Abstract
Evolutionarily conserved Notch signaling controls cell fate determination and differentiation during development, and is also essential for neovascularization in adults. Although recent studies suggest that the Notch pathway is associated with age-related conditions, it remains unclear whether Notch signaling is involved in vascular aging. Here we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling in human endothelial cells induced premature senescence via a p16-dependent pathway. Conversely, over-expression of Notch1 or Jagged1 prolonged the replicative lifespan of endothelial cells. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), while MKP1 further up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells. These findings indicate that Notch1 signaling has a role in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 could be a new therapeutic target for treating age-associated vascular diseases.
Highlights
The Notch pathway is a highly conserved signaling system that controls the fate and differentiation of cells during the development of various tissues
We examined the replicative lifespan of infected cells and found that up-regulation of Notch1 prolonged the lifespan of endothelial cells along with a decrease of senescence-associated bgalactosidase (SA-b-gal) activity and decreased expression of senescence-associated molecules such as p53, p21, and p16 (Figure 1B–D)
We found that introduction of Notch intracellular domain (NICD) led to premature senescence of human endothelial cells along with up-regulation of negative regulators of cell cycle (Figure S1A-C), suggesting that constitutive activation of the Notch pathway negatively regulates cell lifespan
Summary
The Notch pathway is a highly conserved signaling system that controls the fate and differentiation of cells during the development of various tissues. All of the receptors and ligands are transmembrane proteins, so Notch signaling is often mediated by cell-cell interaction. Receptor-ligand interactions induce additional proteolytic cleavage, which frees the Notch intracellular domain (NICD) from the cell membrane. Notch signaling has been implicated in the regulation of cardiomyocyte differentiation, the epithelial-to-mesenchymal transition during heart valve development, and vascular development. Notch signaling is essential for neovascularization and has been reported to be involved in age-associated conditions such as cancer, neurodegenerative disorders, and impaired regeneration of aged skeletal muscle [6,7,8,9,10]
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