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(Circulation. 2003;107:2250.)
© 2003 American Heart Association, Inc.

Basic Science Reports

TRAIL Promotes the Survival and Proliferation of Primary Human Vascular Endothelial Cells by Activating the Akt and ERK Pathways

Paola Secchiero, PhD; Arianna Gonelli, PhD; Edvige Carnevale, PhD; Daniela Milani, PhD; Assunta Pandolfi, PhD; Davide Zella, PhD; Giorgio Zauli, MD, PhD

From the Department of Morphology and Embryology, University of Ferrara, Ferrara (P.S., A.G., D.M.), the Department of Normal Human Morphology, University of Trieste, Trieste (E.C., G.Z.), and the Department of Biomorphology, G. D’Annunzio University of Chieti, Chieti (A.P.), Italy; and the Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Md (P.S., D.Z.).

Correspondence to Paola Secchiero, PhD, Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy. E-mail secchier{at}mail.umbi.umd.edu

Background— TRAIL protein is expressed in the medial smooth cell layer of aorta and pulmonary artery, whereas endothelial cells express all TRAIL receptors (TRAIL-Rs).

Methods and Results— The role of TRAIL/TRAIL-Rs in vascular biology was investigated in primary human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells, which showed comparable surface expression of death (TRAIL-R1 and -R2) and decoy (TRAIL-R3 and -R4) TRAIL-Rs. TRAIL activated the protein kinase Akt in HUVECs, as assessed by Western blot for phospho-Akt. Moreover, experiments performed with a pharmacological inhibitor of the phosphatidylinositol 3-kinase/Akt pathway (LY294002) or a dominant-negative Akt (K179M) demonstrated that TRAIL significantly protected HUVECs from apoptosis induced by trophic withdrawal via Akt and that inhibition of Akt sensitized HUVECs to TRAIL-induced caspase-dependent apoptosis. TRAIL also stimulated the ERK1/2 but not the p38 or the JNK pathways and induced a significant increase in endothelial cell proliferation in an ERK-dependent manner. Conversely, TRAIL did not activate NF-B or affect the surface expression of the inflammatory markers E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1.

Conclusions— The ability of TRAIL to promote the survival/proliferation of endothelial cells without inducing NF-B activation and inflammatory markers suggests that the TRAIL/TRAIL-R system plays an important role in endothelial cell physiology.

Key Words: endothelium • signal transduction • inflammation

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