EGFL7: a unique angiogenic signaling factor in vascular development and disease

Abstract

EGFL7 is a secreted angiogenic factor that is highly conserved in vertebrates. Most secreted angiogenic signaling molecules, including VEGF and fibroblast growth factor-2, are mainly expressed by non-endothelial cell types such as fibroblasts. In contrast, EGFL7 is unique because it is almost exclusively expressed by and acts on endothelial cells. Egfl7 expression is highest when the endothelium is in an active, proliferating state. This factor acts as a chemoattractant for endothelial cells and binds to components of the extracellular matrix. In vivo, Egfl7 is important for regulating tubulogenesis in zebrafish and for controlling vascular patterning and integrity in mice. Its function in blood vessel development is mediated, at least in part, through modulation of Notch signaling. In this review, we summarize the findings that support a role for Egfl7 in developmental and postnatal angiogenesis and describe the EGFL7-signaling pathways that underlie these processes. In addition, we discuss a potential role for EGFL7 in vascular repair and its possible use as a therapeutic target for treatment of hypoxia-induced injury. Finally, we consider EGFL7 action during tumorigenesis and its potential as an antiangiogenic agent.

Figure 1

Gene structure and protein organization of Egfl7. (A) The Egfl7 gene consists of 11 exons and a miRNA, miR126, embedded in the intronic region located downstream of exon 7. The protein is encoded in exons 3-10 (red boxes). (B) The EGFL7 protein sequence contains several putative protein domains, including a signal peptide (blue box), an EMI domain (yellow box), an EGF domain that contains a Delta-Serrate-LAG-2 (DSL) motif (orange box), and a Ca2⁺ binding EGF domain (red box).

Figure 2

Model depicting the role of EGFL7 in angiogenesis and stem cell behavior. (A-B) EGFL7 is a secreted protein that is expressed by endothelial cells, including the stalk and tip cells of sprouting vessels. Once secreted, EGFL7 binds to the ECM and shows overlapping expression with fibronectin and collagen type IV. (A) EGFL7 controls endothelial cell sprouting, migration, and proliferation. (B). EGFL7 also signals to the ECM and modulates its rigidity by inhibiting lysyl oxidase (LOX)–mediated conversion of tropoelastin into elastin. (C) EGFL7 promotes embryonic stem cell proliferation and inhibits proliferation of adult neuronal stem cells.

Figure 3

Model describing the putative role of EGFL7 in Notch signaling in different vascular beds. (A) EGFL7 signaling in the postnatal retina. EGFL7 antagonizes Notch/ligand interaction by either binding to the receptor or its corresponding ligand and inhibits target gene expression. (B) EGFL7 signaling in the embryo. EGFL7 indirectly enhances DLL4/Notch signaling by binding to Jagged1, preventing an interaction with the glycosylated Notch receptor, and promoting DLL4 interaction with Notch. ECD indicates extracellular domain; and NICD, Notch intracellular domain.