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Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization

Item Type:Article
Title:Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization
Creators Name:Potente, M. and Urbich, C. and Sasaki, K.I. and Hofmann, W.K. and Heeschen, C. and Aicher, A. and Kollipara, R. and DePinho, R.A. and Zeiher, A.M. and Dimmeler, S.
Abstract:Forkhead box O (Foxo) transcription factors are emerging as critical transcriptional integrators among pathways regulating differentiation, proliferation, and survival, yet the role of the distinct Foxo family members in angiogenic activity of endothelial cells and postnatal vessel formation has not been studied. Here, we show that Foxo1 and Foxo3a are the most abundant Foxo isoforms in mature endothelial cells and that overexpression of constitutively active Foxo1 or Foxo3a, but not Foxo4, significantly inhibits endothelial cell migration and tube formation in vitro. Silencing of either Foxo1 or Foxo3a gene expression led to a profound increase in the migratory and sprout-forming capacity of endothelial cells. Gene expression profiling showed that Foxo1 and Foxo3a specifically regulate a nonredundant but overlapping set of angiogenesis- and vascular remodeling-related genes. Whereas angiopoietin 2 (Ang2) was exclusively regulated by Foxo1, eNOS, which is essential for postnatal neovascularization, was regulated by Foxo1 and Foxo3a. Consistent with these findings, constitutively active Foxo1 and Foxo3a repressed eNOS protein expression and bound to the eNOS promoter. In vivo, Foxo3a deficiency increased eNOS expression and enhanced postnatal vessel formation and maturation. Thus, our data suggest an important role for Foxo transcription factors in the regulation of vessel formation in the adult.
Keywords:Cultured Cells, Endothelial Cells, Forkhead Box Protein O1, Forkhead Box Protein O3, Forkhead Transcription Factors, Gene Expression Profiling, Ischemia, Knockout Mice, Molecular Sequence Data, Nitric Oxide Synthase Type III, Oligonucleotide Array Sequence Analysis, Physiologic Neovascularization, Protein Isoforms, Small Interfering RNA, Vascular Endothelium, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:2382-2392
Date:1 September 2005
Official Publication:https://doi.org/10.1172/JCI23126
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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