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(Circulation Research. 2003;92:732.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) Sequentially Upregulates Nitric Oxide and Prostanoid Production in Primary Human Endothelial Cells

Giorgio Zauli^*, Assunta Pandolfi^*, Arianna Gonelli, Roberta Di Pietro, Simone Guarnieri, Giovanni Ciabattoni, Rosalba Rana, Marco Vitale, Paola Secchiero

From the Department of Normal Human Morphology (G.Z., M.V.), University of Trieste, Trieste, Italy; the Department of Biomorphology (A.P., R.D.P., R.R.), "G. D’Annunzio" University of Chieti, Chieti Scalo, Chieti, Italy; the Department of Morphology and Embryology (A.G., P.S.), Human Anatomy Section, University of Ferrara, Ferrara, Italy; and the Department of Drug Sciences (G.C.), Laboratory of Cell Physiology (S.G.), "G. D’Annunzio" University of Chieti, Chieti, Italy.

Correspondence to Giorgio Zauli, MD, PhD, Department of Normal Human Morphology, University of Trieste, Via Manzoni 16, 34138 Trieste. E-mail zauli{at}units.it

Endothelial cells express tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptors, but the function of TRAIL in endothelial cells is not completely understood. We explored the role of TRAIL in regulation of key intracellular signal pathways in endothelial cells. The addition of TRAIL to primary human endothelial cells increased phosphorylation of endothelial nitric oxide synthase (eNOS), NOS activity, and NO synthesis. Moreover, TRAIL induced cell migration and cytoskeleton reorganization in an NO-dependent manner. TRAIL did not activate the NF-B or COX-2 pathways in endothelial cells. Instead, TRAIL increased prostanoid production (PGE₂=PGI₂>TXA₂), which was preferentially inhibited by the COX-1 inhibitor SC-560. Because NO and prostanoids play a crucial role in the state of blood vessel vasodilatation and angiogenesis, our data suggest that TRAIL might play an important role in endothelial cell function.

Key Words: tumor necrosis factor–related apoptosis-inducing ligand • nitric oxide • prostanoids

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