title: Inhibition of the PI3K-Akt and mTORC1 signaling pathways promotes the elongation of vascular endothelial cells.
abstract: Endothelial cell morphology needs to be properly regulated during angiogenesis. Vascular endothelial growth factor (VEGF) induces endothelial cell elongation, which promotes sprouting of pre-existing vessels. However, therapeutic angiogenesis using VEGF has been hampered by side effects such as elevated vascular permeability. Here, we attempted to induce endothelial cell elongation without an overdose of VEGF. By screening a library of chemical inhibitors, we identified phosphatidylinositol 3-kinase (PI3K)-Akt pathway inhibitors and mammalian target of rapamycin complex 1 (mTORC1) inhibitors as potent inducers of endothelial cell elongation. The elongation required VEGF at a low concentration, which was insufficient to elicit the same effect by itself. The elongation also depended on Foxo1, a transcription factor indispensable for angiogenesis. Interestingly, the Foxo1 dependency of the elongation was overridden by inhibition of mTORC1, but not by PI3K-Akt, under stimulation by a high concentration of VEGF. Dual inhibition of mTORC1 and mTORC2 failed to induce cell elongation, revealing mTORC2 as a positive regulator of elongation. Our findings suggest that the PI3K-Akt-Foxo1 and mTORC1-mTORC2 pathways differentially regulate endothelial cell elongation, depending on the microenvironmental levels of VEGF.
authors.affiliation: Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan ktamura@kumamoto-u.ac.jp ogawamin@kumamoto-u.ac.jp.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Tsuji-Tamura
authors.affiliation: Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan ktamura@kumamoto-u.ac.jp ogawamin@kumamoto-u.ac.jp.
authors.forename: Minetaro
authors.initials: M
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D048429:Cell Size; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D046912:Multiprotein Complexes; D042461:Vascular Endothelial Growth Factor A; D058539:Phosphatidylinositol 3-Kinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt; Cell elongation; Embryonic stem cell; Endothelial cell; Foxo1; PI3K; mTOR