Mycophenolate mofetil induces angiogenesis disorders in zebrafish embryos by inhibiting the mitogen-activated protein kinase signaling pathway

As a commonly used immunosuppressant, mycophenolate mofetil (MMF) is widely prescribed after organ transplantation because it is not toxic to the liver and kidney. However, its use is associated with certain gastrointestinal toxicity and increased risk of opportunistic infections. Meanwhile, whether it affects vascular development is unclear. Herein, a zebrafish model was utilized to evaluate whether MMF affects vascular development, and the results showed that MMF exhibited teratogenicity, shortened the body length, caused pericardial edema, and delayed yolk sac absorption in zebrafish. In addition, although Intersegmental vessels showed hyperbranching, opposite changes were observed in cerebrovascular, with cerebrovascular inhibition. Moreover, MMF exposure upregulated oxidative stress levels, inhibited notch signaling and mitogen-activated protein kinase (MAPK) signaling, and affected the expression of vascular endothelial growth factor and receptor tyrosine kinase. Treatment with the antioxidant astaxanthin and the notch signaling pathway activator sodium valproate did not rescue the vascular development defects, indicating that MMF affects multiple signal pathways. However, the treatment of MMF-exposed zebrafish with guanosine and the MAPK signaling activators diprovocim significantly rescued the angiogenesis-related defects, suggesting that MMF induces ISV hyperbranching in zebrafish by inhibiting MAPK signaling and inosine 5'-monophosphate dehydrogenase (IMPDH).