Wang, Y.; (2009) Regulation of the angiogenic growth of blood and lymphatic vessels by Ephrin-B2. Doctoral thesis, UCL (University College London).
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The angiogenic growth of blood vessels and lymphatic vessels plays important roles during embryonic development as well as in disease conditions such as cancer. Previous work has shown that ephrin-B2, a transmembrane protein and ligand for Eph family receptor tyrosin kinases, regulates the growth of these endothelial networks. In mice, inactivation of ephrin-B2 in endothelial cells (ECs) results in similar vascular defects and embryonic lethality as in global Efnb2 knockouts, indicating that the main function of ephrin-B2 is in the endothelium. Despite its importance, the functional roles of ephrin-B2 in vascular endothelium are incompletely understood. To gain further insight into the function of ephrin-B2 in ECs in mice, I have used EC-specific and temporally controlled loss-of-function and gain-of-function genetic approaches, and analysed the function of ephrin-B2 in different vascular beds. My data show that ephrin-B2 has two distinct functional roles in the blood vasculature. In arteries, the domain with the highest expression of ephrin-B2, the ligand is critical for arterial remodelling. Outside arteries, in the microvessels of capillary beds, ephrin-B2 is essential for endothelial motility and invasiveness during angiogenic sprouting. Furthermore, ephrin-B2 is an important regulator of angiogenic lymphatic endothelial cell (LEC) behaviour, which may be associated with VEGFR3-mediated signalling. In addition, ephrin-B2 is essential for the maintenance of LEC differentiation and, at least during embryonic development, normal Prox1 expression. Moreover, my data indicates that ephrin-B2 is critical for the postnatal remodeling of the primary dermal lymphatic plexus, which appears to be mainly mediated through ephrin-B2 reverse signalling. The sum of my findings demonstrates that ephrin-B2 is a key regulator of EC motility during the angiogenic growth of blood vessels and lymphatic vessels. Ephrin-B2 plays multiple indispensable and vascular domain-specific roles in the angiogenic growth of endothelial networks.
|Title:||Regulation of the angiogenic growth of blood and lymphatic vessels by Ephrin-B2|
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