The angiotensin II type 1 (AT 1 ) receptor is a G protein-coupled receptor that has a crucial role in the development of load-induced cardiac hypertrophy. Here, we show that cell stretch leads to activation of the AT 1 receptor, which undergoes an anticlockwise rotation and a shift of transmembrane (TM) 7 into the ligandbinding pocket. As an inverse agonist, candesartan suppressed the stretch-induced helical movement of TM7 through the bindings of the carboxyl group of candesartan to the specific residues of the receptor. A molecular model proposes that the tight binding of candesartan to the AT 1 receptor stabilizes the receptor in the inactive conformation, preventing its shift to the active conformation. Our results show that the AT 1 receptor undergoes a conformational switch that couples mechanical stress-induced activation and inverse agonist-induced inactivation.

Vascular endothelial (VE)-cadherin is a cell-cell adhesion molecule involved in endothelial barrier function. Here, we show that initial circumferential actin bundling induced by cyclic AMP-Epac-Rap1 signal and its linkage to VE-cadherin through α- and β-catenins lead to the stabilization of VE-cadherin at cell-cell contacts.

Abstract-Rho-kinase, an effector of Rho GTPase, increases the contractility of vascular smooth muscle by phosphorylating myosin light chain (MLC) and by inactivating MLC phosphatase. A wide variety of extracellular stimuli activate RhoA via G protein-coupled receptors. In the present study, we demonstrate a novel cell-cell interaction-mediated Rho activation signaling pathway in vascular smooth muscle cells (VSMCs). Among many receptor tyrosine kinases, the Eph family receptors are unique in that they require cell-cell interaction to engage their ligands, ephrin. We found that a novel VSMC-specific guanine nucleotide exchange factor (GEF) for Rho (Vsm-RhoGEF/KIAA0915) was expressed specifically in VSMCs of several organs including the heart, aorta, liver, kidney, and spleen, as examined by the immunohistochemical analysis using a specific antibody against Vsm-RhoGEF. Based on the association of Vsm-RhoGEF with EphA4 in quiescent cells, we tested whether EphA4 and Vsm-RhoGEF were expressed in the same tissue and further studied the molecular mechanism of Vsm-RhoGEF regulation by EphA4. Immunohistochemical analysis showed that EphA4 and Vsm-RhoGEF expression overlapped in VSMCs. Additionally, tyrosine phosphorylation of Vsm-RhoGEF induced by EphA4 upon ephrin-A1 stimulation enhanced the Vsm-RhoGEF activity for RhoA. The requirement of Vsm-RhoGEF for ephrin-A1-induced assembly of actin stress fibers in VSMCs was shown by the overexpression of a dominant-negative form of VSM-RhoGEF and by the depletion of Vsm-RhoGEF using RNA interference. These results suggested that ephrin-A1-triggered EphA4-Vsm-RhoGEF-RhoA pathway is involved in the cell-cell interaction-mediated RhoA activation that regulates vascular smooth muscle contractility. Key Words: smooth muscle cells Ⅲ Rho Ⅲ Eph Ⅲ ephrin Ⅲ contraction V ascular smooth muscle cell (VSMC) contractility regulates vascular tone to maintain blood circulation. Increased vascular smooth muscle contraction results in spasm and chronic contraction leads to hypertension, both of which contribute to cardiovascular pathology. Vascular contraction is regulated by actin-myosin II coupling in a Ca 2ϩ -dependent manner and a Ca 2ϩ -independent manner. The Rho GTPases play an important role in the Ca 2ϩ -independent vascular contraction, known as Ca 2ϩ sensitization. 1 Myosin II is regulated by phosphorylation and dephosphorylation of the myosin regulatory light chain. The former is controlled by myosin light chain (MLC) kinase regulated by Ca 2ϩ /calmodulin, and the latter is regulated by MLC phosphatase (MLCP). Recently, RhoA has been shown to be involved in the inhibition of MLCP via the Rho effector molecule, Rho-kinase. The phosphorylation of MLCP inhibits the phosphatase activity and thereby activates MLC, 2 resulting in contraction of smooth muscle. In addition to MLCP phosphorylation, Rho-kinase directly phosphorylates MLC and increases the contractility of myosin II. 3 These data support that Rho activation is clinically involved in vasospastic angina and unfavorable smooth mu...

Landiolol and bisoprolol prevented postoperative AF. The anti-ischemic, anti-inflammatory, and anti-oxidant effects of these beta-blockers presumably inhibited the onset of AF.