Nitric oxide mediates lymphatic vessel activation via soluble guanylate cyclase α1β1-impact on inflammation
Nitric oxide mediates lymphatic vessel activation via soluble guanylate cyclase α1β1-impact on inflammation
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DOI：
10.1096/fj.07-8873com
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发表时间：
2008-02-01
期刊：
影响因子：
4.8
通讯作者：
Detmar, Michael
中科院分区：
文献类型：
--
作者：
Kajiya, Kentaro;Huggenberger, Reto;Detmar, Michael
淋巴血管系统调节组织液稳态和免疫反应的传入阶段，也参与肿瘤转移。越来越多的证据表明淋巴管还介导急性和慢性炎症。然而，炎症条件下淋巴管生成的机制和功能后果在很大程度上尚不清楚。在这里，我们发现淋巴内皮细胞（LEC）特异性表达可溶性鸟苷酸环化酶（sGC）的α1β1亚型，血管内皮生长因子-A有效诱导sGCα1β1，一氧化氮（NO）诱导的LEC增殖、迁移和cGMP产生特别依赖于sGCα1β1。 sGC抑制剂NS-2028完全预防体内紫外线B照射引起的淋巴管扩张、水肿形成和皮肤炎症。这些发现确定了 NO/sGC α1β1/cGMP 通路在调节淋巴管功能中的关键作用。阻断 sGC α 1 β 1 信号传导除了对血管系统有影响外，还可能作为一种抑制淋巴管生成和炎症的新治疗策略。
The lymphatic vascular system regulates tissue fluid homeostasis and the afferent phase of the immune response, and it is also involved in tumor metastasis. There is increasing evidence that lymphatic vessels also mediate acute and chronic inflammation. However, the mechanisms and functional consequences of lymphangiogenesis under inflammatory conditions are largely unknown. Here, we show that lymphatic endothelial cells (LECs) specifically express the alpha 1 beta 1 isoform of soluble guanylate cyclase (sGC), that vascular endothelial growth factor-A potently induces sGC alpha 1 beta 1, and that nitric oxide (NO)-induced LEC proliferation, migration, and cGMP production in LECs are specifically dependent on sGC alpha 1 beta 1. Moreover, the specific sGC inhibitor NS-2028 completely prevents ultraviolet B-irradiation-induced lymphatic vessel enlargement, edema formation, and skin inflammation in vivo. These findings identify a crucial role of the NO/sGC alpha 1 beta 1/cGMP pathway in modulating lymphatic vessel function. The blockade of sGC alpha 1 beta 1 signaling might serve as a novel therapeutic strategy for inhibiting lymphangiogenesis and inflammation, in addition to its effects on the blood vasculature.