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.
Highlights
Morphogenesis is driven by coordinated and dynamic cell movements, which are regulated by a combination of chemical and physical cues (Jaalouk and Lammerding, 2009)
We propose that non-canonical Wnt signaling coordinates collective cell behavior during vascular morphogenesis by fine-tuning junctional mechanocoupling between endothelial cells
Non-canonical Wnt signaling is required for the coordination of collective cell polarity
Summary
Morphogenesis is driven by coordinated and dynamic cell movements, which are regulated by a combination of chemical and physical cues (Jaalouk and Lammerding, 2009). Morphogenic cues are sensed and read at the single cell-level, yet biomechanical information is relayed to and integrated by neighboring cells leading to tissue-level collective cell behaviors These emergent collective behaviors arise by mechanically coupling cadherin-based adhesion and actomyosin-based contraction, allowing propagation of cell-cell interactions across large cell populations (Friedl and Mayor, 2017; Lecuit and Yap, 2015; Yap et al, 2018). One of such morphogenic processes is the formation of blood vessels. The mechanisms controlling and coordinating polarity patterns of endothelial cells during sprouting angiogenesis remain elusive
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