| dc.description.abstract | Angiogenesis, the formation of new blood vessels from pre-existing ones, is a key process
during development, wound healing and the female reproductive cycle. However, it is also a
pathological feature of many diseases such as cancer, age-related macular degeneration and
chronic inflammatory pathologies. Given the complexity underlying the fine regulation of this
process, despite the great number of studies, our understanding of it is not yet exhaustive.
Syndecans are heparan sulphate proteoglycans with roles in cell adhesion, migration and
growth factor interactions. The aim of this body of work was to investigate the role of these
molecules in the regulation of angiogenesis. For this purpose, in the first part of my project, I
investigated the effects of the extracellular core proteins of all four syndecans on endothelial
cell functions. These studies identified that all four proteins are able to inhibit angiogenesis
and strongly suppress endothelial cell migration, invasion and tube formation. On the basis of
these discoveries, I focused on the syndecan-2 extracellular core protein and showed that it is
shed during inflammation and can interact with the endothelial cell surface tyrosine
phosphatase receptor CD148. Upon binding to CD148, the syndecan-2 extracellular core
protein reduces the expression of active β1 integrins on endothelial cell surface and inhibits
endothelial cell migration. This provides a mechanism through which shed syndecan-2 can
regulate angiogenesis. Critically, this is an entirely novel pathway for the reduction of
angiogenesis which is independent to the main angiogenic factor VEGF. Lastly, since previous
works suggested that the syndecan-4-null mouse may exhibit angiogenic defects, I set out to
determine the role of syndecan-4 in angiogenesis. Here, I observed an up-regulation of
syndecan-4 on endothelial cells in angiogenic settings both in vitro and in vivo. Furthermore,
through analysis of in vivo models of pathological angiogenesis, I observed that syndecan-4 is
critical for VEGF-A-mediated angiogenesis. This effect was partially explained by impaired
activation of VEGFR2 in syndecan-4-null endothelial cells. This data suggests that syndecan-
4 is the main heparan sulphate proteoglycan to act as VEGFR2 co-receptor during pathological
angiogenesis.
Collectively, the findings of this research have identified previously unknown roles for
syndecans in the regulation of angiogenesis. | en_US |
