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

Abstract

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.

CD47 Promotes Age-Associated Deterioration in Angiogenesis, Blood Flow and Glucose Homeostasis

“…Aging itself was sufficient to upregulate arterial TSP1 and CD47 expression, while simultaneously downregulating essential self-renewal factors genes (OSKM) in rodent and human arteries. These data are in line with reports of increased renal and myocardial TSP1 expression with age [41,42] and extend our previous findings in human pulmonary arteries that TSP1 expression positively correlated with advancing age [20]. Together, our data support the idea that vascular CD47 expression is age-sensitive.…”

“…In contrast, arterial rings from aged CD47-null mice had cell sprouting comparable to vessels from young mice ( Figure 4 G,H), which was persistently greater than sprouting from aged WT animals ( Figure 4 H,I). TSP1 has previously been implicated in aging and inflammation [ 20 , 27 ]. To determine whether the effects of CD47 are cell autonomous or dependent on TSP1 in aged arteries, we monitored angiogenic sprouting in aged WT and CD47-null aortic rings after incubation with exogenous TSP1 (2.2 nM).…”

“…Our previous findings show that TSP1 is increased in the pulmonary vasculature of older individuals [19,20]. Furthermore, TSP1, via CD47, suppresses self-renewal transcription factors in cell culture [10].…”

Diabetes Impairs Angiogenesis and Induces Endothelial Cell Senescence by Up-Regulating Thrombospondin-CD47-Dependent Signaling

“…Further, the lack of CD47 expression in endothelial cells enabled these cells to spontaneously gain characteristics of embryonic stem cells [30]. More recent reports revealed that TSP1 promotes ROS generation via the up-regulation of Nox1 [63]. The current data confirmed that the process of angiogenesis was inhibited as a function of diabetes both in in vitro and in vivo sponge model of wound healing.…”

CD47 as a Potential Target to Therapy for Infectious Diseases

“…CD47 has high binding affinity to SIRPa, TSP-1 and other integrin molecules on platelets, sickle red blood cells, microglia, B lymphocytes, etc. [ 51 , 52 , 53 , 54 , 55 ]. Due to the varieties of binding molecules, the type of signal induce by CD47 depends on the type of ligand and the condition on which the binding occur.…”