Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase

Virginia Guarani, Gianluca Deflorian, Claudio A. Franco, Marcus Krüger, Li Kun Phng, Katie Bentley, Louise Toussaint, Franck Dequiedt, Raul Mostoslavsky, Mirko H.H. Schmidt, Barbara Zimmermann, Ralf P. Brandes, Marina Mione, Christoph H. Westphal, Thomas Braun, Andreas M. Zeiher, Holger Gerhardt, Stefanie Dimmeler, Michael Potente

Research output: Contribution to journalArticlepeer-review

315 Scopus citations


Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD +-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.

Original languageEnglish
Pages (from-to)234-238
Number of pages5
Issue number7346
StatePublished - 12 May 2011
Externally publishedYes


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