title: Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development: Implications for the Treatment of Vein Graft Failure.
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.
  
  
  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.
authors.affiliation: The Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Jun-Ichiro
authors.initials: JI
authors.lastname: Koga
authors.affiliation: The Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakano
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, MA.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA.|Institutes for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: James E
authors.initials: JE
authors.lastname: Dahlman
authors.affiliation: The Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|the Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.affiliation: the Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Hengmin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: the Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Julius
authors.initials: J
authors.lastname: Decano
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, MA.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA.|Institutes for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Omar F
authors.initials: OF
authors.lastname: Khan
authors.affiliation: The Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Tomiharu
authors.initials: T
authors.lastname: Niida
authors.affiliation: the Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, MA.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA.|Institutes for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: C Keith
authors.initials: CK
authors.lastname: Ozaki
authors.affiliation: The Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|the Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Aikawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D002339:Carotid Arteries / Q000601:surgery; D002450:Cell Communication; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058426:Neointima; D034622:RNA Interference; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012501:Saphenous Vein / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling; D014682:Vena Cava, Inferior / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C519665:DLL4 protein, mouse; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011973:Receptors, LDL
keywords: endothelial cells; inflammation; lipid; macrophage; nanoparticles