title: TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype.
abstract: 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 NFkappaB-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 NFkappaB-dependent pathway, it concomitantly primes endothelial cells (ECs) for sprouting once the initial inflammatory wave has passed.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, USA.
authors.forename: Richard C A
authors.initials: RC
authors.lastname: Sainson
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Johnston
authors.forename: Henry C
authors.initials: HC
authors.lastname: Chu
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Holderfield
authors.forename: Martin N
authors.initials: MN
authors.lastname: Nakatsu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Crampton
authors.forename: Jaeger
authors.initials: J
authors.lastname: Davis
authors.forename: Erin
authors.initials: E
authors.lastname: Conn
authors.forename: Christopher C W
authors.initials: CC
authors.lastname: Hughes
mesh_terms: D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007249:Inflammation; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010641:Phenotype; D020574:Proto-Oncogene Proteins c-sis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D020574:Proto-Oncogene Proteins c-sis; D014409:Tumor Necrosis Factor-alpha; D040301:Vascular Endothelial Growth Factor Receptor-2