Mechanisms and therapeutic potential of ozone therapy in enhancing vasculogenesis and angiogenesis through growth factor activation and oxidative signaling pathways

Ozone therapy has attracted growing interest because of its potential to promote tissue repair by stimulating vasculogenesis and angiogenesis. This review evaluates the pathways through which ozone enhances vascular growth, focusing on key factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), hypoxia-inducible factor 1-alpha (HIF-1α), and thymosin β4 (Tβ4). A comprehensive search of PubMed, Scopus, and Web of Science identified 57 eligible studies for inclusion. Data on ozone concentration (10–80 µg/mL), administration methods, and angiogenic outcomes were extracted from the included studies. Pearson’s correlation analysis revealed strong associations between ozone exposure and VEGF expression (r = 0.84), endothelial progenitor cell (EPC) mobilization (r = 0.82), and HIF-1α stabilization (r = 0.81). Ozone-induced reactive oxygen species (ROS) are also correlated with EPC activation and mesenchymal stem cell function. Additional mechanisms include nitric oxide signaling, NF-κB activation, and platelet-derived cytokine release. Thus, ozone therapy promotes angiogenesis through interconnected oxidative, inflammatory, and regenerative pathways. These findings support the therapeutic potential of this compound for vascular and ischemic disorders and highlight the need for further clinical validation and dose-response studies.