Abstract 16798: Notch Ligand Delta-Like 4 Promotes Vein Graft Disease: A Novel Mechanism
Background: Vein graft failure occurs frequently, and leads to loss of limb/life. Despite its serious clinical burden, no effective medical therapy is available. Macrophage accumulation contributes to the formation of “unstable” vein graft lesions. We previously demonstrated that Notch signaling, triggered by its ligand Delta-like 4 (Dll4), promotes macrophage activation and atherosclerosis. The present study has explored the role of the Dll4-Notch axis in vein graft disease.
Method and Results: We examined the effects of the blocking antibody (Dll4-Ab) or control IgG in the inferior vena cava implanted in the carotid artery in fat-fed LDL-receptor deficient mice for 4 weeks (n = 5-7; 250 μ g, i.p., twice a week). Dll4 Ab treatment significantly reduced neointima formation and macrophage accumulation (Figure). Collagen hue analysis after the picrosirius red staining revealed the accumulation of thicker collagen fibers in Dll4-Ab treated vein grafts (p<0.05), suggesting a more “stable” lesion phenotype. Dll4 blockade tended to reduce the expression of markers associated with an activated macrophage phenotype (“M1”) in the graft, e.g., IL-1β, IL-6 (qPCR). In vitro gain- and loss-of-function studies further revealed that Dll4 regulates molecules associated with macrophage activation and the pathogenesis of vein graft disease, e.g., IL-1β, iNOS, MMPs. Conditioned media from cultured macrophages overexpressing Dll4 increased SMC proliferation and migration, and suppressed their diffferentiation markers (αSMA, SM22α, calponin-1, SM-MHC) as compared with the media from control macrophages. Immunostaining revealed that lesional macrophages of human and mouse vein grafts express Dll4.
Conclusions: These results suggest a novel mechanism that Dll4 promotes lesion development in vein grafts via macrophage activation and their crosstalk with SMC, supporting the Dll4-Notch axis as a potential therapeutic target for vein graft disease.
- © 2012 by American Heart Association, Inc.