Venous malformations are mainly of sporadic origin, but a small proportion, including glomuvenous malformations (OMIM #138000) and cutaneomucosal venous malformations (VMCMs; OMIM #600195), are inherited. VMCMs present as bluish patches mainly at the mucosa, and are caused by dilation of blood vessels. VMCMs have been genetically linked to endothelial-specific receptor tyrosine kinase 2 (TIE2; also known as TEK): several different mutations in this gene have been identified in VMCM patients. In line with the proposed roles of TIE2 in vascular remodeling and maintenance of mammalian vessel integrity, VMCM patients have a relative lack of mural cells in affected regions of the endothelium, and some VMCM patients have ventricular septal defects. Tie-2−/−mice die during embryogenesis mainly owing to heart defects, providing clues about the role of TIE2 in the pathology of VMCM in humans. However, the precise functions of TIE2 in vascular stability and development are still not fully understood.
In this study, the authors generate a zebrafish tie-2 loss-of-function mutant and show that, in contrast to the phenotype of Tie-2−/− mice, tie-2 mutant zebrafish are viable and show no defects in embryonic angiogenesis. However, morpholino-mediated knockdown of Tie-1 function in tie-2 zebrafish mutants shows that combined loss of Tie-1 and Tie-2 function results in defects of myocardial-endocardial contact. Given that a role has been proposed for Tie-2 in vascular permeability, the authors also challenge vessel stability in tie-2 mutants by using statins, which have been shown to induce hemorrhages in specific vascular regions of the zebrafish embryo. Surprisingly, tie-2 mutants are resistant to statin-induced bleeding, and further experiments indicate that this effect depends on VE cadherin, an important intercellular junction protein.
Implications and future directions
This work introduces an additional vertebrate model in which to study the function of Tie-2 in vivo. Because Tie-1 and Tie-2 have redundant roles in cardiac development in zebrafish, this model will allow the study of Tie-2 function in vivo without the complication of cardiac defects. Tie-2 is generally considered to be a vascular stabilizing factor, because it recruits support cells to the endothelium; however, the effect of statins in tie-2 mutants observed in this study suggest that the function of Tie-2 and/or its ligands might be more context-dependent than previously appreciated.