1. ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1
- Author
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Liron Gibbs-Bar, Gregory S. Shelness, Ilana Rogachev, Daniel Castranova, Liran Carmel, Kenna Shaw, Josette Ungos, Moshe Grunspan, Van N. Pham, Tom T. Chen, Oded Mayseless, Yona Ely, Steven A. Farber, Philip M. Murphy, Carmen M. Warren, Brant M. Weinstein, Wuzhou Wan, Guy Malkinson, Gabriella Allmog, Kameha R. Kidd, M. Luisa Iruela-Arispe, Karina Yaniv, Brigid D. Lo, and Inbal Avraham-Davidi
- Subjects
medicine.medical_specialty ,Apolipoprotein B ,Angiogenesis ,Lipoproteins ,Apolipoprotein C-II ,Molecular Sequence Data ,Neovascularization, Physiologic ,Article ,General Biochemistry, Genetics and Molecular Biology ,Microsomal triglyceride transfer protein ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Bacterial Proteins ,Downregulation and upregulation ,Internal medicine ,Hyperlipidemia ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Receptor ,Cells, Cultured ,Zebrafish ,Apolipoproteins B ,030304 developmental biology ,0303 health sciences ,Vascular Endothelial Growth Factor Receptor-1 ,biology ,General Medicine ,medicine.disease ,3. Good health ,Lipoproteins, LDL ,Mice, Inbred C57BL ,Luminescent Proteins ,Endocrinology ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Carrier Proteins ,030217 neurology & neurosurgery ,Lipoprotein - 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.
- Published
- 2012