Ginkgolide A-Gold Nanoparticles Inhibit Vascular Smooth Muscle Proliferation and Migration In Vitro and Reduce Neointimal Hyperplasia in a Mouse Model 1

BackgroundNeointimal formation is mediated by phenotypic changes in vascular smooth muscle cells (SMC) and is an important mediator of restenosis following arterial reconstruction. We conjugated antioxidant ginkgolide A (GA) to gold nanoparticles (GNP) to determine the effect of GA delivery on neointimal formation.Materials and MethodsGA was conjugated to 80 nm GNP in an overnight incubation. Mouse P53LMAC01 vascular SMC were treated with various doses of GA-GNP, GA alone, GNP alone, and no treatment control. Cell proliferation and migration were analyzed, and superoxide anion levels and the phosphorylation status of ERK1/2 were determined. Mice underwent ligation of the common carotid artery along with local treatment with GNP (control) or GA-GNP. The carotid artery was harvested and subjected to immunohistochemical analysis.ResultsGA-GNP treatment significantly inhibited SMC proliferation and migration in vitro in comparison to GNP treatment alone, and the effect persisted for up to 72 h after treatment. Treatment with GA-GNP also reduced superoxide anion levels in vitro. PDGF-BB substantially induced ERK1/2 phosphorylation in GNP control cells; this PDGE-BB induced ERK1/2 phosphorylation was significantly inhibited in GA-GNP-treated cells compared with GNP only. GA-GNP significantly reduced neointimal hyperplasia after injury in mice, and proliferating cell nuclear antigen (PCNA) staining was reduced substantially in the arteries of mice treated with GA-GNP.ConclusionsGA-GNP reduce vascular SMC proliferation and migration in vitro through reduced activation of ERK1/2. Local treatment with GA-GNP in areas of arterial injury reduced neointimal hyperplasia and subsequent stenosis.