MAGP‐1 and fibronectin control EGFL7 functions by driving its deposition into distinct endothelial extracellular matrix locations

Abstract

The extracellular matrix (ECM) is essential to provide mechanical support to tissues but is also a bioactive edifice which controls cell behavior. Cell signaling generated by ECM components through integrin‐mediated contacts, modulates cell biological activity. In addition, by sequestrating or releasing growth factors, the ECM is an active player of physiological and pathological processes such as vascular development. EGFL7 is mainly expressed during blood vessel development and is deposited in the ECM after secretion by endothelial cells. While EGFL7 is known to control various endothelial cell molecular mechanisms [i.e., the repression of endothelial‐derived lysyl oxidase (LOX) enzyme, the regulation of the Notch pathway, and the expression of leukocyte adhesion molecules and of RHOA by endothelial cells], it is not established whether EGFL7 functions when bound to the ECM. Here, we show that microfibrillar‐associated glycoprotein‐1 (MAGP‐1) and fibronectin drive the deposition of EGFL7 into both fibers and individual aggregates in endothelial ECM. Although EGFL7 does not need to be docked into the ECM to control endothelial adhesion molecule expression, the ECM accumulation of EGFL7 is required for its regulation of LOX activity and of HEY2 expression along the Notch pathway. The interaction of EGFL7 with MAGP‐1 is necessary for LOX activity repression by EGFL7 while it does not participate in the control of the Notch pathway by this protein. Altogether, this study highlights the roles played by EGFL7 in controlling various endothelial molecular mechanisms upon its localization and shows how the ECM can modulate its functions.

Spatiotemporal single-cell RNA sequencing of developing chicken hearts identifies interplay between cellular differentiation and morphogenesis

“…2b). Interestingly, these C3 cells expressed high levels of extracellular matrix transcripts implicated in cell migration, including fibronectin (FN1), periostin (POSTN), epidermal growth factor-like domain multiple 7 (EGFL7) 17,18 , and agrin (AGRN) [19][20][21][22] ( Supplementary Fig. 3b, Supplementary Fig.…”

Molecular structure and function of microfibrillar‐associated proteins in skeletal and metabolic disorders and cancers

“…Interestingly, MFAP2 deficient mice exhibited progressive osteopenia, accompanied by increased osteoclast formation and elevated receptor activator of NF-kB ligand (RANKL) expression (Craft et al, 2012). In line with this, mice with conditional knockout of MFAP2 was found to promote the deposition of EGFL7 into fibres in endothelial ECM, which is important for vascular development (Villain et al, 2018).…”

Identification of the growth factor–binding sequence in the extracellular matrix protein MAGP-1

“…Fibrillin-containing microfibrils are particularly important in modulating TGF␤ signaling and the mechanisms whereby microfibril-associated proteins regulate growth factor availability and activity are complex. We and others have shown that the fibrillin-binding partners MAGP-1 and MAGP-2 work together with fibrillin to modulate TGF␤ availability in the ECM (16,(27)(28)(29). Mutations in MAGP genes lead to phenotypes in mice and humans that are associated with abnormal growth factor signaling (15, 16, 18, 30 -33).…”