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Funding Information: 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). Publisher Copyright: © 2022, The Author(s). 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. publishersversion published

The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.