Vascular endothelial dysfunction in cirrhosis Yasuko Iwakiri, Roberto J. Groszmann  Journal of Hepatology  Volume 46, Issue 5, Pages 927-934 (May 2007) DOI: 10.1016/j.jhep.2007.02.006 Copyright © 2007 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Vasoactive molecules known to be involved in the regulation of vascular tone in cirrhosis. In the arterial splanchnic circulation (right panel), agonists such as adrenomedullin, vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNFα) or physical stimuli such as shear stress stimulate Akt, also known as protein kinase B, which directly phosphorylates and activates endothelial nitric oxide (NO) synthase (eNOS). eNOS is calcium (Ca2+)/calmodulin (CaM)-dependent and requires co-factors such as tetrahydrobiopterin (BH4) for its activity. Heat shock protein 90 (Hsp90) is one of positive regulators of eNOS. Like NO, carbon monoxide (CO) produced by hemeoxygenase-1 (HO-1) causes vasodilation by activating soluble guanylate cyclase (sGC) to generate cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells. Prostacyclin (PGI2) is synthesized by cyclooxygenase (COX) and elicits smooth muscle relaxation by stimulating adenylate cyclase (AC) and generation of cyclic adenosine monophosphate (cAMP) [16]. In the intrahepatic circulation (central panel), decreased NO and increased thromboxane A2 (TXA2) productions in SECs result in the net reduction of vasorelaxation in the intrahepatic circulation. Endothelin-1 (ET-1) has dual vasoactive effects, mediating vasoconstriction through binding to endothelin A (ETA) receptors located on HSCs and causing HSCs contraction [25]. Binding of ET-1 to ETB receptor (ETBR) mediates vasodilatation through Akt phosphorylation and eNOS phosphorylation via G-protein-coupled receptor signaling in normal liver [26]. In cirrhosis, G-protein-coupled receptor kinase-2 (GRK2), an inhibitor of G-protein-coupled receptor signaling, is up-regulated in SECs, leading to the impairment of Akt phosphorylation and a reduction in NO production [51]. Endotoxin [52,53] and reactive oxygen species (ROS) reduce NO production by increasing caveolin-1 (Cav-1) expression, increasing the interaction with eNOS, decreasing the association with ETBR and decreasing eNOS phosphorylation at Ser 1177 [46]. An increased production of COX-1-derived vasoconstrictor prostanoid TXA2 is also an example of endothelial dysfunction in cirrhosis [30]. Journal of Hepatology 2007 46, 927-934DOI: (10.1016/j.jhep.2007.02.006) Copyright © 2007 European Association for the Study of the Liver Terms and Conditions