Important roles of SoHo proteins in vascular development: Sorbs1 and Sorbs2 have related but distinct functions in endothelial cells angiogenic properties

Vascular system in all vertebrate organisms has in charge essential functions such as to bring nutrients, oxygen and signalling molecules to distant organs. Vascular network is established through sequential and distinct processes. During embryogenesis, angioblasts give rise to differentiated endothelial cells, which form primary vessels through vasculogenesis. Expansion of this primary network is then achieved through a multistep process known as angiogenesis. During angiogenesis, remodelling of endothelial cell shape relies on cytoskeleton dynamics. In this study, our goal was to investigate the potential role of the SoHo family of adaptor proteins in angiogenesis. The SoHo family comprises three members, Sorbs1, Sorbs2 and Sorbs3. Although accumulative evidence links this protein family to the regulation of cell adhesion and actin cytoskeletal organisation, their expression and potential functions in endothelial cells remain unknown. Using zebrafish loss of function experiments combined with confocal imaging, we show that loss of Sorbs1 affects caudal vein-derived vessel formation, whereas Sorbs2 depletion impairs ISV development essentially derived from the dorsal aorta. We then demonstrated that both members impact on EC behaviour via regulation of RhoGTPases activity, leading to the vascular defects observed in vivo. Using a series of in vitro functional assays, we found that Sorbs1 and Sorbs2 have opposite effects on adhesives properties of HUVECs related to their ability to regulate different RhoGTPases. Sorbs1 depleted ECs adhere excessively to the ECM due to decrease in Rac1 activity. In contrast, loss of Sorbs2 impaired RhoA activation during adhesion and decreases cell adhesiveness to the matrix. Interestingly, these opposite effects on cell adhesion lead to similar outcome on EC migratory abilities, a decrease in cell migration. Here, for the first time, we establish a role for Sorbs1 and Sorbs2 in angiogenesis and demonstrate that these SoHo members are essential for EC adhesiveness and subsequent migratory abilities.