The Staphylococcus aureus Superantigen TSST-1 Directly Impairs Endothelial Migration and Vascular Regeneration

Staphylococcus aureus causes invasive infections characterized by extensive tissue injury and impaired healing. Although staphylococcal superantigens are best known for immune activation, emerging evidence suggests that they also directly disrupt vascular repair. This study investigated how toxic shock syndrome toxin-1 (TSST-1) affects endothelial migration and angiogenic remodeling. Immortalized human aortic endothelial cells were evaluated using viability and proliferation assays, cell-exclusion assays and live-cell imaging, actin staining, and proteomic profiling. Angiogenic effects were examined using a rabbit aortic ring explant culture model combined with tissue and secreted proteomics. TSST-1 suppressed endothelial migration by reducing forward displacement and directional persistence. Treated cells failed to form broad lamellipodia and instead developed multipolar protrusions, persistent rear tethers, and prominent actin bundles, suggesting TSST-1 disrupts protrusion and retraction dynamics. TSST-1 also inhibited angiogenic sprouting and produced dysmorphic vascular networks. Proteomic analyses identified perturbations in endothelial cell pathways associated with polarity, adhesion, extracellular matrix organization, cytoskeletal regulation, trafficking, and stress responses. In rabbit aortic rings, TSST-1 exposure induced proteomic changes associated with adhesion stabilization, reduced proteolytic invasion, and altered matrix composition. These findings expand the pathogenic activities of staphylococcal superantigens beyond immune activation and support direct suppression of vascular regeneration as a potential contributor to persistent tissue injury during invasive S. aureus infection.