title: ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1.
abstract: Despite the clear major contribution of hyperlipidemia to the prevalence of cardiovascular disease in the developed world, the direct effects of lipoproteins on endothelial cells have remained obscure and are under debate. Here we report a previously uncharacterized mechanism of vessel growth modulation by lipoprotein availability. Using a genetic screen for vascular defects in zebrafish, we initially identified a mutation, stalactite (stl), in the gene encoding microsomal triglyceride transfer protein (mtp), which is involved in the biosynthesis of apolipoprotein B (ApoB)-containing lipoproteins. By manipulating lipoprotein concentrations in zebrafish, we found that ApoB negatively regulates angiogenesis and that it is the ApoB protein particle, rather than lipid moieties within ApoB-containing lipoproteins, that is primarily responsible for this effect. Mechanistically, we identified downregulation of vascular endothelial growth factor receptor 1 (VEGFR1), which acts as a decoy receptor for VEGF, as a key mediator of the endothelial response to lipoproteins, and we observed VEGFR1 downregulation in hyperlipidemic mice. These findings may open new avenues for the treatment of lipoprotein-related vascular disorders.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Avraham-Davidi
authors.forename: Yona
authors.initials: Y
authors.lastname: Ely
authors.forename: Van N
authors.initials: VN
authors.lastname: Pham
authors.forename: Daniel
authors.initials: D
authors.lastname: Castranova
authors.forename: Moshe
authors.initials: M
authors.lastname: Grunspan
authors.forename: Guy
authors.initials: G
authors.lastname: Malkinson
authors.forename: Liron
authors.initials: L
authors.lastname: Gibbs-Bar
authors.forename: Oded
authors.initials: O
authors.lastname: Mayseless
authors.forename: Gabriella
authors.initials: G
authors.lastname: Allmog
authors.forename: Brigid
authors.initials: B
authors.lastname: Lo
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Warren
authors.forename: Tom T
authors.initials: TT
authors.lastname: Chen
authors.forename: Josette
authors.initials: J
authors.lastname: Ungos
authors.forename: Kameha
authors.initials: K
authors.lastname: Kidd
authors.forename: Kenna
authors.initials: K
authors.lastname: Shaw
authors.forename: Ilana
authors.initials: I
authors.lastname: Rogachev
authors.forename: Wuzhou
authors.initials: W
authors.lastname: Wan
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
authors.forename: Steven A
authors.initials: SA
authors.lastname: Farber
authors.forename: Liran
authors.initials: L
authors.lastname: Carmel
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Shelness
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
authors.forename: Brant M
authors.initials: BM
authors.lastname: Weinstein
authors.forename: Karina
authors.initials: K
authors.lastname: Yaniv
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053304:Apolipoprotein C-II / Q000502:physiology; D001055:Apolipoproteins B / Q000502:physiology*; D001426:Bacterial Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D008074:Lipoproteins / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis / Q000502:physiology*; D015027:Zebrafish
chemical_list: D053304:Apolipoprotein C-II; D001055:Apolipoproteins B; D001426:Bacterial Proteins; D002352:Carrier Proteins; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D008164:Luminescent Proteins; C106092:microsomal triglyceride transfer protein; C054562:yellow fluorescent protein, Bacteria; D040281:Vascular Endothelial Growth Factor Receptor-1