PUBLICATION

ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1

Authors
Avraham-Davidi, I., Ely, Y., Pham, V.N., Castranova, D., Grunspan, M., Malkinson, G., Gibbs-Bar, L., Mayseless, O., Allmog, G., Lo, B., Warren, C.M., Chen, T.T., Ungos, J., Kidd, K., Shaw, K., Rogachev, I., Wan, W., Murphy, P.M., Farber, S.A., Carmel, L., Shelness, G.S., Iruela-Arispe, M.L., Weinstein, B.M., and Yaniv, K.
ID
ZDB-PUB-120516-11
Date
2012
Source
Nature medicine   18(6): 967-973 (Journal)
Registered Authors
Castranova, Dan, Ely, Yona, Farber, Steven, Kidd, Kameha, Lo, Brigid, Malkinson, Guy, Pham, Van, Ungos, Josette, Weinstein, Brant M., Yaniv, Karina
Keywords
none
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Apolipoprotein C-II/physiology
  • Apolipoproteins B/physiology*
  • Bacterial Proteins/genetics
  • Carrier Proteins/physiology
  • Cells, Cultured
  • Humans
  • Lipoproteins/physiology*
  • Lipoproteins, LDL/metabolism
  • Luminescent Proteins/genetics
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Neovascularization, Physiologic*
  • Vascular Endothelial Growth Factor Receptor-1/analysis
  • Vascular Endothelial Growth Factor Receptor-1/physiology*
  • Zebrafish
PubMed
22581286 Full text @ Nat. Med.
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.

Genes / Markers
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes