Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization.
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.
Potente
Michael
M
Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Frankfurt am Main, Germany.
Urbich
Carmen
C
Sasaki
Ken-ichiro
K
Hofmann
Wolf K
WK
Heeschen
Christopher
C
Aicher
Alexandra
A
Kollipara
Ramya
R
DePinho
Ronald A
RA
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III