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

Dis Model Mech. 2011 Jan;4(1):57-66. doi: 10.1242/dmm.005033. Epub 2010 Nov 2.

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.

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*

Substances

  • Antigens, CD
  • Cadherins
  • Codon, Terminator
  • Heptanoic Acids
  • Pyrroles
  • Zebrafish Proteins
  • cadherin 5
  • Atorvastatin
  • Receptor, TIE-1
  • Receptor, TIE-2
  • tek protein, zebrafish
  • tie1 protein, zebrafish