Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism
Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism
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DOI：
10.1158/0008-5472.can-12-4038
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发表时间：
2014-05-01
期刊：
影响因子：
11.2
通讯作者：
Karsan, Aly
中科院分区：
文献类型：
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作者：
Patenaude, Alexandre;Fuller, Megan;Karsan, Aly
Notch信号在血管内皮生长因子A诱导肿瘤血管生成中起重要作用。阻断Notch配体Dll 4以一种矛盾的方式抑制肿瘤生长。Dll 4抑制增加内皮细胞发芽，但血管显示灌注减少。这种灌注不足的原因目前尚不清楚。在这里，我们报告了使用诱导型二元转基因系统抑制内皮细胞中的Notch信号传导限制了VEGF驱动的肿瘤生长并导致内皮功能障碍。无论是过度的内皮细胞发芽，也没有缺陷的周细胞丰度伴随着抑制肿瘤生长和功能性血管。然而，生物化学和功能分析表明，内皮细胞一氧化氮的产生减少了Notch抑制。用可溶性鸟苷酸环化酶激活剂BAY 41 -2272治疗，BAY 41 -2272是一种血管舒张剂，通过直接激活其可溶性鸟苷酸环化酶受体在内皮型一氧化氮合酶（eNOS）下游起作用，挽救血管功能和肿瘤生长。我们表明，一氧化氮信号的减少是由Notch抑制诱导的早期改变，并表明Notch抑制观察到的功能性血管的缺乏是继发于一氧化氮信号的抑制。共培养和肿瘤生长试验表明，Notch介导的内皮细胞中一氧化氮的产生需要VEGFA信号。总之，我们的数据支持eNOS抑制是由内皮Notch抑制诱导的肿瘤生长和血管功能缺陷的原因。这项研究揭示了肿瘤内皮细胞产生一氧化氮的新机制，对理解肿瘤血管的特殊性质具有重要意义。(C)2014年AACR。
Notch signaling is important for tumor angiogenesis induced by vascular endothelial growth factor A. Blockade of the Notch ligand Dll4 inhibits tumor growth in a paradoxical way. Dll4 inhibition increases endothelial cell sprouting, but vessels show reduced perfusion. The reason for this lack of perfusion is not currently understood. Here we report that inhibition of Notch signaling in endothelial cell using an inducible binary transgenic system limits VEGFA-driven tumor growth and causes endothelial dysfunction. Neither excessive endothelial cell sprouting nor defects of pericyte abundance accompanied the inhibition of tumor growth and functional vasculature. However, biochemical and functional analysis revealed that endothelial nitric oxide production is decreased by Notch inhibition. Treatment with the soluble guanylate cyclase activator BAY41-2272, a vasorelaxing agent that acts downstream of endothelial nitric oxide synthase (eNOS) by directly activating its soluble guanylyl cyclase receptor, rescued blood vessel function and tumor growth. We show that reduction in nitric oxide signaling is an early alteration induced by Notch inhibition and suggest that lack of functional vessels observed with Notch inhibition is secondary to inhibition of nitric oxide signaling. Coculture and tumor growth assays reveal that Notch-mediated nitric oxide production in endothelial cell requires VEGFA signaling. Together, our data support that eNOS inhibition is responsible for the tumor growth and vascular function defects induced by endothelial Notch inhibition. This study uncovers a novel mechanism of nitric oxide production in endothelial cells in tumors, with implications for understanding the peculiar character of tumor blood vessels. (C) 2014 AACR.