Robo4-dependent Slit signaling stabilizes the vasculature during pathologic angiogenesis and cytokine storm.
Robo4-dependent Slit signaling stabilizes the vasculature during pathologic angiogenesis and cytokine storm.
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DOI：
10.1097/moh.0b013e328345a4b9
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发表时间：
2011-05
影响因子：
3.2
通讯作者：
Li DY
中科院分区：
文献类型：
--
作者：
London NR;Li DY
内皮细胞受到多种不稳定的促血管生成和炎性细胞因子的轰击，并且必须对其做出反应。内源性细胞信号传导系统，如Roundabout（Robo）4依赖性Slit信号传导，有助于维持稳态平衡并防止过度不稳定。在Robo4被Slit激活后，桩蛋白与称为GIT 1的ArfGAP一起被募集到胞质结构域沿着。GIT1募集导致Arf6失活，Arf6是一种调节钙粘蛋白细胞表面定位的蛋白质。Slit增加细胞表面的血管内皮钙粘蛋白呈递，并在炎性细胞因子存在下增强血管屏障功能。通过利用Robo4依赖的Slit信号，可以提高败血症和禽流感感染小鼠模型的存活率。这种效应是通过减弱宿主血管对细胞因子的反应来实现的。因此，血管稳定程序应作为潜在的治疗感染性疾病的特点是细胞因子风暴的研究。
The endothelium is bombarded with and must respond to multiple destabilizing proangiogenic and inflammatory cytokines. Endogenous cell signaling systems such as Roundabout (Robo)4-dependent Slit signaling are in place to help maintain homeostatic balance and prevent excessive destabilization. Upon Robo4 activation by Slit, paxillin is recruited to the cytoplasmic domain along with an ArfGAP known as GIT1. GIT1 recruitment results in inactivation of Arf6, a protein shown to regulate cadherin cell surface localization. Slit increases vascular endothelial-cadherin presentation at the cell surface and enhances vascular barrier function in the presence of inflammatory cytokines. Through harnessing Robo4-dependent Slit signaling, survival can be enhanced in mouse models of sepsis and avian flu infection. This effect is achieved by blunting the host vascular response to cytokines. Thus, vascular stabilizing programs should be investigated as potential therapeutics for infectious disease characterized by cytokine storm.