A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to 
angiogenic growth

Ong, Yu Ting; Andrade, Jorge; Armbruster, Max; Shi, Chenyue; Castro, Marco; Costa, Ana S. H.; Sugino, Toshiya; Eelen, Guy; Zimmermann, Barbara; Wilhelm, Kerstin; Lim, Joseph; Watanabe, Shuichi; Guenther, Stefan; Schneider, Andre; Zanconato, Francesca; Kaulich, Manuel; Pan, Duojia; Braun, Thomas; Gerhardt, Holger; Efeyan, Alejo; Carmeliet, Peter; Piccolo, Stefano; Grosso, Ana Rita; Potente, Michael

doi:10.1038/s42255-022-00584-y

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A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth

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Ong, Yu Ting
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228776

Andrade, Jorge
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons275834

Armbruster, Max
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248900

Shi, Chenyue
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons260473

Castro, Marco
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248906

Sugino, Toshiya
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248926

Zimmermann, Barbara
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224368

Wilhelm, Kerstin
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons251578

Lim, Joseph
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224095

Watanabe, Shuichi
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther, Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224082

Schneider, Andre
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224052

Braun, Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224364

Potente, Michael
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Ong, Y. T., Andrade, J., Armbruster, M., Shi, C., Castro, M., Costa, A. S. H., et al. (2022). A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth. NATURE METABOLISM, 4(6), 672-682. doi:10.1038/s42255-022-00584-y.

Cite as: https://hdl.handle.net/21.11116/0000-000A-B004-A

Abstract

Ong et al. report how YAP/TAZ and mTORC1 signalling intersect in endothelial cells to regulate nutrient acquisition and vascular growth.
Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs-elicited by the loss of Rag GTPases-inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.