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Blood, 15 May 2008, Vol. 111, No. 10, pp. 4997-5007. Prepublished online as a Blood First Edition Paper on March 12, 2008; DOI 10.1182/blood-2007-08-108597. This Article Full Text (PDF) All Versions of this Article: blood-2007-08-108597v1 111/10/4997    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 Sainson, R. C. A. Articles by Hughes, C. C. W. Search for Related Content PubMed PubMed Citation Articles by Sainson, R. C. A. Articles by Hughes, C. C. W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 22, 2007 Accepted February 28, 2008 TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype Richard C. A. Sainson, Douglas A Johnston, Henry C Chu, Matthew T Holderfield, Martin N Nakatsu, Steven P Crampton, Jaeger Davis, Erin Conn, and Christopher C. W. Hughes* Department of Molecular Biology & Biochemistry, University of California, Irvine, CA, United States * Corresponding author; email: cchughes{at}uci.edu. Pathological angiogenesis associated with wound healing often occurs subsequent to an inflammatory response that includes the secretion of cytokines such as Tumor Necrosis Factor (TNF). Controversy exists on the angiogenic actions of TNF, with it being generally pro-angiogenic in vivo, but anti-angiogenic in vitro. We find that whereas continuous administration of TNF in vitro or in vivo inhibits angiogenic sprouting, a 2-3 day pulse stimulates angiogenesis by inducing an endothelial "tip cell" phenotype. TNF induces the known tip cell genes Platelet-Derived Growth Factor B (PDGFB) and Vascular Endothelial Cell Growth Factor Receptor-2 (VEGFR2), while at the same time blocking signaling through VEGFR2, thus delaying the VEGF-driven angiogenic response. Notch signaling regulates tip cell function and we find that TNF also induces the notch ligand jagged-1, through an NFB-dependent mechanism. Enrichment of jagged-1 in tip cells was confirmed by immunofluorescent staining as well as by laser capture microdissection/qRT-PCR of tip cells sprouting in vitro. Thus, in angiogenesis the temporal expression of TNF is critical: it delays angiogenesis initially by blocking signaling through VEGFR2, but in addition by inducing a tip cell phenotype through an NFB-dependent pathway, it concomitantly primes EC for sprouting once the initial inflammatory wave has passed. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Gabrielli, E. V. Avvedimento, and T. Krieg Scleroderma N. Engl. J. Med., May 7, 2009; 360(19): 1989 - 2003. [Full Text] [PDF] S. Al-Mahmood, S. Colin, N. Farhat, E. Thorin, C. Steverlynck, and S. Chemtob Potent in Vivo Antiangiogenic Effects of GS-101 (5'-TATCCGGAGGGCTCGCCATGCTGCT-3'), an Antisense Oligonucleotide Preventing the Expression of Insulin Receptor Substrate-1 J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 496 - 504. [Abstract] [Full Text] [PDF] F. De Smet, I. Segura, K. De Bock, P. J. Hohensinner, and P. Carmeliet Mechanisms of Vessel Branching: Filopodia on Endothelial Tip Cells Lead the Way Arterioscler. Thromb. Vasc. Biol., May 1, 2009; 29(5): 639 - 649. [Abstract] [Full Text] [PDF]

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