Zebrafish Tie-2 shares a redundant role with Tie-1 in heart development and regulates vessel integrity.
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.
Hubrecht Institute-KNAW and University Medical Centre, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Evisa
E
Gjini
Liesbeth H
LH
Hekking
Axel
A
Küchler
Pipsa
P
Saharinen
Erno
E
Wienholds
Jan-Andries
JA
Post
Kari
K
Alitalo
Stefan
S
Schulte-Merker
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000069059:Atorvastatin; D001483:Base Sequence; D001808:Blood Vessels / Q000187:drug effects / Q000196:embryology / Q000473:pathology* / Q000648:ultrastructure; D015820:Cadherins / Q000378:metabolism; D018388:Codon, Terminator / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000473:pathology; D004699:Endocardium / Q000187:drug effects / Q000473:pathology; D055785:Gene Knockdown Techniques; D006257:Head / Q000473:pathology; D006321:Heart / Q000187:drug effects / Q000196:embryology*; D006470:Hemorrhage / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology; D042601:Lymphatic Vessels / Q000187:drug effects / Q000196:embryology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000473:pathology; D038081:Organogenesis / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000494:pharmacology; D042810:Receptor, TIE-1 / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D000069059:Atorvastatin; D015820:Cadherins; D018388:Codon, Terminator; D006538:Heptanoic Acids; D011758:Pyrroles; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2; D029961:Zebrafish Proteins; D000099152:Cadherin 5; C468146:tek protein, zebrafish; C467973:tie1 protein, zebrafish