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

Inbal Avraham-Davidi, Yona Ely, Van N. Pham, Daniel Castranova, Moshe Grunspan, Guy Malkinson, Liron Gibbs-Bar, Oded Mayseless, Gabriella Allmog, Brigid Lo, Carmen M. Warren, Tom T. Chen, Josette Ungos, Kameha Kidd, Kenna Shaw, Ilana Rogachev, Wuzhou Wan, Philip M. Murphy, Steven A. Farber, Liran CarmelGregory S. Shelness, M. Luisa Iruela-Arispe, Brant M. Weinstein, Karina Yaniv*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)967-973
Number of pages7
JournalNature Medicine
Volume18
Issue number6
DOIs
StatePublished - Jun 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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