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SIRT1 controls endothelial angiogenic functions during vascular growth

¹ Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, 60590 Frankfurt, Germany; ² Zebrafish Group, FIRC (Fondazione Italiana per la Ricerca sul Cancro) Institute of Molecular Oncology Foundation, European Institute of Oncology (IFOM-IEO Campus), 20139 Milan, Italy; ³ Howard Hughes Medical Institute, The Children’s Hospital, CBR (Center for Blood Research) Institute for Biomedical Research, Harvard University Medical School, Boston 02115, USA; ⁴ Cellular and Molecular Biology Unit, FUSAGx, B-5030 Gembloux, Belgium; ⁵ IFOM—The FIRC Institute of Molecular Oncology, 20139 Milan, Italy

The nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylase Sir2 regulates life-span in various species. Mammalian homologs of Sir2 are called sirtuins (SIRT1–SIRT7). In an effort to define the role of sirtuins in vascular homeostasis, we found that among the SIRT family, SIRT1 uniquely regulates angiogenesis signaling. We show that SIRT1 is highly expressed in the vasculature during blood vessel growth, where it controls the angiogenic activity of endothelial cells. Loss of SIRT1 function blocks sprouting angiogenesis and branching morphogenesis of endothelial cells with consequent down-regulation of genes involved in blood vessel development and vascular remodeling. Disruption of SIRT1 gene expression in zebrafish and mice results in defective blood vessel formation and blunts ischemia-induced neovascularization. Through gain- and loss-of-function approaches, we show that SIRT1 associates with and deacetylates the forkhead transcription factor Foxo1, an essential negative regulator of blood vessel development to restrain its anti-angiogenic activity. These findings uncover a novel and unexpected role for SIRT1 as a critical modulator of endothelial gene expression governing postnatal vascular growth.

[Keywords: SIRT1; HDAC; endothelial cells; angiogenesis; Foxo]

Received March 28, 2007; revised version accepted August 23, 2007.

⁷ Corresponding author.

E-MAIL Dimmeler{at}em.uni-frankfurt.de; FAX 49-69-6301-7113.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.435107

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