EGFL7 meets miRNA-126: an angiogenesis alliance

Abstract

Blood vessels form de novo through the tightly regulated programs of vasculogenesis and angiogenesis. Both processes are distinct but one of the steps they share is the formation of a central lumen, when groups of cells organized as vascular cords undergo complex changes to achieve a tube-like morphology. Recently, a protein termed epidermal growth factor-like domain 7 (EGFL7) was described as a novel endothelial cell-derived factor involved in the regulation of the spatial arrangement of cells during vascular tube assembly. With its impact on tubulogenesis and vessel shape EGFL7 joined the large family of molecules governing blood vessel formation. Only recently, the molecular mechanisms underlying EGFL7's effects have been started to be elucidated and shaping of the extracellular matrix (ECM) as well as Notch signaling might very well play a role in mediating its biological effects. Further, findings in knock-out animal models suggest miR-126, a miRNA located within the egfl7 gene, has a major role in vessel development by promoting VEGF signaling, angiogenesis and vascular integrity. This review summarizes our current knowledge on EGFL7 and miR-126 and we will discuss the implications of both bioactive molecules for the formation of blood vessels.

Autoregulation of glypican-1 by intronic microRNA-149 fine-tunes the angiogenic response to fibroblast growth factor in human endothelial cells

“…Other studies also indicate that intronic miRNAs can directly participate in the regulation of the expression of their host gene [e.g. the regulation of EGFL7 by its intronic miRNA miR-126 (Nikolic et al, 2010), and the regulation of ARPP-21 by miR-128b (Megraw et al, 2010)], providing negative feedback regulation (Lutter et al, 2010). By contrast, there are interesting examples that indicate that intronic miRNAs can also be transcribed from their own regulatory elements (e.g.…”

“…From the set of predicted targets, we selected FGFR1 and GPC1 for further analysis; the rationale for this selection was based on: (1) the well-established role of FGFR1 and its ligand FGF2 in EC angiogenesis (Gerwins et al, 2000;Presta et al, 2005), (2) the role of GPC1 as a low-affinity receptor for FGF (Zhang et al, 2001) that promotes FGF2 binding to its receptor (FGFR1), potentiating FGF signaling (Fico et al, 2011;Filmus et al, 2008;Gerwins et al, 2000;Iozzo and Sanderson, 2011;Presta et al, 2005;Qiao et al, 2003;Su et al, 2006), (3) the fact that GPC1 has been shown to modulate EC proliferation (Qiao et al, 2012;Qiao et al, 2003;Qiao et al, 2008), (4) the finding that FGFR1 regulation by miRNAs negatively controls EC angiogenic functions (Chamorro-Jorganes et al, 2011), (5) the fact that the regulation of host genes by their intronic miRNA has been shown to be biologically relevant (Nikolic et al, 2010) (Megraw et al, 2010), and (6) the finding that these genes showed a relatively high number of predicted binding sites for miR-149 and miR-149* in their 39 untranslated regions (39UTRs). Indeed, miRNA target algorithms found nine binding sites in the FGFR1 39UTR (three for miR-149 and six for miR-149*) and 12 binding sites in the GPC1 39UTR (four for miR-149 and eight for miR-149*) (supplementary material Fig.…”

EGFL7 ligates αvβ3 integrin to enhance vessel formation

“…This is an important finding because the vast majority of recent publications, with the exception of Nichol et al, 18 attributed the role of EGFL7 in angiogenesis to the microRNAs miR-126 and mir-126*, which deprived EGFL7 of its role in vessel formation. 25,26 Clearly, our work demonstrates that the EGFL7 protein regulates angiogenesis in vitro and in vivo and thus points toward a function of EGFL7 in blood vessel formation.…”

MicroRNA-126 Overexpression Inhibits Proliferation and Invasion in Osteosarcoma Cells

“…13 MicroRNA-126 is encoded by the intron 7 of egfl7 and regulates vascular functions and vascular integrity. 14 Previous studies reported that miRNA-126 is highly expressed in vascular tissues such as heart, liver, and lung, and reduced miRNA-126 expression is associated with tumor proliferation, invasion, and cancer progression. 14,15 Consistent with this, miRNA-126 is downregulated in nonsmall cell lung cancer and restoration of high miRNA-126 expression reduces tumor angiogenesis and suppresses tumor growth in lung cancers.…”

“…14 Previous studies reported that miRNA-126 is highly expressed in vascular tissues such as heart, liver, and lung, and reduced miRNA-126 expression is associated with tumor proliferation, invasion, and cancer progression. 14,15 Consistent with this, miRNA-126 is downregulated in nonsmall cell lung cancer and restoration of high miRNA-126 expression reduces tumor angiogenesis and suppresses tumor growth in lung cancers. 16 Although the influence of miRNA-126 has been reported by previous studies in several other types of cancers, the effects of miRNA-126 in development of OS remain largely unexplored, with its involvement suspected in few pathways, such as Sirt-1 and Sox-2, whose expression is likely regulated by miRNA-126 in OS.…”