ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1
| Autor: | 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, Inbal Avraham-Davidi |
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| Rok vydání: | 2012 |
| Předmět: |
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 |
| Zdroj: | Nature Medicine. 18:967-973 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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