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

Gjini, E. and Hekking, L. H. and Kuchler, A. and Saharinen, P. and Wienholds, E. and Post, J. and 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, 57-66. ISSN 1754-8403. Supplementary material for this article is available at http:/​/​​lookup/​suppl/​doi:10.1242/​dmm.005033/​-/​DC1.

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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.

Item Type:Article
Additional Information:Supplementary material for this article is available at http:/​/​​lookup/​suppl/​doi:10.1242/​dmm.005033/​-/​DC1
Institutes:Hubrecht Instituut
ID Code:9469
Deposited On:04 Jan 2011
Last Modified:07 Sep 2012 10:08

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