Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas
- 306 Downloads
Forkhead box protein O1 (FoxO1) is a transcription factor and a critical regulator of angiogenesis. Various environmental stimuli, including growth factors, nutrients, shear stress, oxidative stress and hypoxia, affect FoxO1 subcellular localization and strongly influence its transcriptional activity; however, FoxO1-localization patterns in endothelial cells (ECs) during development have not been clarified in vivo. Here, we reported that FoxO1 expression was observed in three layers of angiogenic vessels in developing mouse retinas and that among these layers, the front layer showed high levels of FoxO1 expression in the nuclei of most tip ECs. Because tip ECs migrate toward the avascular hypoxic area, we focused on hypoxia as a major stimulus regulating FoxO1 subcellular localization in tip cells. In cultured ECs, FoxO1 accumulated into the nucleus under hypoxic conditions, with hypoxia also inducing expression of tip-cell-specific genes, including endothelial-specific molecule 1 (ESM1), which was suppressed by FoxO1 knockdown. Additionally, in murine models, EC-specific FoxO1 deletion resulted in reduced ESM1 expression and suppressed tip-cell migration during angiogenesis. These findings indicated roles for FoxO1 in tip-cell migration and that its transcriptional activity is regulated by hypoxia.
KeywordsTip-cell Migration Hypoxia Forkhead transcription factor ESM1 Mouse retina
We thank Dr. Bernd Arnold for Tie2CreER T 2mice and Manabu Sakai for helpful discussion.
- 9.Suchting S, Freitas C, le Noble F, Benedito R, Breant C, Duarte A et al (2007) The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA 104:3225–3230. https://doi.org/10.1073/pnas.0611177104 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Biggs WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC (1999) Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA 96:7421–7426. https://doi.org/10.1073/pnas.96.13.7421 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Abid R, Guo SD, Minami T, Spokes KC, Ueki K, Skurk C et al (2004) Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol 24:294–300. https://doi.org/10.1161/01.atv.0000110502.10593.06 CrossRefPubMedGoogle Scholar
- 22.Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD et al (2007) Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 104:3219–3224. https://doi.org/10.1073/pnas.0611206104 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Shin JW, Huggenberger R, Detmar M (2008) Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis. Blood 112:2318–2326. https://doi.org/10.1182/blood-2008-05-156331 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Bechard D, Gentina T, Delehedde M, Scherpereel A, Lyon M, Aumercier M et al (2001) Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem 276:48341–48349. https://doi.org/10.1074/jbc.M108395200 CrossRefPubMedGoogle Scholar