Abstract
Here we address the effect of Akt signaling on endothelial progenitor cells (EPCs). Human peripheral blood mononuclear cells (PBMCs) were cultured on fibronectin-coated dishes in EPC differentiation medium. PBMCs differentiated in a series of three steps: proliferation for foci formation, tight attachment to the dishes in the early stages of differentiation, and maturation in the late stages. In Western blot analysis, Akt expression was attenuated in the early stages of differentiation and was gradually upregulated during EPC maturation. Forkhead box−containing protein, class O 3a (FOXO3a), an Akt downstream target, was downregulated through phosphorylation in the late stages of EPC differentiation. Adenovirus-mediated overexpression of activated FOXO3a in PBMCs markedly increased the number of cell foci but reduced the number of DiI-acetyl LDL EPCs that appear at later time points. These data suggest that Akt/FOXO3a signaling is an important regulator of EPC maturation. (Hypertens Res 2008; 31: 153−159)
Similar content being viewed by others
Article PDF
References
Datta SR, Brunet A, Greenberg ME : Cellular survival: a play in three Akts. Genes Dev 1999; 13: 2905–2927.
Mogi M, Yang J, Lambert JF, et al : Akt signaling regulates side population cell phenotype via Bcrp1 translocation. J Biol Chem 2003; 278: 39068–39075.
Fujio Y, Guo K, Mano T, Mitsuuchi Y, Testa JR, Walsh K : Cell cycle withdrawal promotes myogenic induction of Akt, a positive modulator of myocyte survival. Mol Cell Biol 1999; 19: 5073–5082.
Rommel C, Clarke BA, Zimmermann S, et al : Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 1999; 286: 1738–1741.
Chen Y, Li X, Eswarakumar VP, Seger R, Lonai P : Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiation. Oncogene 2000; 19: 3750–3756.
Accili D, Arden KC : FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004; 117: 421–426.
Brunet A, Bonni A, Zigmond MJ, et al : Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857–868.
Birkenkamp KU, Coffer PJ : Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors. Biochem Soc Trans 2003; 31: 292–297.
Bakker WJ, Blazquez-Domingo M, Kolbus A, et al : FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1. J Cell Biol 2004; 164: 175–184.
Engstruöm M, Karlsson R, Jönsson JI : Inactivation of the forkhead transcription factor FoxO3 is essential for PKB-mediated survival of hematopoietic progenitor cells by kit ligand. Exp Hematol 2003; 31: 316–323.
Kashii Y, Uchida M, Kirito K, et al : A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase−Akt activation pathway in erythropoietin signal transduction. Blood 2000; 96: 941–949.
Furuyama T, Kitayama K, Shimoda Y, et al : Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem 2004; 279: 34741–34749.
Hosaka T, Biggs WH 3rd, Tieu D, et al : Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci U S A 2004; 101: 2975–2980.
Kalka C, Masuda H, Takahashi T, et al : Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A 2000; 97: 3422–3427.
Nagata D, Mogi M, Walsh K : AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J Biol Chem 2003; 278: 31000–31006.
Skurk C, Maatz H, Kim HS, et al : The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. J Biol Chem 2004; 279: 1513–1525.
Urbich C, Knau A, Fichtlscherer S, et al : FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J 2005; 19: 974–976.
Kim SJ, Cheon SH, Yoo SJ, et al : Contribution of the PI3K/Akt/PKB signal pathway to maintenance of self-renewal in human embryonic stem cells. FEBS Lett 2005; 579: 534–540.
Reya T, Duncan AW, Ailles L, et al : A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003; 423: 409–414.
Paling NR, Wheadon H, Bone HK, Welham MJ : Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase−dependent signaling. J Biol Chem 2004; 279: 48063–48070.
Potente M, Urbich C, Sasaki K, et al : Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 2005; 115: 2382–2392.
Garry DJ, Meeson A, Elterman J, et al : Myogenic stem cell function is impaired in mice lacking the forkhead/winged helix protein MNF. Proc Natl Acad Sci U S A 2000; 97: 5416–5421.
Winnier GE, Hargett L, Hogan BL : The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo. Genes Dev 1997; 11: 926–940.
Xuan S, Baptista CA, Balas G, Tao W, Soares VC, Lai E : Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres. Neuron 1995; 14: 1141–1152.
Freyaldenhoven BS, Freyaldenhoven MP, Iacovoni JS, Vogt PK : Aberrant cell growth induced by avian winged helix proteins. Cancer Res 1997; 57: 123–129.
Rumpold H, Wolf D, Koeck R, Gunsilius E : Endothelial progenitor cells: a source for therapeutic vasculogenesis? J Cell Mol Med 2004; 8: 509–518.
Grant MB, May WS, Caballero S, et al : Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat Med 2002; 8: 607–612.
Hill JM, Zalos G, Halcox JP, et al : Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593–600.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mogi, M., Walsh, K., Iwai, M. et al. Akt-FOXO3a Signaling Affects Human Endothelial Progenitor Cell Differentiation. Hypertens Res 31, 153–159 (2008). https://doi.org/10.1291/hypres.31.153
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.31.153
Keywords
This article is cited by
-
miR-150 regulates endothelial progenitor cell differentiation via Akt and promotes thrombus resolution
Stem Cell Research & Therapy (2020)