Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an epac-rap1 signaling pathway
Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an epac-rap1 signaling pathway
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DOI：
10.1128/mcb.25.1.136-146.2005
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发表时间：
2005-01-01
影响因子：
5.3
通讯作者：
Mochizuki, N
中科院分区：
文献类型：
--
作者：
Fukuhara, S;Sakurai, A;Mochizuki, N
环腺苷酸（cAMP）是一种众所周知的改善血管内皮细胞屏障功能的细胞内信号分子。在这里，我们描绘了一个新的cAMP触发的信号，调节屏障功能。我们发现，cAMP升高剂，前列环素和毛喉素，降低细胞通透性和增强血管内皮（VE）钙粘蛋白依赖性细胞粘附。尽管前列环素和毛喉素导致的渗透性降低和VE-钙粘蛋白介导的粘附增加对cAMP依赖性蛋白激酶的特异性抑制剂不敏感，但这些作用可被Epac的特异性激活剂8-（4-氯苯硫基）-2 '-O-甲基腺苷-3'，5 '-环一磷酸（Epac是Rap 1的新型cAMP依赖性鸟嘌呤核苷酸交换因子）模拟。因此，我们研究了Rap 1的渗透性和VE-钙粘蛋白介导的细胞粘附的影响，通过表达组成性活性Rap 1或Rap 1GAPII。Rap 1的激活导致渗透性降低和VE-钙粘蛋白依赖性细胞粘附的增强，而Rap 1的失活具有相反的作用。此外，前列环素和毛喉素诱导皮层肌动蛋白重排Rap 1依赖的方式。总之，cAMP-Epac-Rap 1信号通过增强由重排的皮质肌动蛋白排列的VE-钙粘蛋白介导的粘附来促进细胞通透性降低。
Cyclic AMP (cAMP) is a well-known intracellular signaling molecule improving barrier function in vascular endothelial cells. Here, we delineate a novel cAMP-triggered signal that regulates the barrier function. We found that cAMP-elevating reagents, prostacyclin and forskolin, decreased cell permeability and enhanced vascular endothelial (VE) cadherin-dependent cell adhesion. Although the decreased permeability and the increased VE-cadherin-mediated adhesion by prostacyclin and forskolin were insensitive to a specific inhibitor for cAMP-dependent protein kinase, these effects were mimicked by 8-(4-chlorophenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate, a specific activator for Epac, which is a novel cAMP-dependent guanine nucleotide exchange factor for Rap1. Thus, we investigated the effect of Rap1 on permeability and the VE-cadherin-mediated cell adhesion by expressing either constitutive active Rap1 or Rap1GAPII. Activation of Rap1 resulted in a decrease in permeability and enhancement of VE-cadherin-dependent cell adhesion, whereas inactivation of Rap1 had the counter effect. Furthermore, prostacyclin and forskolin induced cortical actin rearrangement in a Rap1-dependent manner. In conclusion, cAMP-Epac-Rap1 signaling promotes decreased cell permeability by enhancing VE-cadherin-mediated adhesion lined by the rearranged cortical actin.