title: Prostaglandin D2-DP signaling promotes endothelial barrier function via the cAMP/PKA/Tiam1/Rac1 pathway.
abstract: 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.
  
  
  RESULTS
  Treatment with PGD(2) (0.1-3 μmol/L) or the DP receptor agonist, BW245C (0.1-3 μmol/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 μmol/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 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 PKA significantly reduced, the DP-mediated barrier enhancement.
  
  
  CONCLUSIONS
  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.
authors: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors: Koji
authors: K
authors: Kobayashi
authors: Yoshiki
authors: Y
authors: Tsubosaka
authors: Masatoshi
authors: M
authors: Hori
authors: Shuh
authors: S
authors: Narumiya
authors: Hiroshi
authors: H
authors: Ozaki
authors: Takahisa
authors: T
authors: Murata
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000201:enzymology; D003911:Dextrans / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054644:Ear Auricle / Q000098:blood supply*; D017097:Electric Impedance; D004789:Enzyme Activation; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015230:Prostaglandin D2 / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D013997:Time Factors; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D003911:Dextrans; D020662:Guanine Nucleotide Exchange Factors; D047428:Protein Kinase Inhibitors; C107953:RAC1 protein, human; C116122:RAPGEF3 protein, human; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; C015219:fluorescein isothiocyanate dextran; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D016650:Fluorescein-5-isothiocyanate; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor