PT - JOURNAL ARTICLE AU - Kida, Taiki AU - Omori, Keisuke AU - Hori, Masatoshi AU - Ozaki, Hiroshi AU - Murata, Takahisa TI - Stimulation of G Protein-coupled Bile Acid Receptor Enhances Vascular Endothelial Barrier Function via Activation of PKA and Rac1 AID - 10.1124/jpet.113.209288 DP - 2013 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.113.209288 4099 - http://jpet.aspetjournals.org/content/early/2013/10/21/jpet.113.209288.short 4100 - http://jpet.aspetjournals.org/content/early/2013/10/21/jpet.113.209288.full AB - Bile acids are end products of cholesterol metabolism, which constantly exist at high concentration in 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 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 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.