Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy

Courtney K. Domigan, Carmen M. Warren, Vaspour Antanesian, Katharina Happel, Safiyyah Ziyad, Sunyoung Lee, Abigail Krall, Lewei Duan, Antoni X. Torres-Collado, Lawrence W. Castellani, David Elashoff, Heather R. Christofk, Alexander M. Van Der Bliek, Michael Potente, M. Luisa Iruela-Arispe*

*Corresponding author for this work

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Autocrine VEGF is necessary for endothelial survival, although the cellular mechanisms supporting this function are unknown. Here, we show that - even after full differentiation and maturation - continuous expression of VEGF by endothelial cells is needed to sustain vascular integrity and cellular viability. Depletion of VEGF from the endothelium results in mitochondria fragmentation and suppression of glucosemetabolism, leading to increased autophagy that contributes to cell death. Gene-expression profiling showed that endothelial VEGF contributes to the regulation of cell cycle and mitochondrial gene clusters, as well as several - but not all - targets of the transcription factor FOXO1. Indeed, VEGF-deficient endothelium in vitro and in vivo showed increased levels of FOXO1 protein in the nucleus and cytoplasm. Silencing of FOXO1 in VEGF-depleted cells reversed expression profiles of several of the gene clusters that were de-regulated in VEGF knockdown, and rescued both cell death and autophagy phenotypes. Our data suggest that endothelial VEGF maintains vascular homeostasis through regulation of FOXO1 levels, thereby ensuring physiological metabolism and endothelial cell survival.

Original languageEnglish (US)
Pages (from-to)2236-2248
Number of pages13
JournalJournal of cell science
Volume128
Issue number12
DOIs
StatePublished - Jun 1 2015

Keywords

  • FOXO1
  • Signal transduction
  • Vascular biology

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Domigan, C. K., Warren, C. M., Antanesian, V., Happel, K., Ziyad, S., Lee, S., Krall, A., Duan, L., Torres-Collado, A. X., Castellani, L. W., Elashoff, D., Christofk, H. R., Van Der Bliek, A. M., Potente, M., & Iruela-Arispe, M. L. (2015). Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy. Journal of cell science, 128(12), 2236-2248. https://doi.org/10.1242/jcs.163774