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

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. EGFL7 is a secreted protein mainly expressed by endothelial cells during angiogenesis and deposited in the extracellular matrix (ECM) through poorly understood molecular mechanisms. We report that EGFL7 is deposited either in thick fibers associated with microfibrillar‐associated glycoprotein‐1 (MAGP‐1) or as aggregates through its interaction with fibronectin in the human umbilical vein endothelial cells ECM. EGFL7 regulates lysyl oxidase activity when associated with MAGP‐1; it must be deposited in the ECM to partially control the Notch pathway, while it represses endothelial cell activation independently of its accumulation in the ECM.