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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1495-1502. Prepublished online as a Blood First Edition Paper on October 12, 2006; DOI 10.1182/blood-2006-06-029298. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-06-029298v1 109/4/1495    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 Min, J.-K. Articles by Kwon, Y.-G. Search for Related Content PubMed PubMed Citation Articles by Min, J.-K. Articles by Kwon, Y.-G. Related Collections Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Receptor activator of nuclear factor (NF)–B ligand (RANKL) increases vascular permeability: impaired permeability and angiogenesis in eNOS-deficient mice Jeong-Ki Min1, Young-Lai Cho2, Jae-Hoon Choi3, Yonghak Kim1, Jeong Hun Kim4,5, Young Suk Yu4,5, Jaerang Rho6, Naoki Mochizuki7, Young-Myeong Kim2, Goo Taeg Oh3, and Young-Guen Kwon1 1 Department of Biochemistry, College of Sciences, Yonsei University, Seoul, Republic of Korea; 2 Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, Kangwon-Do, Republic of Korea; 4 Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 5 Seoul Artificial Eye Center, Clinical Research Institute, Seoul National University Hospital, Republic of Korea; 7 Department of Structural Analysis, National Cardiovascular Center Research Institute, Osaka, Japan; 6 Department of Microbiology, College of Natural Sciences, Chungnam National University, Daejeon, Republic of Korea; 3 Division of Molecular Life Science, Ewha Womans University, Seoul, Republic of Korea Receptor activator of nuclear factor (NF)–B ligand (RANKL) is emerging as an important regulator of vascular pathophysiology. Here, we demonstrate a novel role of RANKL as a vascular permeability factor and a critical role of endothelial nitric oxide synthase (eNOS) in RANKL-induced endothelial function. RANKL increased the vascular permeability and leukocyte infiltration in vivo and caused the breakdown of the blood-retinal barrier in wild-type mice but not in eNOS-deficient mice. In vitro, it increased endothelial permeability and reduced VE-cadherin–facilitated endothelial cell-cell junctions in a NO-dependent manner. RANKL also led to the activation of Akt and eNOS and to NO production in endothelial cells (ECs). These effects were suppressed by the inhibition of TRAF6, phosphoinositide 3'-kinase (PI3K), Akt, or NOS by genetic or pharmacologic means. Inhibition of the TRAF6-mediated NO pathway reduced EC migration and capillary-like tube formation in response to RANKL. Moreover, the effects of RANKL on ECs sprouting from the aorta, and neovessel formation in both the mouse Matrigel plug assay and corneal micropocket assay, were impaired in eNOS-deficient mice. These results demonstrate that RANKL promotes vascular permeability and angiogenesis by stimulating eNOS by a TRAF6-PI3K-Akt–dependent mechanism. These properties may be relevant to the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Novel function of RANKL: eNOS activator Dai Fukumura and Rakesh K. Jain Blood 2007 109: 1339-1340. [Full Text] [PDF] This article has been cited by other articles: Y.-S. Choi, H.-J. Choi, J.-K. Min, B.-J. Pyun, Y.-S. Maeng, H. Park, J. Kim, Y.-M. Kim, and Y.-G. 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Urbich, C. Ihling, A. Orlandi, T. Lapidot, A. M. Zeiher, and S. Dimmeler The Wnt Antagonist Dickkopf-1 Mobilizes Vasculogenic Progenitor Cells via Activation of the Bone Marrow Endosteal Stem Cell Niche Circ. Res., October 10, 2008; 103(8): 796 - 803. [Abstract] [Full Text] [PDF] J. H. Kim, J. H. Kim, Y. S. Yu, K. H. Park, H. J. Kang, H.-Y. Lee, and K.-W. Kim Antiangiogenic Effect of Deguelin on Choroidal Neovascularization J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 643 - 647. [Abstract] [Full Text] [PDF] H. Viita, J. Markkanen, E. Eriksson, M. Nurminen, K. Kinnunen, M. Babu, T. Heikura, S. Turpeinen, S. Laidinen, T. Takalo, et al. 15-Lipoxygenase-1 Prevents Vascular Endothelial Growth Factor A- and Placental Growth Factor-Induced Angiogenic Effects in Rabbit Skeletal Muscles via Reduction in Growth Factor mRNA Levels, NO Bioactivity, and Downregulation of VEGF Receptor 2 Expression Circ. Res., February 1, 2008; 102(2): 177 - 184. [Abstract] [Full Text] [PDF] S. Kiechl, G. Schett, J. Schwaiger, K. Seppi, P. Eder, G. Egger, P. Santer, A. Mayr, Q. Xu, and J. Willeit Soluble Receptor Activator of Nuclear Factor-{kappa}B Ligand and Risk for Cardiovascular Disease Circulation, July 24, 2007; 116(4): 385 - 391. [Abstract] [Full Text] [PDF]

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