Regulation of the angiogenic growth of blood and lymphatic vessels by Ephrin-B2.
Doctoral thesis, UCL (University College London).
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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