title: Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy.
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.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90024, USA.
authors.forename: Courtney K
authors.initials: CK
authors.lastname: Domigan
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90024, USA.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Warren
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90024, USA.
authors.forename: Vaspour
authors.initials: V
authors.lastname: Antanesian
authors.affiliation: Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Happel
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90024, USA.
authors.forename: Safiyyah
authors.initials: S
authors.lastname: Ziyad
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90024, USA.
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Krall
authors.affiliation: Department of Medicine Statistics Core, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Lewei
authors.initials: L
authors.lastname: Duan
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90024, USA.
authors.forename: Antoni X
authors.initials: AX
authors.lastname: Torres-Collado
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA 90024, USA.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Castellani
authors.affiliation: Department of Medicine Statistics Core, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: David
authors.initials: D
authors.lastname: Elashoff
authors.affiliation: Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
authors.affiliation: Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90024, USA Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: van der Bliek
authors.affiliation: Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Potente
authors.affiliation: 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.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
mesh_terms: D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D015415:Biomarkers; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A
keywords: FOXO1; Signal transduction; Vascular biology