Regulation of multiple angiogenic pathways by D114 and Notch in human umbilical vein endothelial cells
Regulation of multiple angiogenic pathways by D114 and Notch in human umbilical vein endothelial cells
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DOI：
10.1016/j.mvr.2007.06.006
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发表时间：
2008-03-01
影响因子：
3.1
通讯作者：
Harris, Adrian L.
中科院分区：
文献类型：
--
作者：
Harrington, Laura S.;Sainson, Richard C. A.;Harris, Adrian L.
Notch配体D114在胚胎血管发育过程中对血管生成是必不可少的，并参与肿瘤血管生成。最近的几篇论文表明，阻断D114信号可以抑制肿瘤的生长，这表明它可能是抗癌治疗的一个很好的候选者。为了在细胞水平上了解D114的作用，我们对HUVEC中D114调控的基因进行了分析。已鉴定的基因包括几个血管生成信号通路，如血管内皮生长因子、成纤维细胞生长因子和肝细胞生长因子。特别是，我们确定了血管内皮生长因子途径组分(VEGFR2，胎盘生长因子PIGF)的下调，导致了限制HUVEC对血管内皮生长因子的反应的总体效果。然而，观察到VEGFR1的广泛上调允许对其配体PIGF的持续反应，但VEGFR1的可溶性形式sVEGFR1也上调。PIGF促进HUVEC的小管生成，提示PIGF下调和VEGFR1上调包括sVEGFR1是D114抑制PIGF和VEGF信号转导的重要机制。D114刺激的HUVECs对血管内皮细胞生长因子和肝细胞生长因子的反应抑制了ERK的激活，表明D114信号负性调节这些通路。在3D小管生成实验中，D114的表达减少了血管萌发长度，证实了D114信号抑制了血管生成。总之，我们的数据表明，D114的表达通过阻止血管内皮细胞的增殖并允许诱导更成熟、分化的表型，起到了从血管生成的增殖期到成熟和稳定阶段的切换作用。SVEGFR1的调节为D114信号提供了一种新的机制来调节远距离的细胞，而不仅仅是相邻的细胞。(C)2007 Elsevier Inc.保留所有权利。
The Notch ligand, D114, is essential for angiogenesis during embryonic vascular development, and is involved in tumour angiogenesis. Several recent publications demonstrated that blockade of D114 signalling inhibits tumour growth, suggesting that it may constitute a good candidate for anti-cancer therapy. In order to understand the role of D114 at the cellular level, we performed an analysis of D114-regulated genes in HUVECs. The genes identified included several angiogenic signalling pathways, such as VEGF, FGF and HGF. In particular we identified downregulation (VEGFR2, placenta growth factor PIGF) of VEGF pathway components resulting in the overall effect of limiting the response of HUVEC to VEGF. However extensive upregulation of VEGFR1 was observed allowing continued response to its ligand PIGF but the soluble form of the VEGFR1, sVEGFR1 was also upregulated. PIGF enhanced tubulogenesis of HUVEC suggesting that downregulation of PIGF and upregulation of VEGFR1 including sVEGFR1 are important mechanisms by which D114 attenuates PIGF and VEGF signalling. D114-stimulated HUVECs had impaired ERK activation in response to VEGF and HGF indicating that D114 signalling negatively regulates these pathways. D114 expression reduced vessel sprout length in a 3D tubulogenesis assay confirming that D114 signalling inhibits angiogenesis. Altogether, our data suggest that D114 expression acts as a switch from the proliferative phase of angiogenesis to the maturation and stabilisation phase by blocking endothelial cell proliferation and allowing induction of a more mature, differentiated phenotype. The regulation of sVEGFR1 provides a novel mechanism for D114 signalling to regulate cells at distance, not just in adjacent cells. (c) 2007 Elsevier Inc. All rights reserved.