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

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.

SUBMITTER: Avraham-Davidi I

PROVIDER: S-EPMC3959651 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Avraham-Davidi Inbal I Ely Yona Y Pham Van N VN Castranova Daniel D Grunspan Moshe M Malkinson Guy G Gibbs-Bar Liron L Mayseless Oded O Allmog Gabriella G Lo Brigid B Warren Carmen M CM Chen Tom T TT Ungos Josette J Kidd Kameha K Shaw Kenna K Rogachev Ilana I Wan Wuzhou W Murphy Philip M PM Farber Steven A SA Carmel Liran L Shelness Gregory S GS Iruela-Arispe M Luisa ML Weinstein Brant M BM Yaniv Karina K

Nature medicine 20120601 6

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 ...[more]

PMID: 22581286

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Project description:ObjectiveDyslipidemia is implicated in abdominal aortic aneurysms (AAAs) in humans and angiotensin (Ang) II-infused mice. This study determined effects of major lipoprotein classes on AngII-induced AAAs using multiple mouse strains with dietary and pharmacological manipulations.Approach and resultsWestern diet had minor effects on plasma cholesterol concentrations and the low incidence of AngII-induced AAAs in C57BL/6J mice. Low incidence of AAAs in this strain was not attributed to protection from high-density lipoprotein, because apolipoprotein (apo) AI deficiency did not increase AngII-induced AAAs. ApoAI deletion also failed to alter AAA occurrence in hypercholesterolemic mice. Low-density lipoprotein receptor-/- mice fed normal diet had low incidence of AngII-induced AAAs. Western diet feeding of this strain provoked pronounced hypercholesterolemia because of increased apoB-containing lipoproteins with attendant increases of atherosclerosis in both sexes, but AAAs only in male mice. ApoE-deficient mice fed normal diet were modestly hypercholesterolemic, whereas this strain fed Western diet was severely hypercholesterolemic because of increased apoB-containing lipoprotein concentrations. The latter augmented atherosclerosis, but did not change the high incidence of AAAs in this strain. To determine whether reductions in apoB-containing lipoproteins influenced AngII-induced AAAs, ezetimibe was administered at a dose that partially reduced plasma cholesterol concentrations to ApoE-deficient mice fed Western diet. This decreased atherosclerosis, but not AAAs. This ezetimibe dose in ApoE-deficient mice fed normal diet significantly decreased plasma apoB-containing lipoprotein concentrations and reduced AngII-induced AAAs.ConclusionsApoB-containing lipoproteins contribute to augmentation of AngII-induced AAA in male mice. However, unlike atherosclerosis, AAA occurrence was not correlated with increases in plasma apoB-containing lipoprotein concentrations.

Dataset Information

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

Publications

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

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