title: Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis.
abstract: BACKGROUND
  Vascular endothelial cell growth factor plays a pivotal role in angiogenesis via regulating endothelial cell proliferation. The X-box binding protein 1 (XBP1) is believed to be a signal transducer in the endoplasmic reticulum stress response. It is unknown whether there is crosstalk between vascular endothelial cell growth factor signaling and XBP1 pathway.
  
  
  RESULTS
  We found that vascular endothelial cell growth factor induced the kinase insert domain receptor internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 α in the endoplasmic reticulum, leading to inositol requiring enzyme 1 α phosphorylation and XBP1 mRNA splicing, which was abolished by siRNA-mediated knockdown of kinase insert domain receptor. Spliced XBP1 regulated endothelial cell proliferation in a PI3K/Akt/GSK3β/β-catenin/E2F2-dependent manner and modulated the cell size increase in a PI3K/Akt/GSK3β/β-catenin/E2F2-independent manner. Knockdown of XBP1 or inositol requiring enzyme 1 α decreased endothelial cell proliferation via suppression of Akt/GSK3β phosphorylation, β-catenin nuclear translocation, and E2F2 expression. Endothelial cell-specific knockout of XBP1 (XBP1ecko) in mice retarded the retinal vasculogenesis in the first 2 postnatal weeks and impaired the angiogenesis triggered by ischemia. Reconstitution of XBP1 by Ad-XBP1s gene transfer significantly improved angiogenesis in ischemic tissue in XBP1ecko mice. Transplantation of bone marrow from wild-type o XBP1ecko mice could also slightly improve the foot blood reperfusion in ischemic XBP1ecko mice.
  
  
  CONCLUSIONS
  These results suggest that XBP1 can function via growth factor signaling pathways to regulate endothelial proliferation and angiogenesis.
authors.affiliation: Cardiovascular Division, King's College London, 125 Coldharbour Lane, London, UK. lingfang.zeng@kcl.ac.uk or
authors.forename: Lingfang
authors.initials: L
authors.lastname: Zeng
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Xiao
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: Andriana
authors.initials: A
authors.lastname: Margariti
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Ivetic
authors.forename: Heping
authors.initials: H
authors.lastname: Xu
authors.forename: Justin
authors.initials: J
authors.lastname: Mason
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Gillian
authors.initials: G
authors.lastname: Cockerill
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Julie Yi-shuan
authors.initials: JY
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004622:Embryo, Mammalian / Q000098:blood supply; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000503:physiopathology / Q000628:therapy; D007866:Leg / Q000098:blood supply; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012326:RNA Splicing / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011828:Radiation Chimera; D000071701:Regulatory Factor X Transcription Factors; D012171:Retinal Vessels / Q000187:drug effects / Q000254:growth & development; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2