Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis
Author(s)
Manavski, Yosif; Carmona, Guillaume; Bennewitz, Katrin; Tang, Zhongshu; Zhang, Fan; Sakurai, Atsuko; Zeiher, Andreas M.; Gutkind, J. Silvio; Li, Xuri; Kroll, Jens; Dimmeler, Stefanie; Chavakis, Emmanouil; ... Show more Show less
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β1-Integrins are essential for angiogenesis. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor for the small Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and angiogenesis and the underlying molecular mechanisms remain unclear. siRNA-mediated Brag2-silencing reduced EC angiogenic sprouting and migration. Brag2-siRNA transfection differentially affected α5β1- and αVβ3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and adhesion on β1-integrin ligands (fibronectin and collagen), while reducing the adhesion on the αVβ3-integrin ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of α5β1-integrin, while reducing surface expression of αVβ3-integrin. Mechanistically, Brag2-mediated αVβ3-integrin-recycling and β1-integrin endocytosis and specifically of the active/matrix-bound α5β1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via β1-integrin endocytosis. Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, β1-integrin endocytosis and the regulation of FA. In vivo silencing of the Brag2-orthologues in zebrafish embryos using morpholinos perturbed vascular development. Furthermore, in vivo intravitreal injection of plasmids containing Brag2-shRNA reduced pathological ischemia-induced retinal and choroidal neovascularization. These data reveal that Brag2 is essential for developmental and pathological angiogenesis by promoting EC sprouting through regulation of adhesion by mediating β1-integrin internalization and link for the first time the process of β1-integrin endocytosis with angiogenesis.
Date issued
2014-02Department
Koch Institute for Integrative Cancer Research at MITJournal
Basic Research in Cardiology
Publisher
Springer-Verlag
Citation
Manavski, Yosif et al. “Brag2 Differentially Regulates β1- and β3-Integrin-Dependent Adhesion in Endothelial Cells and Is Involved in Developmental and Pathological Angiogenesis.” Basic Research in Cardiology, vol. 109, February 2014, pp. 1-19.
Version: Author's final manuscript
ISSN
0300-8428
1435-1803