PUBLICATION
Zebrafish Tie-2 shares a redundant role with Tie-1 in heart development and regulates vessel integrity
- Authors
- Gjini, E., Hekking, L.H., Küchler, A., Saharinen, P., Wienholds, E., Post, J.A., Alitalo, K., and Schulte-Merker, S.
- ID
- ZDB-PUB-101108-26
- Date
- 2011
- Source
- Disease models & mechanisms 4(1): 57-66 (Journal)
- Registered Authors
- Gjini, Evisa, Küchler, Axel, Schulte-Merker, Stefan, Wienholds, Erno
- Keywords
- none
- MeSH Terms
-
- Lymphatic Vessels/drug effects
- Lymphatic Vessels/embryology
- Myocardium/pathology
- Protein Structure, Tertiary
- Receptor, TIE-2/chemistry
- Receptor, TIE-2/genetics
- Receptor, TIE-2/metabolism
- Blood Vessels/drug effects
- Blood Vessels/embryology
- Blood Vessels/pathology*
- Blood Vessels/ultrastructure
- Hemorrhage/pathology
- Codon, Terminator/genetics
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/pathology
- Atorvastatin
- Base Sequence
- Receptor, TIE-1/metabolism
- Zebrafish/embryology*
- Antigens, CD/metabolism
- Head/pathology
- Gene Knockdown Techniques
- Cadherins/metabolism
- Heart/drug effects
- Heart/embryology*
- Mutation/genetics
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Heptanoic Acids/pharmacology
- Organogenesis*/drug effects
- Molecular Sequence Data
- Animals
- Endocardium/drug effects
- Endocardium/pathology
- Pyrroles/pharmacology
- PubMed
- 21045210 Full text @ Dis. Model. Mech.
Citation
Gjini, E., Hekking, L.H., Küchler, A., Saharinen, P., Wienholds, E., Post, J.A., Alitalo, K., and Schulte-Merker, S. (2011) Zebrafish Tie-2 shares a redundant role with Tie-1 in heart development and regulates vessel integrity. Disease models & mechanisms. 4(1):57-66.
Abstract
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping