Fibulin‐5‐integrin binding and vessel development

Abstract

Fibulin‐5 is an ECM protein highly expressed in large arteries during development and is essential for elastic fiber formation. Fibulin‐5 functions as an adaptor protein by binding to tropoelastin, cross‐linking enzymes, and microfibrilar scaffold during elastic fiber assembly. Fibulin‐5 also functions as an inhibitory matrix for proliferation and migration of vascular SMCs. To examine the significance of integrin‐binding of fibulin‐5 in vascular development, we generated a mutant mouse that expresses fibulin‐5 (RGE) by knock‐in strategy. Fbln5RGE/RGE mice were viable and no abnormality was observed in elastogenic tissues, indicating that fibulin‐5‐integrin binding was not essential for elastic fiber formation. Recently, it was reported that fibulin‐5 competes with fibronectin in binding to alpha4beta1 and alpha5beta1 integrins in an RGD‐dependent manner, but does not activate integrin downstream signaling. We found that the level of reactive oxygen species (ROS) was significantly up‐regulated in response to fibronectin in Fbln5‐/‐ and Fbln5RGE/RGE mouse embryonic fibroblasts. In addition, increased periendothelial ROS production in mutant mice resulted in a paradoxical reduction of angiogenesis in tumor bearing tissues. These findings highlight the non‐elastogenic role of fibulin‐5 mediated by integrin binding in the vessel wall.