期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 33, 期 3, 页码 565-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.112.300993
关键词
endothelial permeability; prostaglandin D-2
资金
- Japan Society for the Promotion of Science
- Takeda Science Foundation
- Naito Foundation
- SENSHIN Medical Research Foundation
- Pharmacological Research Foundation
- Grants-in-Aid for Scientific Research [24658243, 22688024] Funding Source: KAKEN
Objective-Prostaglandin D-2 (PGD(2)) is one of the prostanoids produced during inflammation. Although PGD(2) is known to decrease endothelial permeability through D prostanoid (DP) receptor stimulation, the detailed mechanism is unknown. Methods and Results-Treatment with PGD(2) (0.1-3 mu mol/L) or the DP receptor agonist, BW245C (0.1-3 mu mol/L), dose-dependently increased transendothelial electrical resistance and decreased the FITC-dextran permeability of human umbilical vein endothelial cells. Both indicated decreased endothelial permeability. These phenomena were accompanied by Tiam1/Rac1-dependent cytoskeletal rearrangement. BW245C (0.3 ae mol/L) increased the intracellular cAMP level and subsequent protein kinase A (PKA) activity. Pretreatment with PKA inhibitory peptide, but not gene depletion of exchange protein directly activated by cAMP 1 (Epac1), attenuated BW245C-induced Rac1 activation and transendothelial electric resistance increase. In vivo, application of 2.5% croton oil or histamine (100 mu g) caused vascular leakage indexed by dye extravasation. Pretreatment with BW245C (1 mg/kg) attenuated the dye extravasation. Gene deficiency of DP abolished, or inhibition of PKA significantly reduced, the DP-mediated barrier enhancement. Conclusion-PGD(2)-DP signaling reduces vascular permeability both in vivo and in vitro. This phenomenon is mediated by cAMP/PKA/Tiam1-dependent Epac1-independent Rac1 activation and subsequent enhancement of adherens junction in endothelial cell. (Arterioscler Thromb Vasc Biol. 2013;33:565-571.)
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