Research ArticleAging

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

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Science Signaling  17 Oct 2017:
Vol. 10, Issue 501, eaaj1784
DOI: 10.1126/scisignal.aaj1784

Keeping endothelial cells young

Aging causes once-proliferating cells to undergo cell cycle arrest and become senescent, thus impairing tissue and organ function. Meijles et al. delineated a pathway that induced senescence in mouse and human endothelial cells. Binding of the matricellular protein TSP1 to its receptor CD47 activated the enzyme Nox1, which generates reactive oxygen species. The subsequent oxidative stress triggered a p53-dependent DNA damage response pathway that resulted in cell cycle arrest. These results suggest that targeting TSP1, CD47, or Nox1 could delay or reverse cellular senescence in the endothelium, which could help improve the quality of life for the growing aging population.


Senescent cells withdraw from the cell cycle and do not proliferate. The prevalence of senescent compared to normally functioning parenchymal cells increases with age, impairing tissue and organ homeostasis. A contentious principle governing this process has been the redox theory of aging. We linked matricellular protein thrombospondin 1 (TSP1) and its receptor CD47 to the activation of NADPH oxidase 1 (Nox1), but not of the other closely related Nox isoforms, and associated oxidative stress, and to senescence in human cells and aged tissue. In human endothelial cells, TSP1 promoted senescence and attenuated cell cycle progression and proliferation. At the molecular level, TSP1 increased Nox1-dependent generation of reactive oxygen species (ROS), leading to the increased abundance of the transcription factor p53. p53 mediated a DNA damage response that led to senescence through Rb and p21cip, both of which inhibit cell cycle progression. Nox1 inhibition blocked the ability of TSP1 to increase p53 nuclear localization and p21cip abundance and its ability to promote senescence. Mice lacking TSP1 showed decreases in ROS production, p21cip expression, p53 activity, and aging-induced senescence. Conversely, lung tissue from aging humans displayed increases in the abundance of vascular TSP1, Nox1, p53, and p21cip. Finally, genetic ablation or pharmacological blockade of Nox1 in human endothelial cells attenuated TSP1-mediated ROS generation, restored cell cycle progression, and protected against senescence. Together, our results provide insights into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence and suggest potential targets for controlling the aging process at the molecular level.

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