Daniel A. Langer, Vijay H. Shah  Journal of Hepatology 

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Nitric oxide and portal hypertension: Interface of vasoreactivity and angiogenesis  Daniel A. Langer, Vijay H. Shah  Journal of Hepatology  Volume 44, Issue 1, Pages 209-216 (January 2006) DOI: 10.1016/j.jhep.2005.10.004 Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Nitric oxide regulation within liver sinusoids. Extracellular signals modulate eNOS expression and activity at multiple levels including gene transcription, mRNA stabilization, and post-translational modification (phosphorylation, protein–protein interactions). NO is generated as a by-product from the conversion of arginine to citrulline by eNOS. NO exerts paracrine effects on adjacent hepatic stellate cells through cGMP dependent and independent (protein nitrosylation and peroxynitrite formation) pathways. cGMP signaling cascades through PKG regulate intracellular calcium concentrations leading to HSC relaxation. EC, endothelial cell; HSC, hepatic stellate cell; eNOS, endothelial nitric oxide synthase; sGC, soluble guanylate cyclase; PKG, protein kinase G. Journal of Hepatology 2006 44, 209-216DOI: (10.1016/j.jhep.2005.10.004) Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

Fig. 2 Intrahepatic NO signaling defects in portal hypertension. NO bioavailability is decreased within liver sinusoids. NO production from sinusoidal endothelial cells is diminished through several mechanisms. Protein levels of eNOS are unchanged but activity is inhibited due to interaction with caveolin, decreased Akt phosphorylation and decreased calmodulin binding. In addition, HSC display blunted relaxation responses to NO that may be, in part, due to decreased cGMP pathway signaling and protein nitrosylation. eNOS, endothelial nitric oxide synthase; sGC, soluble guanylate cyclase; PKG, protein kinase G. Journal of Hepatology 2006 44, 209-216DOI: (10.1016/j.jhep.2005.10.004) Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

Fig. 3 Extrahepatic (splanchnic) NO signaling defects in portal hypertension. Increased NO generated by splanchnic and systemic endothelial cells promotes surrounding smooth muscle relaxation that results in decreased systemic vascular resistance. eNOS is stimulated through several pathways. Extracellular stimulatory signals include shear stress, VEGF, and TNFα possibly from bacterial translocation and increased endotoxin levels. These signals promote increased eNOS transcription. Post-translational modifications that promote increased enzyme activity include Akt mediated phosphorylation of eNOS and increased eNOS binding of activators/cofactors (calmodulin, tetrahydrobiopterin, and Hsp90). BH4, tetrahydrobiopterin; VEGF, vascular endothelium growth factor; eNOS, endothelial nitric oxide synthase; sGC, soluble guanylate cyclase; PKG, protein kinase G. Journal of Hepatology 2006 44, 209-216DOI: (10.1016/j.jhep.2005.10.004) Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

Fig. 4 NO promotes angiogenesis and collateralization. VEGF may act through stimulation of eNOS derived NO which then promotes local endothelial cell proliferation and migration leading to new vessel formation. NO derived from eNOS is also necessary for bone marrow mobilization of endothelial progenitor cells which home to areas of neovascularization contributing to new vessel formation and stimulating surrounding endothelium through paracrine mediators. EPC, endothelial progenitor cell; EC, endothelial cell; eNOS, endothelial nitric oxide synthase. Journal of Hepatology 2006 44, 209-216DOI: (10.1016/j.jhep.2005.10.004) Copyright © 2005 European Association for the Study of the Liver Terms and Conditions