt%) in external stents effectively modulated local biological responses by suppressing pathological cell proliferation without inducing apoptosis, thereby promoting proper venous arterialization. PCL-3 wt% ZnO stent may be a successful material for clinical use in alleviating intimal hyperplasia and promoting functional arterialization of grafted veins.