SIRT1 controls endothelial angiogenic functions during vascular growth

Genes and Development - Tập 21 Số 20 - Trang 2644-2658 - 2007
Michael Potente1, Laleh Ghaeni1, Danila Baldessari2, Raúl Mostoslavsky3, Lothar Rössig1, Franck Dequiedt4, Judith Haendeler1, Marina Mione2, Elisabetta Dejana5, Frederick W. Alt3, Andreas M. Zeiher1, Stefanie Dimmeler1
1Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, 60590 Frankfurt, Germany
2Zebrafish Group, FIRC (Fondazione Italiana per la Ricerca sul Cancro) Institute of Molecular Oncology Foundation, European Institute of Oncology (IFOM-IEO Campus), 20139 Milan, Italy;
3Howard Hughes Medical Institute, The Children's Hospital, CBR (Center for Blood Research) Institute for Biomedical Research, Harvard University Medical School, Boston 02115, USA;
4Université de Liège - ULiège > > Gembloux Agro-Bio Tech et GIGA-Research > > >
5IFOM-The FIRC Institute of Molecular Oncology, 20139 Milan, Italy

Tóm tắt

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.

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Genes and Development

Tập 21 Số 20

2644-2658

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