TY - JOUR
T1 - ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1
AU - Yaniv, Karina
AU - Avraham-Davidi, Inbal
AU - Ely, Yona
AU - Pham, Van N.
AU - Castranova, Daniel
AU - Grunspan, Moshe
AU - Malkinson, Guy
AU - Gibbs-Bar, Liron
AU - Mayseless, Oded
AU - Allmog, Gabriella
AU - Lo, Brigid
AU - Warren, Carmen M.
AU - Chen, Tom T.
AU - Ungos, Josette
AU - Kidd, Kameha
AU - Shaw, Kenna
AU - Rogachev, Ilana
AU - Wan, Wuzhou
AU - Murphy, Philip M.
AU - Farber, Steven A.
AU - Carmel, Liran
AU - Shelness, Gregory S.
AU - Iruela-Arispe, M. Luisa
AU - Weinstein, Brant M.
N1 - Israel Science Foundation [748/2009]; Marie Curie Actions-International Reintegration [FP7-PEOPLE-2009-RG 256393]; Yeda-Sela Center; Israel Cancer Research Foundation; US National Institutes of Health (NIH) [RO1CA126935]; NIH [T32HL069766, HL049373, R56DK093399, R01GM063904]; Carnegie Institution for Science endowment; G. Harold and Leila Y. Mathers Charitable Foundation; National Institute of Child Health and Human Development, NIH,; Foundation Leducq
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862005373&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/nm.2759
DO - https://doi.org/10.1038/nm.2759
M3 - مقالة
C2 - 22581286
SN - 1078-8956
VL - 18
SP - 967
EP - 973
JO - Nature Medicine
JF - Nature Medicine
IS - 6
ER -
