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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1120-1128. Prepublished online as a Blood First Edition Paper on June 9, 2008; DOI 10.1182/blood-2007-09-112268. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-09-112268v1 112/4/1120    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Alfranca, A. Articles by Redondo, J. M. Search for Related Content PubMed PubMed Citation Articles by Alfranca, A. Articles by Redondo, J. M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 11, 2007 Accepted May 23, 2008 PGE2 induces angiogenesis via the MT1-MMP-mediated activation of the TGF/Alk5 signalling pathway Arantzazu Alfranca, Juan Manuel Lopez-Oliva, Laura Genis, Dolores Lopez-Maderuelo, Isabel Mirones, Dolores Salvado, Antonio J Quesada, Alicia G Arroyo, and Juan Miguel Redondo* Vascular Biology and Inflammation, CNIC, Madrid, Spain * Corresponding author; email: jmredondo{at}cnic.es. The development of a new vascular network is essential for the onset and progression of many pathophysiological processes. Cyclooxygenase-2 displays a proangiogenic activity in in vitro and in vivo models, mediated principally through its metabolite PGE2. Here we provide evidence for a novel signalling route through which PGE2 activates the Alk5-Smad3 pathway in endothelial cells. PGE2 induces Alk5-dependent Smad3 nuclear translocation and DNA binding, and the activation of this pathway involves the release of active TGF from its latent form through a process mediated by the metalloproteinase MT1-MMP, whose membrane clustering is promoted by PGE2. MT1-MMP-dependent TGF signalling through Alk5 is also required for PGE2-induced endothelial cord formation in vitro; and Alk5 kinase activity is required for PGE2-induced neovascularisation in vivo. These findings identify a novel signalling pathway linking PGE2 and TGF, two effectors involved in tumour growth and angiogenesis, and reveal potential targets for the treatment of angiogenesis-related disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Finetti, S. Donnini, A. Giachetti, L. Morbidelli, and M. Ziche Prostaglandin E2 Primes the Angiogenic Switch via a Synergic Interaction With the Fibroblast Growth Factor-2 Pathway Circ. Res., September 25, 2009; 105(7): 657 - 666. [Abstract] [Full Text] [PDF] M. D. Salvado, A. Alfranca, A. Escolano, J. Z. Haeggstrom, and J. M. Redondo COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH2 for Transcellular Metabolism to PGE2 by Tumor Cells Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1131 - 1137. [Abstract] [Full Text] [PDF]

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