Netrins form an heterogeneous family of laminin related molecules with multifunctional activities. Netrin-4, the most distant
member of this family, is related to the laminin beta chain and has recently been proposed to play an important role in embryonic
and pathological angiogenesis. However, the data reported so far lead to the apparently contradictory conclusions supporting
Netrin-4 as either a pro- or an anti-angiogenic factor. To elucidate this controversy, Netrin-4 was analyzed for a vascular
activity in both cell-based models (HUVECs and HUAECs) and 2 zebrafish models: the wild-type AB/Tu strain and the transgenic
Tg(fli1a:EGFP)y1 strain. We show that Netrin-4 is expressed in endothelial cells and in the zebrafish vascular system. We
also evidence that Netrin-4 activates various kinases and induces various biological effects directly linked to angiogenesis
in vitro. Using morpholinos strategy, we demonstrate that Netrin-4 expression is crucial for zebrafish vessel formation and
that blood vessel formation defect induced by netrin-4 morpholinos can be partially rescued through drug delivery leading
to protein kinase activation.
Together these data underline the crucial role of Netrin-4 in blood vessel formation and the involvement of protein kinases
activation in Netrin-4-induced biological effects related to vascular development.