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.

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
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • eIF-2 Kinase
  • Phospholipase C gamma