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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.
 Previous Article | Next Article 
Submitted February 8, 2008
Accepted August 7, 2008
Role of the small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis
Guillaume Carmona, Stephan Gottig, Alessia Orlandi, Jurgen Scheele, Tobias Bauerle, Manfred Jugold, Fabian Kiessling, Reinhard Henschler, Andreas M. Zeiher, Stefanie Dimmeler, and Emmanouil Chavakis*
Molecular Cardiology, J. W. Goethe University Frankfurt, Frankfurt, Germany
DRK Institute of Transfusion Medicine and Immune Hematology, J. W. Goethe University Frankfurt, Frankfurt, Germany
Departments of Medicine I and Pharmacology I, University of Freiburg, Freiburg, Germany
Junior Group Molecular Imaging, German Cancer Research Center, Heidelberg, Germany
Experimental Molecular Imaging, University of Aachen (RWTH), Aachen, Germany
* Corresponding author; email: chavakis{at}em.uni-frankfurt.de.
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 so far. HUVEC express Rap1a and Rap1b mRNA. In order to determine the contribution of Rap1 activity for angiogenesis, we overexpressed Rap1GAP1, a GTPase activating protein, which specifically inhibits Rap1 activity. Overexpression of Rap1GAP1 significantly blocked the angiogenic sprouting and the tube forming activity of HUVEC as well as migration and integrin-dependent adhesion. Additionally, silencing of either Rap1a, Rap1b or both significantly blocked HUVEC sprouting under basal and bFGF-stimulated conditions and reduced HUVEC migration and integrin-dependent adhesion. In line with these results, we found that Rap1a and Rap1b are essential for the conformational activation of  1-integrins in endothelial cells. Furthermore, silencing of Rap1a and Rap1b prevented the phosphorylation of tyrosine 397 in FAK and the VEGF-induced Akt1-activation. Rap1a-/--deficient and Rap1a+/- heterozygote mice displayed reduced neovascularization after hind limb ischemia in comparison to wild-type mice. Moreover, silencing of RAPL significantly blocked the Rap1-induced sprouting of HUVEC suggesting that the angiogenic activity of Rap1 is partly mediated by RAPL. Thus, our data demonstrate a critical role of Rap1 in the regulation of 1-integrin affinity, adhesion and migration in endothelial cells and in postnatal neovascularization.
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