Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development, Implications for the Treatment of Vein Graft Failure
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Anderson_Macrophage notch.pdf
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Author(s)
Koga, Jun-ichiro
Nakano, Toshiaki
Figueiredo, Jose-Luiz
Zhang, Hengmin
Decano, Julius
Khan, Omar F.
Niida, Tomiharu
Iwata, Hiroshi
Aster, Jon C.
Yagita, Hideo
Date Issued
September 2015
Journal
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Wolters Kluwer Health, Inc.
Citation
Koga, Jun-ichiro, Toshiaki Nakano, James E. Dahlman, Jose-Luiz Figueiredo, Hengmin Zhang, Julius Decano, Omar F. Khan, et al. “Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion DevelopmentSignificance.” Arteriosclerosis, Thrombosis, and Vascular Biology 35, no. 11 (September 24, 2015): 2343–2353. © 2015 American Heart Association, Inc.
Version
Author's final manuscript
Abstract
Objective—Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease.
Approach and Results—We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage- or endothelial cell (EC)–targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft lesion development in low-density lipoprotein (LDL) receptor-deficient (Ldlr−/−) mice, and suppressed macrophage accumulation and macrophage expression of proinflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced lesion development and macrophage accumulation, whereas EC-targeted Dll4 small-interfering RNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that Dll4 induces proinflammatory molecules in macrophages. Macrophage Dll4 also stimulated smooth muscle cell proliferation and migration and suppressed their differentiation.
Conclusions—These results suggest that macrophage Dll4 promotes lesion development in vein grafts via macrophage activation and crosstalk between macrophages and smooth muscle cells, supporting the Dll4–Notch axis as a novel therapeutic target.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1161/atvbaha.115.305516
