Abstract 10908: A Crucial Role of Notch Signaling in Vascular Endothelial Cell Senescence
Age-associated changes of blood vessels include an increase of inflammation and a decline of regenerative potential, leading to the development of atherosclerosis. Although vascular cell senescence is critically involved in these changes, the molecular mechanisms remain unclear. The Notch pathway is a highly conserved signaling system that controls a diversity of growth, differentiation, and patterning processes during the development of various tissues. In endothelial cells, Notch signaling has a critical role not only in vascular development and morphogenesis, but also in neovascularization in adults. Here, we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling, by using Notch1 short hairpin RNA, in human umbilical vein endothelial cells (HUVEC) reduced the maximum population doublings, increased the activity of senescence-associated beta-galactosidase, and up-regulated the expression of aging-associated molecules such as p53, p21, and p16. Likewise, knockdown of the Notch ligand Jagged1 attenuated Notch activity in the neighboring cells, thereby inducing premature senescence. Conversely, over-expression of Notch1 or Jagged1 decreased the expression of aging-associated molecules and extended the replicative lifespan of HUVEC. Disruption of p16 restored premature senescence induced by Notch1 deletion. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), and MKP1 up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 or inhibition of p38MAPK down-regulated p16 expression, thereby inhibiting premature senescence in Notch1-deleted endothelial cells. These results identify a novel role of Notch1 signaling in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 will be a new therapeutic target for age-associated vascular diseases.
- © 2012 by American Heart Association, Inc.