Staphylococcus aureus-vascular endothelium interactions: Mechanisms and therapeutic opportunities.

PURPOSE: This review aims to critically synthesize how Staphylococcus aureus (S. aureus) interacts with the vascular endothelium during invasive infection and to link endothelial pathogenic mechanisms with emerging therapeutic opportunities. METHODS: We reviewed the literature on S. aureus virulence factors, endothelial barrier dysfunction, host immune amplification, complement modulation, immunothrombosis, antimicrobial resistance, and adjunctive therapeutic strategies. The evidence was organized according to functional virulence modules, biological stages of endothelial interaction, host-driven amplification pathways, and mechanism-linked therapeutic opportunities. RESULTS: S. aureus-induced endothelial injury arises from the convergence of bacterial virulence and host vascular responses. Adhesins and surface-associated proteins promote endothelial attachment and invasion; toxins disrupt membrane integrity, junctional stability, and immune homeostasis; and enzymes together with immune-evasion factors support dissemination and persistence. These bacterial mechanisms are amplified by complement activation and evasion, neutrophil extracellular traps, inflammasome signaling, immunothrombosis, and immunometabolic reprogramming, ultimately leading to vascular leakage, procoagulant conversion, impaired repair, and organ dysfunction. Evidence is strongest for selected adhesion pathways and α-haemolysin (Hla)-mediated endothelial barrier injury, whereas several host-amplification mechanisms are inferred from non-S. aureus inflammatory or sepsis models. CONCLUSION: Mechanistic understanding of S. aureus-endothelium interactions provides a rationale for adjunctive strategies beyond standard antimicrobial therapy, including anti-adhesion approaches, toxin neutralization, host-directed modulation of excessive inflammation and immunothrombosis, and candidate endothelial biomarker-guided risk stratification. However, most emerging strategies remain preclinical or lack prospective validation in well-defined S. aureus infection cohorts.