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Originally published In Press as doi:10.1074/jbc.M300711200 on March 12, 2003

J. Biol. Chem., Vol. 278, Issue 20, 18008-18014, May 16, 2003
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CD40-dependent Activation of Phosphatidylinositol 3-Kinase/Akt Pathway Mediates Endothelial Cell Survival and in Vitro Angiogenesis*

Maria Chiara Deregibus, Stefano Buttiglieri, Simona Russo, Benedetta Bussolati, and Giovanni CamussiDagger

From the Cattedra di Nefrologia, Dipartimento di Medicina Interna, Università di Torino, and Centro Ricerca Medicina Sperimentale (CeRMS), Torino 10126, Italy

CD40 has been involved in tumor and inflammatory neoangiogenesis. In this study we determined that stimulation of endothelial CD40 with sCD154 induced resistance to apoptosis and in vitro vessel-like formation by human microvascular endothelial cells (HMEC). These effects were determined to be mediated by CD40-dependent signaling because they were inhibited by a soluble CD40-muIg fusion protein. Moreover, apoptosis of HMEC was associated with an impairment of Akt phosphorylation, which was restored by stimulation with sCD154. The anti-apoptotic effect as well as in vitro vessel-like formation and Akt phosphorylation were inhibited by treatment of HMEC with two unrelated pharmacological inhibitors of phosphatidylinositol 3-kinase (PI3K), wortmannin and LY294002. CD40 stimulation induced a rapid increase in Akt enzymatic activity that was not prevented by cycloheximide, an inhibitor of protein synthesis. The enhanced Akt activity induced by stimulation of endothelial CD40 was temporarily correlated with the association of CD40 with TRAF6, c-Cbl, and the p85 subunit of PI3K. Expression of negative-dominant Akt inhibited the activation of endogenous Akt through CD40 stimulation, despite the observation that association of CD40 with TRAF6, c-Cbl, and PI3K was intact. The defective activation of Akt abrogated not only the anti-apoptotic effect of CD40 stimulation but also the proliferative response, the enhanced motility, and the in vitro formation of vessel-like tubular structures by CD40-stimulated HMEC. In conclusion, these results suggest that endothelial CD40, through activation of the PI3K/Akt signaling pathway, regulates cell survival, proliferation, migration, and vessel-like structure formation, all steps considered critical for angiogenesis.

* This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), by Istituto Superiore di Sanità (Targeted Project AIDS), by Italian Ministry of University and Research (MIUR) FIRB project (RBNE01HRS5-001) and COFIN 01, by Italian Ministry of Health (Ricerca Finalizzata 02), and by the special project Oncology, Compagnia San Paolo/FIRMS.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Cattedra di Nefrologia, Dipartimento di Medicina Interna, Ospedale Maggiore S. Giovanni Battista, Corso Dogliotti 14, 10126, Torino, Italy. Tel.: 39-011-6336708; Fax: 39-011-6631184; E-mail: giovanni.camussi@unito.it.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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