Affiliation:
1. Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Abstract
Abstract
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.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
62 articles.
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