TY  - JOUR
AU  - Manavski, Yosif
AU  - Carmona, Guillaume
AU  - Bennewitz, Katrin
AU  - Tang, Zhongshu
AU  - Zhang, Fan
AU  - Sakurai, Atsuko
AU  - Zeiher, Andreas M
AU  - Gutkind, J Silvio
AU  - Li, Xuri
AU  - Kroll, Jens
AU  - Dimmeler, Stefanie
AU  - Chavakis, Emmanouil
TI  - Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis.
JO  - Basic research in cardiology
VL  - 109
IS  - 2
SN  - 0300-8428
CY  - Berlin
PB  - Springer65829
M1  - DKFZ-2017-04060
SP  - 404
PY  - 2014
AB  - 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.
KW  - Antigens, CD29 (NLM Chemicals)
KW  - Guanine Nucleotide Exchange Factors (NLM Chemicals)
KW  - IQSEC1 protein, human (NLM Chemicals)
KW  - Integrin alphaVbeta3 (NLM Chemicals)
KW  - Integrin beta3 (NLM Chemicals)
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - Receptors, Vitronectin (NLM Chemicals)
KW  - VEGFA protein, human (NLM Chemicals)
KW  - Vascular Endothelial Growth Factor A (NLM Chemicals)
KW  - integrin alphavbeta1 (NLM Chemicals)
KW  - ADP-Ribosylation Factors (NLM Chemicals)
KW  - ADP-ribosylation factor 6 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24522833
DO  - DOI:10.1007/s00395-014-0404-2
UR  - https://inrepo02.dkfz.de/record/128038
ER  -