Abstract
EGFL7 is a secreted angiogenic factor, which in contrast to the well-known secreted angiogenic molecules VEGF and FGF-2, is almost exclusively expressed by endothelial cells and may act in an autocrine fashion. Prior studies have shown EGFL7 to mediate its angiogenic effects by interfering with the Notch pathway and/or via the intronic miR126. Less is known about its effects on VEGF signaling. We wanted to investigate the role of epidermal growth factor-like domain 7 (EGFL7) in VEGF-driven angiogenesis using an ex vivo Matrigel-embedded mouse eye cup assay and siRNA mediated knockdown of EGFL7 by siRNA. Our results suggested that VEGF-induced vascular tube formation was significantly impaired after siRNA downregulation of EGFL7. In addition, knockdown of EGFL7 suppressed VEGF upregulation of phospho-Akt and phospho-Erk(1/2) in endothelial cells, but did not alter VEGFR phosphorylation and neuropilin-1 protein expression or miR126 expression. Thus, in conclusion, EGFL7 is required for VEGF upregulation of the Akt/Erk (1/2) pathway during angiogenesis, and may represent a new therapeutic target in diseases of pathological neovascularization.
Highlights
Angiogenesis is an important biological process under physiological conditions, and in a variety of diseases including cancer, rheumatoid arthritis [1,2,3,4], age-related macular degeneration [5], diabetic retinopathy [6], retinal vein occlusion [7], and retinopathy of prematurity [8]
In unique contrast to the well-known secreted angiogenic molecules vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2, which are mainly produced by non-endothelial cells, epidermal growth factor-like domain 7 (EGFL7) is almost exclusively expressed by endothelial cells and may act in an autocrine fashion [16,17,18,19]
In zebrafish, morpholino antisense oligonucleotides targeting egfl7 resulted in vascular defects that were rescued by co-injection of egfl7 mRNA [18]; this indicates that EGFL7 has a defined function that is not being compensated by other genes [18]
Summary
Angiogenesis is an important biological process under physiological conditions, and in a variety of diseases including cancer, rheumatoid arthritis [1,2,3,4], age-related macular degeneration [5], diabetic retinopathy [6], retinal vein occlusion [7], and retinopathy of prematurity [8]. It is fundamental in many biological processes including development, reproduction and wound repair. Numerous inducers of angiogenesis have been identified, including the members of the vascular endothelial growth factor (VEGF) family, angiopoietins, transforming growth factors (TGFs), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF-a), interleukins, and members of the fibroblast growth factor (FGF) family [13,14]
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