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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 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 Citation Map 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. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY PGE2 induces angiogenesis via MT1-MMP–mediated activation of the TGFβ/Alk5 signaling pathway Arántzazu Alfranca1, Juan Manuel López-Oliva1, Laura Genís1, Dolores López-Maderuelo1, Isabel Mirones1, Dolores Salvado1, Antonio J. Quesada1, Alicia G. Arroyo1, and Juan Miguel Redondo1 1 Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain The development of a new vascular network is essential for the onset and progression of many pathophysiologic processes. Cyclooxygenase-2 displays a proangiogenic activity in in vitro and in vivo models, mediated principally through its metabolite prostaglandin E2 (PGE2). Here, we provide evidence for a novel signaling 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 TGFβ from its latent form through a process mediated by the metalloproteinase MT1-MMP, whose membrane clustering is promoted by PGE2. MT1-MMP–dependent transforming growth factor β (TGFβ) signaling through Alk5 is also required for PGE2-induced endothelial cord formation in vitro, and Alk5 kinase activity is required for PGE2-induced neovascularization in vivo. These findings identify a novel signaling pathway linking PGE2 and TGFβ, 2 effectors involved in tumor 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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