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.

Regulation of β1 Integrin-Klf2-Mediated Angiogenesis by CCM Proteins

“…Within the ccm2 m201 mutant vasculature, the lateral dorsal aortas (LDAs) exhibited significant increases in EC numbers at 48 hrpf, providing evidence for increased angiogenesis signaling (Figures 2D,2E,and 2J). Similarly, within the trunk region region of ccm2 m201 mutants, the subintestinal vein (SIV) exhibited a higher density of vessel branch points, which is another established marker for increased angiogenesis (Figures 2G, 2H, and 2K;Yu et al, 2010;Avraham-Davidi et al, 2012;Ghajar et al, 2013).…”

Antagonistic Function of the RNA-binding Protein HuR and miR-200b in Post-transcriptional Regulation of Vascular Endothelial Growth Factor-A Expression and Angiogenesis

“…Alkaline Phosphatase Staining Assay-In situ detection of zebrafish vessels was done using the staining method described (39).…”

Development of an ImageJ-based method for analysing the developing zebrafish vasculature

“…In order to compare this ImageJ based method with commonly used analyses of zebrafish vessel development we scored ISV connectivity, a method used in many studies [4][5][6][7]18]. Thus each ISV was examined to determine if it had reached and connected with the DLAV, and the percentage of connected vessels calculated for each embryo.…”

“…Typically researchers focus on the growth of intersegmental vessels (ISVs) and the formation of the dorsal longitudinal anastomotic vessel (DLAV) in zebrafish, as the ISVs represent the first angiogenic vessels formed in this organism [ 1]. The majority of ISV analysis methods involve manually scoring images of zebrafish embryos, typically counting the number of normal ISVs formed [4][5][6] or determining the percentage of embryos with defective ISVs [ 7]. These methods are laborious and reflect the difficulties associated with analysing complex images of whole organisms.…”