Ephrin-B2 overexpression in the vascular endothelium

Previous work has established that Eph family receptor tyrosine kinases and ephrin ligands control a wide range of morphogenetic processes in vertebrate embryos through cell-contact dependent signalling interactions. In the developing cardiovascular system, ephrin-B2, a transmembrane protein is expressed by arterial endothelial cells (ECs) whereas the cognate receptor EphB4 is predominantly found on the venous endothelium. Gene targeting studies in mice have demonstrated that both molecules are critically required for angiogenic remodelling of embryonic blood vessels and survival beyond midgestation. To gain more insight into the role of ephrin-B2 in vascular development and its arterial expression, I have used the tetracycline-controlled expression systems to overexpress the ligand in the endothelium of all vascular beds (i.e. in arteries, veins and microvessels) of transgenic mice. In the course of this study, I have employed several different transgenic EC-specific driver lines in combination with tetracycline-controlled (tTA, Tet-OFF) and reverse tetracycline-controlled (rtTA, Tet-ON) transactivators. Ephrin-B2 overexpression triggers enhanced activation of EphB receptors particularly in the venous endothelium. This leads to severe vascular malformations such as oedema and haemorrhaging. Induction of ephrin-B2 expression at different stages of embryonic development controls not only vascular patterning and the recruitment of supporting pericytes and vascular smooth muscle cells but it can also trigger tissue-specific responses. In summary, my work has established that ephrin-B2 is an important regulator of blood vessel morphogenesis throughout embryonic development. Some results suggest that the ligand may also be involved in pathological conditions such as fibrosis as ectopic expression of ephrin-B2 in the embryonic liver triggers the activation of hepatic stellate cells. The resulting increase in matrix deposition around hepatic blood vessels could represent early signs of a fibrotic phenotype.