Wasp controls oriented migration of endothelial cells to achieve functional vascular patterning

Endothelial cell migration and proliferation are essential for the
establishment of a hierarchical organization of blood vessels and optimal
distribution of blood. However, how these cellular processes are
quantitatively coordinated to drive vascular network morphogenesis remains
unknown. Here, using the zebrafish vasculature as a model system, we
demonstrate that the balanced distribution of endothelial cells as well as
the resulting regularity of vessel caliber, is a result of migration of
cells from veins connected to arteries and cell proliferation in veins. We
identify the Wiskott-Aldrich Syndrome protein (WASp) as an
important molecular regulator of this process and show that loss of
coordinated migration from veins to arteries
upon wasb depletion results in aberrant vessel
morphology and the formation of persistent arteriovenous shunts. We
demonstrate that WASp achieves its function through the coordination of
junctional actin assembly and PECAM1 recruitment and provide evidence that
this is conserved in human. Together, we demonstrate that functional
vascular patterning in the zebrafish trunk utilizes differential cell
movement regulated by junctional actin, and that interruption of
differential migration may represent a pathomechanism in vascular
malformations.