• Rong Wan, Rui Guo, Cheng Chen, Lai Jin, Chao Zhu, Qichun Zhang, Youhua Xu, and Shengnan Li.
• Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, P.R. China.
• J. Cell. Physiol. 2013 Jun 1; 228 (6): 1295-303.

AbstractUrocortin (Ucn1), a member of corticotrophin-releasing hormone (CRH) family, has been reported to be upregulated in inflammatory diseases and function as an autocrine or paracrine inflammatory mediator. Growing evidence shows that Ucn1 increases the endothelial permeability in inflammatory conditions; however, the detailed mechanisms are not clear. In the present study, we investigated the mechanisms of increased endothelial permeability by Ucn1 in human umbilical vein endothelial cells (HUVECs) exposed to lipopolysaccharide (LPS). Pretreatment of HUVECs with Ucn1 increased the endothelial cell permeability, which was augmented by LPS synergistically. Significant downregulation of VE-cadherin expression was also observed. Moreover, Ucn1 increased phosphorylation of protein kinase D (PKD) and heat shock protein 27 (HSP27) in a time- and CRHR(2) -dependent manner. Inhibition of PKD and HSP27 drastically attenuated Ucn1-induced downregulation of VE-cadherin expression. Further investigations demonstrated that Ucn1 phosphorylated β-catenin at Ser552 to disrupt the cadherin-catenin complex and hence promote the disassociation of β-catenin and VE-cadherin. Disassociation of β-catenin and VE-cadherin resulted in decreased VE-cadherin expression while on the contrary β-catenin was increased, which may due to the inactivation of GSK-3β. Increased β-catenin translocated into the nucleus and subsequently bound to TCF/LEF site, contributing to the elevated expression of vascular endothelial growth factor (VEGF). The above effects of Ucn1 were completely reversed by CRHR(2) receptor blocker, antisauvagine-30. Taken together, our data suggest that Ucn1 increase LPS-induced endothelial permeability by disrupting the VE-cadherin-β-catenin complex via activation of CRHR(2) and PKD-HSP27 signaling pathway.Copyright © 2012 Wiley Periodicals, Inc.

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