%0 Journal Article
%A Manavski, Yosif
%A Carmona, Guillaume
%A Bennewitz, Katrin
%A Tang, Zhongshu
%A Zhang, Fan
%A Sakurai, Atsuko
%A Zeiher, Andreas M
%A Gutkind, J Silvio
%A Li, Xuri
%A Kroll, Jens
%A Dimmeler, Stefanie
%A Chavakis, Emmanouil
%T Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis.
%J Basic research in cardiology
%V 109
%N 2
%@ 0300-8428
%C Berlin
%I Springer65829
%M DKFZ-2017-04060
%P 404
%D 2014
%X 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.
%K Antigens, CD29 (NLM Chemicals)
%K Guanine Nucleotide Exchange Factors (NLM Chemicals)
%K IQSEC1 protein, human (NLM Chemicals)
%K Integrin alphaVbeta3 (NLM Chemicals)
%K Integrin beta3 (NLM Chemicals)
%K RNA, Small Interfering (NLM Chemicals)
%K Receptors, Vitronectin (NLM Chemicals)
%K VEGFA protein, human (NLM Chemicals)
%K Vascular Endothelial Growth Factor A (NLM Chemicals)
%K integrin alphavbeta1 (NLM Chemicals)
%K ADP-Ribosylation Factors (NLM Chemicals)
%K ADP-ribosylation factor 6 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:24522833
%R 10.1007/s00395-014-0404-2
%U https://inrepo02.dkfz.de/record/128038