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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.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Endothelial apoptosis induced by inhibition of integrins {alpha}v{beta}3 and {alpha}v{beta}5 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 {alpha}v{beta}3/{alpha}v{beta}5 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 {alpha}v{beta}3/{alpha}v{beta}5 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 {alpha}v{beta}3/{alpha}v{beta}5, and propose a novel molecular mechanism for the antiangiogenic effect of RGDfV.


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