Abstract 286: Sirt1 Controls Endothelial Angiogenic Functions During Vascular Growth And Maturation
The NAD-dependent histone deacetylase Sir2 regulates organismal lifespan in various species. Mammalian homologues of Sir2, the sirtuins (SIRTs), have been shown to play a critical role in the regulation of several essential physiological processes, however, no information is available on a putative role of SIRTs for vascular homeostasis. Here, we demonstrate that uniquely among the seven SIRT proteins, SIRT1 plays a key role in angiogenesis signaling. SIRT1 is highly expressed in the vascular endothelium during blood vessel growth, where it controls the angiogenic activity of endothelial cells. Loss of SIRT1 function by either siRNA-mediated gene silencing or Cre-mediated excision of a floxed SIRT1 allele blocks sprouting angiogenesis (935±39um vs. 202±58um) and branching morphogenesis (12059±487 um vs. 4278±1221 um) of endothelial cells in vitro. The anti-angiogenic effect of SIRT1 gene silencing is unlikely the consequence of excessive cell death or increased cell cycle arrest, since knock down of SIRT1 has only a minor effect on apoptosis and cell cycle progression. Consistent with these data, disruption of SIRT1 gene expression in zebrafish and mice results in defective vascular growth and maturation. More importantly, conditional deletion of SIRT1 specifically in the endothelial lineage (Tie2Cretg;SIRT1flox/−) blunts ischemia-induced neovascularization indicating that the angiogenic processes during vascular growth are exquisitely sensitive to the proper function of SIRT1. Microarray analysis revealed that loss of SIRT1 expression leads to the dysregulation of genes involved in vascular differentiation and remodeling such as Fli1, Flt1, Hex or MMP14. SIRT1 binds, deacetylates and represses the transcriptional activity of the forkhead transcription factor Foxo1, an essential negative regulator of blood vessel development. Knock down of Foxo1 partially rescued the inhibitory effects of SIRT1 gene silencing on sprout formation suggesting that SIRT1 regulates endothelial angiogenic functions, at least in part, by restraining the anti-angiogenic activity of Foxo1. These findings uncover a novel and unexpected role for SIRT1 as a critical modulator of endothelial gene expression governing vascular growth and maturation.