Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis
Name
395_2014_Article_404.pdf
Size
4.99 MB
Format
Adobe PDF
Checksum (MD5)
d7004af483ca80f8f3d8914f18be7a0b
Author(s)
Manavski, Yosif
Carmona, Guillaume
Bennewitz, Katrin
Tang, Zhongshu
Zhang, Fan
Sakurai, Atsuko
Zeiher, Andreas M.
Gutkind, J. Silvio
Li, Xuri
Kroll, Jens
Date Issued
February 2014
Journal
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
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1007/s00395-014-0404-2
