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Molecular and Cellular Biology, January 2005, p. 136-146, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.136-146.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cyclic AMP Potentiates Vascular Endothelial Cadherin-Mediated Cell-Cell Contact To Enhance Endothelial Barrier Function through an Epac-Rap1 Signaling Pathway

Shigetomo Fukuhara,1 Atsuko Sakurai,1 Hideto Sano,2 Akiko Yamagishi,1 Satoshi Somekawa,1,3 Nobuyuki Takakura,2 Yoshihiko Saito,3 Kenji Kangawa,4 and Naoki Mochizuki1*

Department of Structural Analysis,1 Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka,4 Department of Stem Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa,2 First Department of Internal Medicine, Nara Medical University, Nara, Japan3

Received 2 August 2004/ Returned for modification 2 September 2004/ Accepted 28 September 2004

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.

* Corresponding author. Mailing address: Department of Structural Analysis, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Phone: 81-6-6833-5012, ext. 2508. Fax: 81-6-6835-5461. E-mail: nmochizu{at}ri.ncvc.go.jp.

Molecular and Cellular Biology, January 2005, p. 136-146, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.136-146.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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