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Blood, 8 January 2009, Vol. 113, No. 2, pp. 488-497. Prepublished online as a Blood First Edition Paper on September 19, 2008; DOI 10.1182/blood-2008-02-138438. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2008-02-138438v1 113/2/488    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Carmona, G. Articles by Chavakis, E. Search for Related Content PubMed PubMed Citation Articles by Carmona, G. Articles by Chavakis, E. Related Collections Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Role of the small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis Guillaume Carmona1, Stephan Göttig2, Alessia Orlandi1, Jürgen Scheele3, Tobias Bäuerle4, Manfred Jugold4, Fabian Kiessling4,5, Reinhard Henschler2, Andreas M. Zeiher1, Stefanie Dimmeler*,1, and Emmanouil Chavakis*,1 1 Molecular Cardiology, Department of Internal Medicine III, and 2 Deutsches Rotes Kreuz (DRK) Institute of Transfusion Medicine and Immune Hematology, J. W. Goethe University Frankfurt, Frankfurt; 3 Departments of Medicine I and Pharmacology I, University of Freiburg, Freiburg; 4 Junior Group Molecular Imaging, German Cancer Research Center, Heidelberg; and 5 Experimental Molecular Imaging, University of Aachen, Aachen, Germany Ras-associated protein 1 (Rap1), a small GTPase, attracted attention because of its involvement in several aspects of cell adhesion, including integrin- and cadherin-mediated adhesion. Yet, the role of Rap1 genes and of Rap1 effectors for angiogenesis has not been investigated. Human umbilical vein endothelial cells (HUVECs) express Rap1a and Rap1b mRNA. To determine the contribution of Rap1 activity for angiogenesis, we overexpressed Rap1GAP1, a GTPase-activating protein that inhibits Rap1 activity. Overexpression of Rap1GAP1 significantly blocked angiogenic sprouting and tube-forming activity of HUVECs as well as migration and integrin-dependent adhesion. Silencing of Rap1a, Rap1b, or both significantly blocked HUVECs sprouting under basal and basic fibroblast growth factor-stimulated conditions and reduced HUVEC migration and integrin-dependent adhesion. We found that Rap1a and Rap1b are essential for the conformational activation of β1-integrins in endothelial cells. Furthermore, silencing of Rap1a and Rap1b prevented phosphorylation of tyrosine 397 in focal adhesion kinase (FAK) and vascular endothelial growth factor-induced Akt1-activation. Rap1a–/–-deficient and Rap1a+/– heterozygote mice displayed reduced neovascularization after hind limb ischemia compared with wild-type mice. Silencing of RAPL significantly blocked the Rap1-induced sprouting of HUVECs, suggesting that the angiogenic activity of Rap1 is partly mediated by RAPL. Our data demonstrate a critical role of Rap1 in the regulation of β1-integrin affinity, adhesion, and migration in endothelial cells and in postnatal neovascularization. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Cao, X. Huang, Y. Han, Y. Wan, L. Birnbaumer, G.-S. Feng, J. Marshall, M. Jiang, and W.-M. Chu G{alpha}i1 and G{alpha}i3 Are Required for Epidermal Growth Factor-Mediated Activation of the Akt-mTORC1 Pathway Sci. Signal., April 28, 2009; 2(68): ra17 - ra17. [Abstract] [Full Text] [PDF] C. Ruiz de Almodovar, D. Lambrechts, M. Mazzone, and P. Carmeliet Role and Therapeutic Potential of VEGF in the Nervous System Physiol Rev, April 1, 2009; 89(2): 607 - 648. [Abstract] [Full Text] [PDF]

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