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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 10, 2004 Accepted January 26, 2005 Endothelial apoptosis induced by inhibition of integrins v3 and v5 involves ceramide metabolic pathways Anat Erdreich-Epstein*, Linda B Tran, Orla T Cox, Elaine Huang, Walter E Laug, Hiroyuki Shimada, and Melissa Millard Division of Hematology-Oncology, Department of Pediatrics, The Saban Research Institute at Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Department of Pathology, The Saban Research Institute at Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA * Corresponding author; email: epstein{at}usc.edu. Matrix ligation of integrins v3/v5 is critical for endothelial survival and angiogenesis. We have previously shown that ceramide, a pro-apoptotic 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 (HBMEC) 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 similar increase in ceramide and apoptosis in HBMEC on poly-L-lysine or vitronectin, although cells only detached 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 anti-angiogenic 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. A. 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