Role of Jagged1 in arterial lesions after vascular injury.

OBJECTIVE: Impaired regeneration of endothelial cells (EC) and overactivity of vascular smooth muscle cells (VSMC) are hallmarks of the arterial lesions associated with aging. The occurrence of 2 opposing cellular processes in the same arterial milieu makes pharmaceutical treatment difficult to develop. We previously reported that endothelial expression of a Notch ligand (Jagged1) was reduced in aged animals and that growth of the neointima was enhanced in these animals.

METHODS AND RESULTS: Similar to aged animals, Tie2-cre(+) Jagged1(lox/+) mice (with heterologous knockout of Jagged1 in EC) showed exaggerated intimal and medial thickening after carotid artery ligation. Unexpectedly, these mice showed little increase of Jagged1 expression not only in EC but also in VSMC, in contrast to a significant upregulation of Jagged1 in wild-type arteries after ligation. Coculture of VSMC with Jagged1-null EC resulted in the transition of VSMC from the contractile to the synthetic phenotype, along with decreased Jagged1 expression by VSMC. Conversely, overexpression of Jagged1 by EC or VSMC was shown to prevent the unfavorable phenotypic transition of VSMC, under both monoculture and coculture conditions.

CONCLUSIONS: These findings suggest a unidirectional effect of Jagged1 on both EC and VSMC that contributes to inhibition of arterial lesions after vascular injury. Our data also indicate that Jagged1 may be a novel therapeutic target for aging-related vascular diseases.