Sainson Richard C A, Johnston Douglas A, Chu Henry C, Holderfield Matthew T, Nakatsu Martin N, Crampton Steven P, Davis Jaeger, Conn Erin, Hughes Christopher C W
Department of Molecular Biology and Biochemistry, University of California, Irvine, USA.
Blood. 2008 May 15;111(10):4997-5007. doi: 10.1182/blood-2007-08-108597. Epub 2008 Mar 12.
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.
与伤口愈合相关的病理性血管生成通常发生在炎症反应之后，炎症反应包括细胞因子如肿瘤坏死因子（TNF）的分泌。关于TNF的血管生成作用存在争议，它在体内通常具有促血管生成作用，但在体外具有抗血管生成作用。我们发现，虽然在体外或体内持续给予TNF会抑制血管生成芽生，但2至3天的脉冲通过诱导内皮“尖端细胞”表型来刺激血管生成。TNF诱导已知的尖端细胞基因血小板衍生生长因子B（PDGFB）和血管内皮细胞生长因子受体2（VEGFR2），同时阻断通过VEGFR2的信号传导，从而延迟VEGF驱动的血管生成反应。Notch信号传导调节尖端细胞功能，我们发现TNF还通过NFκB依赖性机制诱导Notch配体锯齿状蛋白1（jagged-1）。通过免疫荧光染色以及体外芽生的尖端细胞的激光捕获显微切割/定量逆转录聚合酶链反应（qRT-PCR）证实了尖端细胞中jagged-1的富集。因此，在血管生成中，TNF的时间表达至关重要：它最初通过阻断VEGFR2信号传导来延迟血管生成，但此外，通过NFκB依赖性途径诱导尖端细胞表型，一旦初始炎症波过去，它会同时使内皮细胞（ECs）做好芽生的准备。
