SIRT1 Controls Endothelial Angiogenic Functions During Vascular Growth

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2007 Oct 17

PMID 17938244

Citations 281

Authors

Michael Potente

Laleh Ghaeni

Danila Baldessari

Raul Mostoslavsky

Lothar Rossig

Franck Dequiedt

Judith Haendeler

Marina Mione

Elisabetta Dejana

Frederick W Alt

Andreas M Zeiher

Stefanie Dimmeler

Affiliations

Soon will be listed here.

Abstract

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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