Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development: Implications for the Treatment of Vein Graft Failure.
Arterioscler Thromb Vasc Biol
; 35(11): 2343-2353, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26404485
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 ANDRESULTS:
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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Vena Safena
/
Vena Cava Inferior
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Péptidos y Proteínas de Señalización Intercelular
/
Péptidos y Proteínas de Señalización Intracelular
/
Neointima
/
Macrófagos
/
Proteínas de la Membrana
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Asunto de la revista:
ANGIOLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Marruecos