APEX1-STAT3 signaling mediates the force-coordinated endothelial regeneration

Endothelial regeneration is critical for maintaining vascular homeostasis and inhibiting neointimal formation during vascular repair following injury. While extracellular matrix (ECM) stiffness of the vascular wall is known to influence vascular endothelial cell (EC) behavior, its role in post-injury endothelial regeneration remains poorly understood. Here, we demonstrate a dynamic change in vascular wall stiffness post-injury, with an initial transient decrease within 5 days, followed by a subsequent increase. Our findings reveal that ECM stiffness enhances the interaction between Apurinic/apyrimidinic endonuclease 1 (APEX1) and the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). Their interaction promotes ROCK2-dependent phosphorylation of STAT3, facilitating its nuclear translocation and activation. Activated STAT3 drives EC proliferation, migration, and re-establishment of endothelial junctions. Additionally, we identify that STAT3 forms cytoplasmic condensates that impede its activation. ECM stiffening or APEX1 overexpression suppresses these condensates, enabling STAT3 activation. This study elucidates a novel mechanotransduction mechanism by which ECM stiffness regulates EC function through the APEX1-STAT3 signaling axis, offering insights into the coordination of endothelial regeneration during vascular repair.