VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress

Evdoxia Karali; Sofia Bellou; Dimitris Stellas; Apostolos Klinakis; Carol Murphy; Theodore Fotsis

doi:10.1016/j.molcel.2014.03.022

VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress

Mol Cell. 2014 May 22;54(4):559-72. doi: 10.1016/j.molcel.2014.03.022. Epub 2014 Apr 17.

Authors

Evdoxia Karali¹, Sofia Bellou², Dimitris Stellas³, Apostolos Klinakis³, Carol Murphy⁴, Theodore Fotsis⁵

Affiliations

¹ 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.
² 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.
³ Department of Cancer Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
⁴ Division of Biomedical Research, Foundation of Research and Technology-Hellas, Institute of Molecular Biology and Biotechnology, University Campus, 45110 Ioannina, Greece.
⁵ 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.

PMID: 24746698
DOI: 10.1016/j.molcel.2014.03.022

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 6 / genetics
Activating Transcription Factor 6 / metabolism*
Animals
Cell Survival
Endoplasmic Reticulum Stress* / genetics
Endothelial Cells / physiology*
Gene Expression Regulation
HeLa Cells
Human Umbilical Vein Endothelial Cells
Humans
Male
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Inbred C57BL
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism
Neovascularization, Pathologic* / genetics
Neovascularization, Pathologic* / metabolism
Phospholipase C gamma / metabolism
Phosphorylation
Protein Unfolding
Signal Transduction / genetics
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism
Unfolded Protein Response* / genetics
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism*
eIF-2 Kinase / genetics
eIF-2 Kinase / metabolism*

Substances

Activating Transcription Factor 6
Multiprotein Complexes
Vascular Endothelial Growth Factor A
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
eIF-2 Kinase
Phospholipase C gamma