Articles tagués TNF

Inflammation Dysregulates Notch Signaling In Endothelial Cells: Implication Of Notch2 And Notch4 To Endothelial Dysfunction

Inflammation Dysregulates Notch Signaling In Endothelial Cells: Implication Of Notch2 And Notch4 To Endothelial Dysfunction

Thibaut Quillard, a, Julie Devallière, Stéphanie Coupel and Béatrice Charreau

Biochemical Pharmacology Article in Press, Accepted Manuscript doi:10.1016/j.bcp.2010.07.010

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TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype.

TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype.

Sainson RC, Johnston DA, Chu HC, Holderfield MT, Nakatsu MN, Crampton SP, Davis J, Conn E, Hughes CC.

Blood, 15 May 2008, Vol. 111, No. 10, pp. 4997-5007.

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.

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