title: VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress.
abstract: Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates IRE1α, ATF6, and PERK cascades, leading to a transcriptional/translational response known as unfolded protein response (UPR). Here we show that VEGF activates UPR mediators through a PLCγ-mediated crosstalk with the mTORC1 complex without accumulation of unfolded proteins in the ER. Activation of ATF6 and PERK contributes to the survival effect of VEGF on endothelial cells (ECs) by positively regulating mTORC2-mediated phosphorylation of AKT on Ser473, which is required for full activity of AKT. Low levels of CHOP allow ECs to evade the proapoptotic effect of this UPR product. Depletion of PLCγ, ATF6, or eIF2α dramatically inhibited VEGF-induced vascularization in mouse Matrigel plugs, suggesting that the ER and the UPR machinery constitute components of the VEGF signaling circuit that regulates EC survival and angiogenesis, extending their role beyond adaptation to ER stress.
authors.affiliation: Division of Biomedical Research, Foundation of Research and Technology-Hellas, Institute of Molecular Biology and Biotechnology, University Campus, 45110 Ioannina, Greece; Laboratory of Biological Chemistry, Medical School, University of Ioannina, 45110 Ioannina, Greece.
authors.forename: Evdoxia
authors.initials: E
authors.lastname: Karali
authors.affiliation: Department of Informatics and Telecommunications Engineering, University of Western Macedonia, 50100 Kozani, Greece; Division of Biomedical Research, Foundation of Research and Technology-Hellas, Institute of Molecular Biology and Biotechnology, University Campus, 45110 Ioannina, Greece.
authors.forename: Sofia
authors.initials: S
authors.lastname: Bellou
authors.affiliation: Department of Cancer Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Stellas
authors.affiliation: Department of Cancer Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
authors.affiliation: Division of Biomedical Research, Foundation of Research and Technology-Hellas, Institute of Molecular Biology and Biotechnology, University Campus, 45110 Ioannina, Greece.
authors.forename: Carol
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Division of Biomedical Research, Foundation of Research and Technology-Hellas, Institute of Molecular Biology and Biotechnology, University Campus, 45110 Ioannina, Greece; Laboratory of Biological Chemistry, Medical School, University of Ioannina, 45110 Ioannina, Greece. Electronic address: thfotsis@uoi.gr.
authors.forename: Theodore
authors.initials: T
authors.lastname: Fotsis
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D058767:Protein Unfolding; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D051702:Activating Transcription Factor 6; D046912:Multiprotein Complexes; D042461:Vascular Endothelial Growth Factor A; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase; D051966:Phospholipase C gamma