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MBC in Press, published online ahead of print April 2, 2004
Mol. Biol. Cell 10.1091/mbc.E04-01-0059

A more recent version of this article appeared on June 1, 2004
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Submitted on January 22, 2004
Revised on March 16, 2004
Accepted on March 17, 2004

THE ROLE OF OSTEOPROTEGERIN AND TNF-RELATED APOPTOSIS INDUCING LIGAND IN HUMAN MICROVASCULAR ENDOTHELIAL CELL SURVIVAL

L. B. Pritzker1, M. Scatena1, and C. M. Giachelli1*

1 Department of Bioengineering, University of Washington, Box 351720, Seattle WA, 98195-1720

* Corresponding author. E-mail address: ceci{at}u.washington.edu.

Endothelial cell survival and antiapoptotic pathways, including those stimulated by extracellular matrix, are critical regulators of vasculogenesis, angiogenesis, endothelial repair and shear-stress-induced endothelial activation. One of these pathways is mediated by {alpha}v{beta}3 integrin ligation, downstream activation of nuclear factor-kappa B (NF-{kappa}B), and subsequent upregulation of osteoprotegerin (OPG). In this study, the mechanism by which OPG protects endothelial cells from death was examined. Serum-starved human microvascular endothelial cells (HMEC) plated on the {alpha}v{beta}3 ligand, osteopontin (OPN), were protected from cell death. Immunoprecipitation experiments indicated that OPG formed a complex with TNF-related apoptosis-inducing ligand (TRAIL) in HMEC under these conditions. Furthermore, inhibitors of TRAIL including recombinant soluble TRAIL receptors and a neutralizing antibody against TRAIL blocked apoptosis of serum-starved HMEC plated on the nonintegrin attachment factor, poly-D-lysine (PDL). While TRAIL was unable to induce apoptosis in HMEC plated on OPN, the addition of recombinant TRAIL did increase the percentage of apoptotic HMEC plated on PDL. This evidence indicates that OPG blocks endothelial cell apoptosis through binding TRAIL and preventing its interaction with death-inducing TRAIL-receptors






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