YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

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Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels.
FN was financially supported by the Fundação para a Ciência e a Tecnologia (FCT), CRUK-CRICK and the MDC. ACV, AKB and EBK were supported by the DZHK (German Centre for Cardiovascular Research), AS was supported by the EMBO (European Molecular Biology Organization), JRC was supported by the FCT. CAF is supported by the FCT, EC-ERC Starting Grant, Portugal2020 program. MP is supported by the Max Planck Society, the ERC Starting Grant ANGIOMET, the Deutsche Forschungsgemeinschaft, the Excellence Cluster Cardiopulmonary System, the LOEWE grant Ub-Net, the DZHK, the Stiftung Charité and the EMBO Young Investigator Program. HG is supported by the DZHK and ERC Consolidator Grant Reshape 311719.