Thrombospondin-1 signaling through CD47 inhibits cell cycle progression and induces senescence in endothelial cells.
CD47 signaling in endothelial cells has been shown to suppress angiogenesis, but little is known about the link between CD47 and endothelial senescence. Herein, we demonstrate that the thrombospondin-1 (TSP1)-CD47 signaling pathway is a major mechanism for driving endothelial cell senescence. CD47 deficiency in endothelial cells significantly improved their angiogenic function and attenuated their replicative senescence. Lack of CD47 also suppresses activation of cell cycle inhibitors and upregulates the expression of cell cycle promoters, leading to increased cell cycle progression. Furthermore, TSP1 significantly accelerates replicative senescence and associated cell cycle arrest in a CD47-dependent manner. These findings demonstrate that TSP1-CD47 signaling is an important mechanism driving endothelial cell senescence. Thus, TSP1 and CD47 provide attractive molecular targets for treatment of aging-associated cardiovascular dysfunction and diseases involving endothelial dysregulation.
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Qi
Q
Gao
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Kexin
K
Chen
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Lu
L
Gao
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.
Yang
Y
Zheng
The First Hospital and Institute of Immunology, Jilin University, Changchun, China.|Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Yong-Guang
YG
Yang
D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000098:blood supply / Q000166:cytology; D051928:CD47 Antigen / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D007797:Laminin / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D061251:Primary Cell Culture; D011509:Proteoglycans / Q000737:chemistry; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics* / Q000378:metabolism
D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse; C059485:matrigel; D003094:Collagen