1. Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy.
- Author
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Domigan CK, Warren CM, Antanesian V, Happel K, Ziyad S, Lee S, Krall A, Duan L, Torres-Collado AX, Castellani LW, Elashoff D, Christofk HR, van der Bliek AM, Potente M, and Iruela-Arispe ML
- Subjects
- Animals, Blotting, Western, Cell Differentiation, Cell Proliferation, Cells, Cultured, Endothelium, Vascular metabolism, Forkhead Box Protein O1, Forkhead Transcription Factors genetics, Gene Expression Profiling, Humans, Hypoxia physiopathology, Mice, Mice, Knockout, Mitochondria metabolism, Phosphorylation, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Apoptosis, Autocrine Communication, Autophagy, Biomarkers metabolism, Endothelium, Vascular pathology, Forkhead Transcription Factors metabolism, Mitochondria pathology, Vascular Endothelial Growth Factor A physiology
- 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., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2015
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