Vascular Cell Senescence and Age-Related Endothelial Dysfunction: The Role of the Senescence-Associated Secretory Phenotype and CXCL12

Senescent endothelial cells demonstrated increased abundance of transcripts related to cardiovascular pathology and high expression of SASP factors. Of the identified SASP factors that had higher expression with aging, Cxcl12 mRNA was the most highly upregulated with old age and downregulated with senolytic treatment and this pattern persisted in circulating CXCL12 protein concentrations in plasma. We next sought to determine the causal role of the circulating SASP milieu and CXCL12 in regulating endothelial function with aging and fisetin supplementation.

Ex vivo exposure of isolated arteries and cultured endothelial cells to plasma from young, old and old fisetin-supplemented mice revealed that the aged circulating SASP milieu directly induced endothelial dysfunction through induction of cellular senescence induction, reduced NO bioactivity, and increased mitochondrial oxidative stress. The circulating SASP milieu-mediated impairments were in part mediated by CXCL12 and subsequently alleviated by fisetin supplementation.

These findings establish the circulating SASP milieu as an underlying mechanism of age-related endothelial dysfunction and identify CXCL12 as a novel mediator and therapeutic target of cellular senescence-induced endothelial dysfunction with aging.