Prostaglandin D2-D Prostanoid Signaling Promotes Endothelial Barrier Function via the cAMP/Protein Kinase A/Tiam1/Rac1 Pathway
Objective—Prostaglandin D2 is one of the prostanoids produced during inflammation. Although prostaglandin D2 is known to decrease endothelial permeability through D prostanoid (DP) receptor stimulation, the detailed mechanism is unknown.
Methods and Results—Treatment with prostaglandin D2 (0.1–3 μmol/L) or the DP-receptor agonist, BW245C (0.1–3 μmol/L), dose-dependently increased transendothelial electric 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 μmol/L) increased the intracellular cAMP level and subsequent protein kinase A activity. Pretreatment with protein kinase A inhibitory peptide, but not gene depletion of exchange protein, directly activated by cAMP 1, attenuated BW245C-induced Rac1 activation and transendothelial electric resistance increase. In vivo, application of 2.5% croton oil or histamine (100 μg) 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 protein kinase A significantly reduced, the DP-mediated barrier enhancement.
Conclusion—Prostaglandin D2-DP signaling reduces vascular permeability both in vivo and in vitro. This phenomenon is mediated by cAMP/protein kinase A/Tiam1-dependent exchange protein directly activated by cAMP 1–independent Rac1 activation and subsequent enhancement of adherens junction in endothelial cell.
- Received February 1, 2012.
- Accepted December 26, 2012.
- © 2013 American Heart Association, Inc.