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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4353-4361. Prepublished online as a Blood First Edition Paper on February 10, 2005; DOI 10.1182/blood-2004-08-3098. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-08-3098v1 105/11/4353    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 Erdreich-Epstein, A. Articles by Millard, M. Search for Related Content PubMed PubMed Citation Articles by Erdreich-Epstein, A. Articles by Millard, M. Related Collections Hemostasis, Thrombosis, and Vascular Biology Apoptosis Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Endothelial apoptosis induced by inhibition of integrins v3 and v5 involves ceramide metabolic pathways Anat Erdreich-Epstein, Linda B. Tran, Órla T. Cox, Elaine Y. Huang, Walter E. Laug, Hiroyuki Shimada, and Melissa Millard From the Division of Hematology-Oncology, Department of Pediatrics and Department of Pathology, The Saban Research Institute at Childrens Hospital Los Angeles, CA; and Keck School of Medicine, University of Southern California, Los Angeles, CA. Matrix ligation of integrins v3/v5 is critical for endothelial survival and angiogenesis. We have previously shown that ceramide, a proapoptotic lipid second messenger, increases during endothelial anoikis (detachment-induced apoptosis). We now show that RGDfV, an integrin v3/v5 cyclic function-blocking peptide, increased ceramide and decreased sphingomyelin in human brain microvascular endothelial cells (HBMECs) plated on vitronectin, suggesting that sphingomyelin hydrolysis contributes to RGDfV-induced ceramide increase. Desipramine and imipramine, inhibitors of acid sphingomyelinase (ASMase), suppressed RGDfV-induced ceramide increase. Importantly, desipramine, imipramine, and a third ASMase inhibitor, SR33557, but not inhibitors of neutral sphingomyelinase, suppressed RGDfV-induced apoptosis, suggesting that ASMase was required for integrin-mediated apoptosis. Myriocin, an inhibitor of de novo ceramide synthesis, had no effect on RGDfV-induced HBMEC apoptosis. Interestingly, ASMase inhibitors also suppressed the RGDfV-induced loss of spreading on vitronectin. RGDfV induced a similar increase in ceramide and apoptosis in HBMECs on poly-L-lysine or vitronectin, although cells detached only from vitronectin, indicating that cell detachment was not required for RGDfV-induced apoptosis. Our results suggest involvement of ASMase and ceramide in endothelial apoptosis induced by inhibition of integrins v3/v5, and propose a novel molecular mechanism for the antiangiogenic effect of RGDfV. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Kiessling, J. Huppert, C. Zhang, J. Jayapaul, S. Zwick, E. C. Woenne, M. M. Mueller, H. Zentgraf, M. Eisenhut, Y. Addadi, et al. RGD-labeled USPIO Inhibits Adhesion and Endocytotic Activity of {alpha}v{beta}3-Integrin-expressing Glioma Cells and Only Accumulates in the Vascular Tumor Compartment Radiology, November 1, 2009; 253(2): 462 - 469. [Abstract] [Full Text] [PDF] J. R. Gamble, W. Y. Sun, X. Li, C. N. Hahn, S. M. Pitson, M. 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[Abstract] [Full Text] [PDF] H. M. Heikkila, S. Latti, M. J. Leskinen, J. K. Hakala, P. T. Kovanen, and K. A. Lindstedt Activated Mast Cells Induce Endothelial Cell Apoptosis by a Combined Action of Chymase and Tumor Necrosis Factor-{alpha} Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 309 - 314. [Abstract] [Full Text] [PDF] S. Maubant, D. Saint-Dizier, M. Boutillon, F. Perron-Sierra, P. J. Casara, J. A. Hickman, G. C. Tucker, and E. Van Obberghen-Schilling Blockade of {alpha}vbeta3 and {alpha}vbeta5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells Blood, November 1, 2006; 108(9): 3035 - 3044. [Abstract] [Full Text] [PDF] M. Garcia-Marcos, E. Perez-Andres, S. Tandel, U. Fontanils, A. Kumps, E. Kabre, A. Gomez-Munoz, A. Marino, J.-P. Dehaye, and S. Pochet Coupling of two pools of P2X7 receptors to distinct intracellular signaling pathways in rat submandibular gland J. Lipid Res., April 1, 2006; 47(4): 705 - 714. [Abstract] [Full Text] [PDF] E. Gulbins and P. L. Li Physiological and pathophysiological aspects of ceramide Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R11 - R26. [Abstract] [Full Text] [PDF]

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