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J Cell Sci. 2015 Jun 15;128(12):2236-48. doi: 10.1242/jcs.163774. Epub 2015 May 8.

Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy.

Author information

1
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90024, USA.
2
Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
3
Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90024, USA.
4
Department of Medicine Statistics Core, University of California, Los Angeles, Los Angeles, CA 90024, USA.
5
Department of Medicine, University of California, Los Angeles, CA 90024, USA.
6
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90024, USA Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90024, USA.
7
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90024, USA Molecular Biology Institute, University of California, Los Angeles, CA 90024, USA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90024, USA arispe@mcdb.ucla.edu.

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 glucose metabolism, 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.

KEYWORDS:

FOXO1; Signal transduction; Vascular biology

PMID:
25956888
PMCID:
PMC4487014
DOI:
10.1242/jcs.163774
[Indexed for MEDLINE]
Free PMC Article

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