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Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

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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.

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Acknowledgments

We thank Peggy Schuster and Carmen Janczyk for excellent technical assistance. We thank Dr. M. Vaughan (National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, U.S.A.) and Dr. A. Someya (Juntendo University, School of Medicine, Tokyo, Japan) for providing us Brag2 plasmids and Dr. J.E. Casanova (Department of Cell Biology, University of Virginia Health System, Charlottesville, VA, USA) for providing us Brag2 plasmids and the Brag2 antibody. Moreover, we thank Dr. Martin J. Humphries (Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK) for providing us the SNAKA51 antibody. In addition, we thank Dr. J.C. Norman (Beatson Institute for Cancer Research, Glasgow, Scotland, UK) for providing us the protocol for the biotinylation-based integrin internalization assay. This work was supported by DFG (Deutsche Forschungsgemeinschaft, Transregional Collaborative Research Centre SFB/TR23, Project A2 to E.C. and S.D., Project Z5 to J.K.) and by the Else Kröner-Fresenius-Stiftung (2013_A2 to E.C.). E.C. and S.D. are members of the Excellence Cluster Cardiopulmonary System (DFG; Exc147-1), the German Centre for Cardiovascular Research (BMBF) and the LOEWE Center for Gene and Cell Therapy (Hessen). Moreover, J.S.G., A.S., and F.Z. are supported by the Intramural Research Program of the NIH.

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The authors declare no competing financial interests.

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  1. Guillaume Carmona

    Present address: David H Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA, 02139-4307, USA

Authors and Affiliations

  1. Department of Internal Medicine III, Cardiology, Goethe University of Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Andreas M. Zeiher & Emmanouil Chavakis

  2. Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany

    Yosif Manavski, Guillaume Carmona, Stefanie Dimmeler & Emmanouil Chavakis

  3. Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Katrin Bennewitz & Jens Kroll

  4. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, People’s Republic of China

    Zhongshu Tang & Xuri Li

  5. NEI, National Institutes of Health, Bethesda, MD, USA

    Fan Zhang

  6. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    Atsuko Sakurai & J. Silvio Gutkind

  7. Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany

    Jens Kroll

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Correspondence to Emmanouil Chavakis.

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Y. Manavski and G. Carmona contributed equally.

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Manavski, Y., Carmona, G., Bennewitz, K. et al. Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis. Basic Res Cardiol 109, 404 (2014). https://doi.org/10.1007/s00395-014-0404-2

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