Abstract 11744: Notch Signaling Regulates Vascular Endothelial Cell Senescence via a p53-Dependent Pathway
Features of aged vasculature include an increase of inflammation and a decline of regenerative potential, which cause vascular dysfunction and atherosclerosis. Although these phenomena are known to be associated with cellular senescence, the molecular mechanisms of these age-related changes remain unclear. Notch pathway is a highly conserved signaling system that controls cell fate determination and differentiation during the development of various tissues. In endothelial cells, Notch signaling has been recognized as an important determinant for arterializations and tip cell formation, and has also been reported to be essential for neovascularization in adults. Here, we show that Notch signaling has a crucial role in endothelial cell senescence. We found that inhibition of Notch signaling, using Notch1 short hairpin RNA (shRNA), in human umbilical vein endothelial cells (HUVEC) reduced the maximum population doublings, increased the activity of senescence-associated beta-galactosidase, and induced the expression of aging-associated molecules such as p53, p21, and p16. Knockdown of the Notch ligand Jagged1 resulted in the attenuation of Notch signaling in the neighboring cells, thereby inducing premature senescence similar to the knockdown of Notch1. In contrast, over-expression of Notch1 or Jagged1 extended the replicative lifespan of HUVEC and decreased the expression of aging-associated molecules. To elucidate the mechanism how the decline in Notch signaling induces premature senescence in endothelial cells, we co-infected HUVEC with p53 shRNA and Notch-1 shRNA. We found that knockdown of p53 effectively rescued premature senescence induced by knockdown of Notch-1. These results reveal a novel role of Jagged1-Notch1 signaling in the regulation of endothelial cell senescence via a p53-dependent pathway and suggest that Notch signaling may be a new therapeutic target for age-associated vascular diseases.
- © 2011 by American Heart Association, Inc.