Abstract
Vascular endothelial cell senescence is involved in human aging and age-related vascular disorders. Guidance receptor UNC5B is implicated in oxidative stress and angiogenesis. Nonetheless, little is known about the role of UNC5B in endothelial cell senescence. Here, we cultured primary human umbilical vein endothelial cells to young and senescent phases. Subsequently, the expression of UNC5B was identified in replicative senescent cells, and then, its effect on endothelial cell senescence was confirmed by UNC5B-overexpressing lentiviral vectors and RNA interference. Overexpression of UNC5B in young endothelial cells significantly increased senescence-associated β-galactosidase-positive cells, upregulated the mRNAs expression of the senescence-associated secretory phenotype genes, reduced total cell number, and inhibited the potential for cell proliferation. Furthermore, overexpression of UNC5B promoted the generation of intracellular reactive oxygen species (ROS) and activated the P53 pathway. Besides, overexpression of UNC5B disturbed endothelial function by inhibiting cell migration and tube formation. Nevertheless, silencing UNC5B generated conflicting outcomes. Blocking ROS production or inhibiting the function of P53 rescued endothelial cell senescence induced by UNC5B. These findings suggest that UNC5B promotes endothelial cell senescence, potentially by activating the ROS-P53 pathway. Therefore, inhibiting UNC5B might reduce endothelial cell senescence and hinder age-related vascular disorders.
Highlights
Cardiovascular and cerebrovascular disorders immensely contribute to the global health and economic burden [1]
Our preliminary research indicated that UNC5B participated in restoring endothelial cell senescence and age-related endothelial dysfunction with young human plasm
By providing morphological and functional evidence, we showed that UNC5B induced endothelial cell senescence by inhibiting cell proliferation causing endothelial dysfunction by impairing tube formation and migration
Summary
Cardiovascular and cerebrovascular disorders immensely contribute to the global health and economic burden [1]. Similar to most cellular senescence, endothelial cell senescence program is triggered by extracellular and intracellular stresses like telomere shortening, oxidative stress, DNA damage, and epigenetic changes [4]. These stressors could be interrelated and engage various downstream effector pathways but activate P53, P16, or both [5, 6]. Oxidative stress, triggered by the accumulation of the reactive oxygen species (ROS), is a primary mechanism underlying the cellular senescence process [7] and promotes age-associated endothelial dysfunction [8]. We examined the impacts of UNC5B on age-related vascular function
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