Euonymine inhibits in-stent restenosis through enhancing contractile phenotype of vascular smooth muscle cells via modulating the PTEN/AKT/mTOR signaling pathway

•In the present study, we used the rabbit carotid balloon injury model, wherein the main pathological process simulates intimal hyperplasia development after infliction of balloon dilation injury, while the pathological process of the porcine coronary implantation model encompasses the pathological process of mechanical injury inflicted by stent dilation and intimal hyperplasia development after the occurrence of stent injury. The dynamic development process of ISR caused by intimal hyperplasia in the two animal models are similar to the clinical/pathological process of ISR after PCI, which presents with avaluable clinical reference value.•In addition, we evaluated the effect of Euonymine on post-PCI ISR by quantitative coronary angiography (QCA) and optical coherence tomography (OCT) techniques in a porcine coronary artery stent model. QCA has long been recognized the gold standard for coronary artery disease detection and coronary stenosis evaluation. However, coronary angiography reflects luminal changes but not vessel wall pathology. OCT is an in vivo test that can help compensate for QCA and has garnered attention as the new gold standard for intravascular imaging of stents, atherosclerotic progression, vulnerable plaques, and neointimal hyperplasia. Our QCA and OCT results confirmed that coronary intimal hyperplasia was effectively suppressed in the ISR stent model after implantation of Euo-coated stents and showed good histocompatibility and safety.•With an ox-LDL-injured cell model, we showed that Euo suppressed the proliferation and migration of the rabbit thoracic aorta primary VSMCs, while inducing their apoptosis. Mechanistically, Euo may enhance the VSMCs contractile phenotype by modulating the PTEN/AKT/mTOR signaling pathway. Furthermore, with two in vivo models, the porcine coronary artery implantation model and the rabbit carotid balloon injury model, we demonstrated that Euro-eluting stents indeed inhibited ISR after PCI.•For the first time, this study delineates the potential efficacy of Euo, derived from THH, in ameliorating ISR after PCI. The phytochemical targets PTEN/AKT/mTOR signaling to increase the contractile phenotype of VSMCs and exerts anti-proliferative, anti-migratory as well as pro-apoptotic effects, thereby alleviating the ISR.