Targeting Soluble Epoxide Hydrolase with TPPU Alleviates Irradiation‐Induced Hyposalivation in Mice via Preventing Apoptosis and Microcirculation Disturbance

IR irradiation‐induced dysfunction of the salivary gland and hyposalivation are one of the main complications of radiotherapy treatment for malignant head and neck tumors, and its mechanisms are not fully understood. IR‐induced microcirculation disturbance and apoptosis is one of the most important mechanisms. Most recent studies have focused on the regenerative effects of epoxyeicosatrienoic acids (EETs) through the process of increased angiogenesis. This study suggests that increasing endogenous EETs by the soluble epoxide hydrolase (sEH) inhibitor TPPU can reverse dysfunctional salivary glands and hyposalivation by improving the associated microenvironment and tissue regeneration. The findings suggest that TPPU alleviates hyposalivation and histological lesions, increases angiogenesis and reduces apoptosis of acinar cells significantly in IR‐damaged mice. The results in vitro demonstrate that TPPU promotes the proliferation and inhibits apoptosis of human salivary gland (HSG) cells, and enhances the motility and angiogenesis of human umbilical vein endothelial cells (HUVECs). The results also suggest that TPPU‐induced synergy and crosstalk between acinar cells and vascular endothelial cells might contribute to angiogenesis. Together, this study proves the feasibility of targeting sEH using TPPU to promote angiogenesis and reduce apoptosis, and also indicates the potential of sEH inhibitors for functional reconstruction of IR‐induced salivary glands damage.