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¹ Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
² Department of Cardiovascular Surgery, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
³ Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 860-8555, Japan
⁴ Department of Liberal Arts and Sciences, Kagawa Prefectural College of Health Sciences, Kagawa 761-0123, Japan

Foxo1, a member of the Foxo subfamily of forkhead box transcription factors, is known to be essential for progression of normal vascular development in the mouse embryos. In the cultures of endothelial cells derived from embryonic stem cells, Foxo1-deficient endothelial cells exhibit an abnormal morphological response to vascular endothelial growth factor-A (VEGF-A), which is characterized by a lack of cell elongation, yet the molecular mechanisms governing endothelial cell morphology under angiogenic stimulation remain unknown. Here, we report that transforming growth actor-β also induces endothelial cell elongation in collaboration with Foxo1 and VEGF-A. Furthermore, tetracycline-regulated induction of Foxo3, another member of the Foxo subfamily, into Foxo1-null endothelial cells failed to restore abnormal morphological response to VEGF-A at an early differentiation stage. In contrast, Foxo1 and Foxo3 exerted the same function at a late differentiation stage, i.e. enhancement of VEGF responsiveness and promotion of cell elongation. Our results provide evidence that endothelial cell morphology is regulated by several mechanisms in which Foxo1 and Foxo3 express distinct functional properties depending on differentiation stages.

^* Correspondence: ogawamin{at}kumamoto-u.ac.jp