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

© 2019, Carvalho et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.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.Research was supported by European Research Council starting grant (679368), the H2020-Twinning grant (692322), the Fundação para a Ciência e a Tecnologia funding (grants: IF/00412/2012; EXPL-BEX-BCM-2258–2013; PRECISE-LISBOA-01–0145-FEDER-016394; UID/BIM/50005/2019, a project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência,Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado; and a grant from the Fondation Leducq (17CVD03); and personal fellowships: BD/52224/2013​​ to JRC, BD/105856/2014 to PB, and BD/128375/2017 to CF) and LISBOA-01–0145-FEDER-007391, project cofunded by FEDER, through POR Lisboa 2020 - Programa Operacional Regional de Lisboa, PORTUGAL 2020, and Fundação para a Ciência e a Tecnologia.info:eu-repo/semantics/publishedVersio

Competition for endothelial cell polarity drives vascular morphogenesis in the mouse retina

© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Blood-vessel formation generates unique vascular patterns in each individual. The principles governing the apparent stochasticity of this process remain to be elucidated. Using mathematical methods, we find that the transition between two fundamental vascular morphogenetic programs-sprouting angiogenesis and vascular remodeling-is established by a shift of collective front-to-rear polarity of endothelial cells in the mouse retina. We demonstrate that the competition between biochemical (VEGFA) and mechanical (blood-flow-induced shear stress) cues controls this collective polarity shift. Shear stress increases tension at focal adhesions overriding VEGFA-driven collective polarization, which relies on tension at adherens junctions. We propose that vascular morphogenetic cues compete to regulate individual cell polarity and migration through tension shifts that translates into tissue-level emergent behaviors, ultimately leading to uniquely organized vascular patterns.Funding: European Research Council: C.A.F. (679368); X.T. (883739). European Commission: C.A.F. and M.O.B. (801423); X.T. and P.R.-C. (731957). H2020-MSCA-PF grants to M.G.-G. (797621) and M.O. (842498). Fondation LeDucq: C.A.F., A.E., and M.O.B. (17CVD03). EPSRC: M.O.B. (EP/T008806/1; EP/R029598/1). Fundação para a Ciência e Tecnologia: C.A.F. (PTDC/MED-PAT/31639/2017; PTDC/BIA-CEL/32180/2017; CEECIND/04251/2017). Spanish Ministry of Science and Innovation: P.R.-C. (PID2019-110298GB-I00); X.T. (PGC2018-099645-B-I00). Generalitat de Catalunya: X.T. and P.R.-C. (2017-SGR-1602). La Caixa Foundation: X.T. and P.R.-C. (LCF/PR/HR20/52400004). Fundació la Marató de TV3: X.T. (201903-30-31-32). EMBO: L.M.F. (ALTF 2-2018)info:eu-repo/semantics/publishedVersio