Zebrafish Tie-2 shares a redundant role with Tie-1 in heart development and regulates vessel integrity

Gjini, E., Hekking, L.H., Küchler, A., Saharinen, P., Wienholds, E., Post, J.A., Alitalo, K., and Schulte-Merker, S.
Disease models & mechanisms   4(1): 57-66 (Journal)
Registered Authors
Gjini, Evisa, Küchler, Axel, Schulte-Merker, Stefan, Wienholds, Erno
MeSH Terms
  • Animals
  • Antigens, CD/metabolism
  • Atorvastatin
  • Base Sequence
  • Blood Vessels/drug effects
  • Blood Vessels/embryology
  • Blood Vessels/pathology*
  • Blood Vessels/ultrastructure
  • Cadherins/metabolism
  • Codon, Terminator/genetics
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/pathology
  • Endocardium/drug effects
  • Endocardium/pathology
  • Gene Knockdown Techniques
  • Head/pathology
  • Heart/drug effects
  • Heart/embryology*
  • Hemorrhage/pathology
  • Heptanoic Acids/pharmacology
  • Lymphatic Vessels/drug effects
  • Lymphatic Vessels/embryology
  • Molecular Sequence Data
  • Mutation/genetics
  • Myocardium/pathology
  • Organogenesis*/drug effects
  • Protein Structure, Tertiary
  • Pyrroles/pharmacology
  • Receptor, TIE-1/metabolism
  • Receptor, TIE-2/chemistry
  • Receptor, TIE-2/genetics
  • Receptor, TIE-2/metabolism
  • Zebrafish/embryology*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
21045210 Full text @ Dis. Model. Mech.
Tie-2 is a member of the receptor tyrosine kinase family and is required for vascular remodeling and maintenance of mammalian vessel integrity. A number of mutations in the human TIE2 gene have been identified in patients suffering from cutaneomucosal venous malformations and ventricular septal defects. How exactly Tie-2 signaling pathways play different roles in both vascular development and vascular stability is unknown. We have generated a zebrafish line carrying a stop mutation in the kinase domain of the Tie-2 receptor. Mutant embryos lack Tie-2 protein, but do not display any defect in heart and vessel development. Simultaneous loss of Tie-1 and Tie-2, however, leads to a cardiac phenotype. Our study shows that Tie-1 and Tie-2 are not required for early heart development, yet they have redundant roles for the maintenance of endocardial-myocardial connection in later stages. Tie-2 and its ligand Angiopoietin-1 have also been reported to play an important role in vessel stability. We used atorvastatin and simvastatin, drugs that cause bleeding in wild-type zebrafish larvae, to challenge vessel stability in tie-2 mutants. Interestingly, recent clinical studies have reported hemorrhagic stroke as a side effect of atorvastatin treatment. Exposure of embryos to statins revealed that tie-2 mutants are significantly protected from statin-induced bleeding. Furthermore, tie-2 mutants became less resistant to bleeding after VE-cadherin knockdown. Taken together, these data show that atorvastatin affects vessel stability through Tie-2, and that VE-cadherin and Tie-2 act in concert to allow vessel remodeling while playing a role in vessel stability. Our study introduces an additional vertebrate model to study in vivo the function of Tie-2 in development and disease.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes