Foo, S.S.C.; (2004) The role of ephrinB2 in blood vessel development. Doctoral thesis , University of London.

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Abstract

The development of the vascular network is a complex process that is controlled by precisely balanced angiogenic and anti-angiogenic factors. Several studies have established that ephrinB2 and its receptor EphB4 are important regulators of angiogenic remodelling in the embryonic vasculature. The ablation of either gene in mice leads to fatal cardiovascular defects and early lethality. As ephrinB2 is expressed in different cell types within blood vessels, specifically in arterial endothelial cells, pericytes and vascular smooth muscle cells, the function of the molecule in each cell population has remained unclear. To determine the role of ephrinB2 expression in the luminal endothelial lining of blood vessels, tissue-specific knockout mice were generated with the Cre-loxP method. The resulting mutants displayed fatal defects in the development of blood vessels and the heart that resembled the phenotype of the global ephrinB2 null mice. This demonstrated that ephrinB2 is essential in the endothelial cells and that its expression in other cell types within the cardiovascular system is not sufficient to compensate for this loss. Pericytes and vascular smooth muscle cells, so-called mural cells, are associated with the endothelium and are essential for the formation of a stable and mature vascular network. To study the role of ephrinB2 in mural cells that express progressively increasing levels of the ligand during the second half of embryonic development, a transgenic mouse line expressing Cre recombinase under the control of a fragment from the PDGFR? gene was established. This permitted the generation of mural cell-specific ephrinB2 knockouts in which the investment of pericytes and smooth muscle cells in the microvasculature was impaired so the vessel wall assembly was defective. Consequently, these mutants displayed oedema, haemorrhaging and presumably died of respiratory arrest. These findings demonstrate that ephrinB2 expression in mural cells is essential for the maturation of the microvessels but apparently not for the remodelling of the endothelium. As insufficient support by mural cells and the resulting increase in blood vessel permeability is a relevant factor in human disease, such as diabetic retinopathy and tumours, the findings presented here argue that the ligand may be a potential target for therapeutic intervention.

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