ZONAB regulates DNA methylation and mitochondrial function to control endothelial cell senescence

Regulation of the endothelial stress response is important for blood vessel homeostasis and angiogenesis, processes disrupted in common vascular diseases and ageing. Here, we discovered that the Y-box factor ZONAB (ZO-1-associated nucleic acid binding protein; YBX3), a gene associated with risk loci for severe vascular disorders, regulates endothelial homeostasis and angiogenesis. By combining cell-based assays with primary endothelial cells and genome-wide expression and methylation measurements, we found that ZONAB depletion results in mitochondrial deregulation, increased reactive oxygen species and a defective oxidative stress response, as well as increased promoter methylation of cell cycle genes. Consequently, ZONAB depletion triggered cellular senescence via a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway, which was attenuated by an antioxidant or by drugs targeting mitochondrial function or fragmentation. Thus, our results reveal how ZONAB controls changes in gene expression and DNA methylation to regulate endothelial proliferation, inflammation, and angiogenesis, indicating a central role of ZONAB in vascular health.