Apoliporotein L3 interferes with endothelial tube formation via regulation of ERK1/2, FAK and Akt signaling pathway. (December 2018)

• Record Type: Journal Article
• Authors: Khalil, Alia; Poelvoorde, Philippe; Fayyad-Kazan, Mohammad; Rousseau, Alexandre; Nuyens, Vincent; Uzureau, Sophie; Biston, Patrick; EL-Makhour, Yolla; Badran, Bassam; Van Antwerpen, Pierre; Boudjeltia, Karim Zouaoui; Vanhamme, Luc
• Is Part Of: Atherosclerosis. Volume 279(2018)
• Page Start: 73
• Page End: 87
• Publication Date: 2018-12
• Subjects: Apolipoprotein L -- Angiogenesis -- Endothelial cell -- Endothelial dysfunction -- Inflammation; APOL Apolipoprotein -- CRISPR Clustered Regularly Interspaced Short Palindromic Repeats -- CYR61 Cysteine Rich Angiogenic Inducer 61 -- EC Endothelial Cell -- ERK1/2 Extracellular signal-Regulated Kinase -- FGF Fibroblast Growth Factor -- FAK Focal Adhesion Kinase -- HES Hes Family BHLH Transcription Factor -- HEY Hairy-Related Transcription Factor -- HMEC Human Microvascular Endothelial Cells -- ID Inhibitor Of DNA Binding -- IER2 Immediate Early Response 2 -- IFN-γ Interferon gamma -- KO Knock Out -- LDL Low Density Lipoprotein -- MPO Myeloperoxidase -- MoxLDL Myeloperoxidase-modified LDL -- NRARP NOTCH-Regulated Ankyrin Repeat Protein -- Ox-LDL Oxidized Low Density Lipoprotein -- PDGF Platelet-Derived Growth Factor -- SNAI-1 Snail Family Transcriptional Repressor 1 -- VEGF Vascular Endothelial Growth Factor -- TNF-α Tumor Necrosis Factor alpha; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2018.10.023
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Endothelial cells are main actors in vascular homeostasis as they regulate vascular pressure and permeability as well as hemostasis and inflammation. Disturbed stimuli delivered to and by endothelial cells correlate with the so-called endothelial dysfunction and disrupt this homeostasis. As constituents of the inner layer of blood vessels, endothelial cells are also involved in angiogenesis. Apolipoprotein Ls (APOL) comprise a family of newly discovered apolipoproteins with yet poorly understood function, and are suggested to be involved in inflammatory processes and cell death mechanisms. Here we investigate the role of APOLs in endothelial cells stimulated with factors known to be involved in atherogenesis and their possible contribution to endothelial dysfunction with an emphasis on inflammation driven-angiogenesis in vitro . Methods: Using the CRISPR/Cas9 technique, we analyzed the effect of APOL3 gene knock out in HMEC-1 endothelial cells on cell migration, tubulogenesis, endothelial permeability, intracellular signal transduction as assessed by kinase phosphorylation, and angiogenesis gene expression (measured by qRT-PCR). Results: Our results indicate that among the family, APOL3 was the only member induced by myeloperoxidase, oxidized LDL, VEGF and FGF treatments. APOL3 invalidation increased endothelial permeability, reduced wound repair and tubule formation in vitro, the latter only in MPO and VEGF-induced conditions. Accordingly, some pro-angiogenic signaling pathways (ERK1/2 and FAK but not Akt) and some pro-angiogenic genes were partially inhibited in APOL3 knock out cells. Conclusions: These findings suggest the involvement of APOL3 in angiogenesis in vitro and as a modulator of MAPK and FAK signaling in endothelial cells. Graphical abstract: Image 1 Highlights: Members of the Apolipoprotein L family (APOL) are induced in endothelial cells by a variety of inflammatory stimuli. APOL3 is the only APOL commonly induced by atherogenic stimuli such as thrombin, MPO or oxidized LDL. APOL3 is also induced by angiogenic stimuli such as VEGF and FGF. APOL3 invalidation decreases tubulogenesis and endothelial wound repair. It increases endothelial permeability. APOL3 invalidation correlates with inhibition of pro-angiogenic pathways and reduces expression of pro-angiogenic genes.