Basic research in cardiology, 2014-03, Vol.109 (2), p.404-404, Article 404
2014
Details
- Autor(en) / Beteiligte
- Titel
- Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis
- Ist Teil von
- Basic research in cardiology, 2014-03, Vol.109 (2), p.404-404, Article 404
- Ort / Verlag
- Berlin/Heidelberg: Springer Berlin Heidelberg
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Quelle
- SpringerNature Journals
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0300-8428eISSN: 1435-1803DOI: 10.1007/s00395-014-0404-2Titel-ID: cdi_proquest_miscellaneous_1499146390
- Format
- –
- Schlagworte
- ADP-Ribosylation Factors - metabolism, Animals, Animals, Genetically Modified, Cardiology, Cell Adhesion - physiology, Cell Movement - physiology, Cercopithecus aethiops, Choroidal Neovascularization - genetics, Choroidal Neovascularization - metabolism, Choroidal Neovascularization - physiopathology, COS Cells, Disease Models, Animal, Guanine Nucleotide Exchange Factors - genetics, Guanine Nucleotide Exchange Factors - metabolism, Human Umbilical Vein Endothelial Cells, Humans, Integrin alphaVbeta3 - genetics, Integrin alphaVbeta3 - metabolism, Integrin beta1 - metabolism, Integrin beta3 - metabolism, Medicine, Medicine & Public Health, Mice, Inbred C57BL, Neovascularization, Pathologic - genetics, Neovascularization, Pathologic - metabolism, Neovascularization, Pathologic - physiopathology, Neovascularization, Physiologic - genetics, Neovascularization, Physiologic - physiology, Original Contribution, Receptors, Vitronectin - genetics, Receptors, Vitronectin - metabolism, Retinopathy of Prematurity - genetics, Retinopathy of Prematurity - metabolism, Retinopathy of Prematurity - physiopathology, RNA, Small Interfering - genetics, Vascular Endothelial Growth Factor A - metabolism, Zebrafish