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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 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 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 CrossRef Google Scholar Articles by Sainson, R. C. A. Articles by Hughes, C. C. W. PubMed PubMed Citation Articles by Sainson, R. C. A. Articles by Hughes, C. C. W. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype Richard C. A. Sainson1, Douglas A. Johnston1, Henry C. Chu1, Matthew T. Holderfield1, Martin N. Nakatsu1, Steven P. Crampton1, Jaeger Davis1, Erin Conn1, and Christopher C. W. Hughes1 1 Department of Molecular Biology and Biochemistry, University of California, Irvine 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 proangiogenic in vivo, but antiangiogenic in vitro. We find that whereas continuous administration of TNF in vitro or in vivo inhibits angiogenic sprouting, a 2- to 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/quantitative reverse-transcription–polymerase chain reaction (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 endothelial cells (ECs) for sprouting once the initial inflammatory wave has passed. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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