CO2-rich solution promotes angiogenesis and accelerates wound healing associated with Ca2⁺, AKT and ERK signaling

The promotion of rapid wound healing remains a primary concern in skin repair, as delayed healing is associated with pain, increased infection risk, and loss of function. The wound microenvironment and complex interplays among various cell types are crucial for the sequential phases of repair, including inflammation, proliferation, re-epithelialization, and remodeling. Carbon dioxide therapy exerts beneficial effects on cutaneous wound healing. To elucidate the molecular mechanisms underlying CO 2 -mediated effects, in this study, human dermal fibroblasts and human umbilical vein endothelial cells (HUVECs) were exposed to a CO 2 -enriched medium. CO 2 treatment enhanced cell migration and proliferation. In HUVECs, CO 2 exposure induced a rapid increase in intracellular Ca 2+ levels, followed by phosphorylation of AKT and ERK. Intracellular ATP levels were elevated, whereas reactive oxygen species and mitochondrial superoxide were reduced, suggesting attenuation of cellular stress. In a murine wound-healing model, CO 2 bathing significantly accelerated wound closure. Histological analysis demonstrated enhanced angiogenesis and more organized collagen fiber alignment in CO 2 -treated wounds, corroborated by immunohistochemical staining for Ki-67 and von Willebrand factor. The findings of this study suggest that CO 2 bathing promotes wound repair by modulating cellular metabolism and stress responses, and may represent a safe, non-invasive, and effective therapeutic approach for postoperative and chronic wounds.