title: Stimulation of G protein-coupled bile acid receptor enhances vascular endothelial barrier function via activation of protein kinase A and Rac1.
abstract: Bile acids are end products of cholesterol metabolism, and they constantly exist at high concentrations in the blood. Since vascular endothelial cells express G protein-coupled bile acid receptor (GPBAR), bile acids potentially modulate endothelial function. Here, we investigated whether and how GPBAR agonism affects endothelial barrier function. In bovine aortic endothelial cells (BAECs), treatment with a GPBAR agonist, taurolithocholic acid (TLCA) increased the transendothelial electrical resistance. In addition, TLCA suppressed the thrombin-induced dextran infiltration through the endothelial monolayer. Knockdown of GPBAR abolished the inhibitory effect of TLCA on hyperpermeability. These results indicate that stimulation of GPBAR enhances endothelial barrier function. TLCA increased intracellular cAMP production in BAECs. Inhibition of protein kinase A (PKA) or Rac1 significantly attenuated the TLCA-induced endothelial barrier protection. TLCA induced cortical actin polymerization, which was attenuated by a Rac1 inhibitor. In vivo, local administration of TLCA into the mouse ear significantly inhibited vascular leakage and edema formation induced by croton oil or vascular endothelial growth factor. These results indicate that stimulation of GPBAR enhances endothelial barrier function by cAMP/PKA/Rac1-dependent cytoskeletal rearrangement.
authors.affiliation: Department of Veterinary Pharmacology (T.K., K.O., M.H., H.O., T.M.) and Department of Animal Radiology (T.M.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Kida
authors.forename: Keisuke
authors.initials: K
authors.lastname: Omori
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
mesh_terms: D000818:Animals; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013656:Taurocholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C513561:Gpbar1 protein, mouse; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D043562:Receptors, G-Protein-Coupled; C037351:tauromuricholic acid; D013656:Taurocholic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D020830:rac1 GTP-Binding Protein