1. Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy
- Author
-
Domigan, Courtney K, Warren, Carmen M, Antanesian, Vaspour, Happel, Katharina, Ziyad, Safiyyah, Lee, Sunyoung, Krall, Abigail, Duan, Lewei, Torres-Collado, Antoni X, Castellani, Lawrence W, Elashoff, David, Christofk, Heather R, van der Bliek, Alexander M, Potente, Michael, and Iruela-Arispe, M Luisa
- Subjects
Genetics ,Cardiovascular ,Aetiology ,Underpinning research ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Animals ,Apoptosis ,Autocrine Communication ,Autophagy ,Biomarkers ,Blotting ,Western ,Cell Differentiation ,Cell Proliferation ,Cells ,Cultured ,Endothelium ,Vascular ,Forkhead Box Protein O1 ,Forkhead Transcription Factors ,Gene Expression Profiling ,Humans ,Hypoxia ,Mice ,Mice ,Knockout ,Mitochondria ,Phosphorylation ,RNA ,Messenger ,Real-Time Polymerase Chain Reaction ,Reverse Transcriptase Polymerase Chain Reaction ,Signal Transduction ,Vascular Endothelial Growth Factor A ,Vascular biology ,FOXO1 ,Signal transduction ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - 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.
- Published
- 2015