Non-canonical Wnt signaling regulates junctional mechanocoupling during angiogenic collective cell migration

Abstract

Morphogenesis of hierarchical vascular networks depends on the integration of multiple biomechanical signals by endothelial cells, the cells lining the interior of blood vessels. Expansion of vascular networks arises through sprouting angiogenesis, a process involving extensive cell rearrangements and collective cell migration. Yet, the mechanisms controlling angiogenic collective behavior remain poorly understood. Here, we show this collective cell behavior is regulated by non-canonical Wnt signaling. We identify that Wnt5a specifically activates Cdc42 at cell junctions downstream of ROR2 to reinforce coupling between adherens junctions and the actin cytoskeleton. We show that Wnt5a signaling stabilizes vinculin binding to alpha-catenin, and abrogation of vinculin in vivo and in vitro leads to uncoordinated polarity and deficient sprouting angiogenesis in Mus musculus. Our findings highlight how non-canonical Wnt signaling coordinates collective cell behavior during vascular morphogenesis by fine-tuning junctional mechanocoupling between endothelial cells.When a new blood vessel is created, a leader cell branches out from the lining of an existing vessel before being joined by other cells moving together in the same direction. A protein called Wnt5a regulates this process by helping the cells to orient themselves and finely coordinating their migration, but the exact details of this mechanism are still unclear.One way that cells can communicate is by touching and physically exerting forces on each other. This is made possible by structures called cellular junctions, which are present at the interface between cells. These can transmit forces within a tissue because they are connected with elements that form the cells’ internal skeletons. A protein known as vinculin is involved in these connections.To find out what role Wnt5a plays in cell migration, Carvalho et al. prevented blood vessel cells from creating the protein. The results showed that Wnt5a helps cells to move together by stabilizing vinculin at cell junctions. This strengthens the physical communication between cells and allows them to efficiently coordinate their movements. Indeed, in the mouse retina, deleting vinculin from cells that make blood cells impaired the formation of new blood vessels.Problems in the way that blood vessels grow are very common in the human population. In addition, Wnt5a is linked to cancer progression, which also relies on coordinated movement of cells. A better grasp of the role of this protein could therefore be relevant to understand how blood vessels are formed, but also how certain cancers invade surrounding tissues.