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Updated: Aug 6, 2026
In Vivo Imaging and Quantitation of the Host Angiogenic Response in Zebrafish Tumor Xenografts
Published on: August 14, 2019
Mycophenolate mofetil induces angiogenesis disorders in zebrafish embryos by inhibiting the mitogen-activated protein
Mengqi Wan1,2, Zhonghao Xiao1, Xiaowen Shi1
1Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, College of Life Sciences, Clinical Research Center of Jinggangshan University, Jinggangshan University, Ji'an, 343009, China.
Abstract:
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).
Insights
Mycophenolate mofetil (MMF), an immunosuppressant, causes developmental defects in zebrafish, including vascular abnormalities. Guanosine and diprovocim partially reversed these MMF-induced vascular issues by targeting MAPK signaling.
Area of Science:
- Developmental biology
- Pharmacology
- Toxicology
Background:
- Mycophenolate mofetil (MMF) is a widely used immunosuppressant post-organ transplantation.
- While generally safe for liver and kidney, MMF is linked to gastrointestinal issues and infections.
- Its impact on vascular development remains largely unknown.
Purpose of the Study:
- To investigate the effects of MMF on vascular development using a zebrafish model.
- To elucidate the molecular pathways affected by MMF exposure during vascular development.
Main Methods:
- Zebrafish embryos were exposed to MMF.
- Vascular development was assessed morphologically and molecularly.
- Interventions included antioxidants, signaling pathway activators (notch, MAPK), guanosine, and diprovocim.
Main Results:
- MMF caused teratogenicity, including shortened body length, pericardial edema, and delayed yolk sac absorption.
- MMF induced intersegmental vessel hyperbranching but inhibited cerebrovascular development.
- MMF upregulated oxidative stress and inhibited Notch and MAPK signaling pathways.
Conclusions:
- MMF significantly impacts embryonic development and vascular patterning in zebrafish.
- MMF-induced vascular defects are associated with oxidative stress and inhibition of Notch and MAPK pathways.
- Targeting MAPK signaling with diprovocim and IMPDH with guanosine shows potential for mitigating MMF's vascular toxicity.
