A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic 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.
Author:Yu Ting OngORCiDGND, Jorge AndradeORCiD, Max Armbruster, Chenyue ShiORCiDGND, Marco CastroORCiD, Ana S. H. Costa, Toshiya Sugino, Guy Eelen, Barbara Zimmermann, Kerstin WilhelmORCiDGND, Joseph LimORCiD, Shuichi Watanabe, Stefan GüntherORCiD, Andre Schneider, Francesca ZanconatoGND, Manuel KaulichORCiD, Duojia PanORCiD, Thomas BraunORCiDGND, Holger GerhardtORCiDGND, Alejo EfeyanORCiD, Peter CarmelietORCiDGND, Stefano PiccoloORCiDGND, Ana Rita GrossoORCiD, Michael PotenteORCiDGND
Parent Title (English):Nature metabolism
Publisher:Springer Nature
Place of publication:[London]
Document Type:Article
Date of Publication (online):2022/06/20
Date of first Publication:2022/06/20
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/03/06
Tag:Angiogenesis; HIPPO signalling; Metabolism; TOR signalling
Page Number:33
First Page:672
Last Page:682
RNA- and ChIP–seq datasets have been deposited in National Center for Biotechnology Information Gene Expression Omnibus with the accession number GSE163459. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD026872. Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author upon reasonable request.
Open access funding provided by Max Planck Society.
The research in the M.P. laboratory was supported by the Max Planck Society, the European Research Council (ERC) Consolidator Grant EMERGE (no. 773047), the Deutsche Forschungsgemeinschaft (DFG, Project-ID 75732319 – SFB 834), the Leducq Foundation, the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action (no. 814316), the Excellence Cluster Cardio-Pulmonary Institute (EXC 2026, Project-ID 390649896), the DZHK (German Centre for Cardiovascular Research), the Stiftung Charité and the European Molecular Biology Organization (EMBO) Young Investigator Programme. Work in the H.G. laboratory was supported by the DFG, Project-ID 427826188 – SFB 1444 and Project-ID 437531118 – SFB1470. Research in the Carmeliet laboratory is supported by Methusalem funding by the Flemish government and by an ERC Advanced Research grant (no. EU-ERC269073). This work was performed with assistance from the CSHL Mass Spectrometry Shared Resource, which is supported by a Cancer Centre Support grant (no. 5P30CA045508).
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International