Functional aspects on the pathophysiology of portal hypertension in cirrhosis

Portal hypertension is a severe and frequent complication of chronic liver disease. Its consequences, bleeding from gastro-esophageal varices and portal hypertensive gastropathy, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary/portopulmonary syndromes, and hepatic encephalopathy, represent the first cause of death and liver transplantation in patients with cirrhosis. The primary factor in the development of portal hypertension is a marked increase in hepatic vascular resistance (HVR) to portal blood flow, which was classically attributed to distortion of the liver architecture inherent to cirrhosis. However, over the past 20 years, a better understanding of the liver microcirculation has demonstrated that a dynamic component due to an increased hepatic vascular tone further contributes to augment HVR. Secondarily to the increased HVR, there is a progressive splanchnic vasodilatation that increments portal blood flow, which aggravates and perpetuates the portal hypertension syndrome [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar] (Fig. 1).Intrahepatic vascular regulationThe analysis of the structural factors (fibrosis, vascular remodeling, vascular occlusion, nodule formation) contributing to increase HVR is out of the scope of this review that will focus on the dynamic component of the increased HVR.During progression to cirrhosis, sinusoidal endothelial cells (SEC) become dysfunctional and among other features acquire a vasoconstrictor phenotype, characterized by elevated production of vasoconstrictors and reduced release of vasodilators. The resulting imbalance promotes the contraction of different cells of the cirrhotic liver, such as hepatic stellate cells (HSC), portal myofibroblasts and vascular smooth muscle cells that lead to increased hepatic vascular tone and portal pressure. HSC in turn also experience a profound phenotypical transformation, with morphologic and functional consequences: loss of vitamin A droplets, alpha-smooth muscle actin overexpression, hyper-response to vasoconstrictors and enhanced proliferative and fibrogenic activity. Interestingly, in experimental models of cirrhosis, strategies aimed at improving the hepatic vascular tone by targeting SEC have also been shown to improve liver fibrosis. This may be due to the fact that cellular phenotype alterations share pathophysiological mechanisms, but also because SEC phenotype amelioration positively affects HSC phenotype [[2]DeLeve L.D. Wang X. Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence.Hepatology. 2008; 48: 920-930Crossref PubMed Scopus (245) Google Scholar].Increase of vasoconstrictors in the liverIncreased activity of several endogenous vasoconstrictors, such as endothelin, norepinephrine, angiotensin II, vasopressin, leukotrienes, and thromboxane A2 has been demonstrated in the cirrhotic liver (Fig. 2). Additionally, there is an increased vasoconstrictive response of the hepatic vascular bed to these vasoconstrictors. Although all these systems are potential targets to decrease HVR in cirrhosis, the phospholipase A2 – cycloxygenase-1 – thromboxane A2 pathway has been one of the most extensively studied. This system has been shown to be upregulated in cirrhotic SEC and Kupffer cells [3Gracia-Sancho J. Lavina B. Rodriguez-Vilarrupla A. Garcia-Caldero H. Bosch J. Garcia-Pagan J.C. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers.J Hepatol. 2007; 47: 220-227Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 4Steib C.J. Gerbes A.L. Bystron M. Op d.W. Hartl J. Roggel F. et al.Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A(2).J Hepatol. 2007; 47: 228-238Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar], and its blockade significantly improves endothelial dysfunction and reduces HVR in the cirrhotic liver [[5]Graupera M. Garcia-Pagan J.C. Pares M. Abraldes J.G. Rosello J. Bosch J. et al.Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers.J Hepatol. 2003; 39: 515-521Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar].Fig. 2Intrahepatic vascular resistance modulation. Hyperactive hepatic stellate cells overcontract in response to several vasoactive mediators from neighbor cells or from systemic circulation. Sinusoidal endothelial cells exhibit a marked dysfunctional phenotype defined by reduced vasodilators bioavailability, mainly nitric oxide (NO) but probably also carbon monoxide (CO) and hydrogen sulfide (H2S), and exaggerated vasoconstrictors production. Kupffer cells further contribute to HSC vasoconstriction liberating, among others, thromboxane A2 (TXA2) and cysteinyl-leukotrienes (CysLT). ET-1, endothelin-1; ETR, endothelin receptor; UTR, urotensin-II receptor; PLA2, phospholipase A2; 5-LO, 5-lipooxygenase; COX-1, cyclooxygenase-1; PGH2, prostaglandin H2; TXA2S, thromboxane A2 synthase; TP, TXA2/PGH2 receptor; α1, α1 adrenergic receptor; O2−, superoxide; ONOO−, peroxynitrite; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; BH4, tetrahydrobiopterin; GC, guanylate cyclase; cGMP, cyclic guanosine monophosphate; Rho K, rho kinase; MLC, myosin light chain.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Reduced bioavailability of intrahepatic vasodilatorsNitric oxide (NO) is probably the most important vasodilator involved in the regulation of hepatic vascular tone. Cirrhotic livers exhibit reduced NO availability, which is due both to decreased endothelial Nitric Oxide Synthase (eNOS) activity and to increased NO scavenging by elevated oxidative stress (Fig. 2).Reduced eNOS activity is attributed to several alterations in its post-translational regulation, which have been described in detail in a recent review [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. These alterations include reduced eNOS phosphorylation, low levels of its co-factor tetrahydrobiopterin (BH4), increased caveolin expression and release of asymmetric-dimethyl-arginine [[6]Wiest R. Groszmann R.J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.Hepatology. 2002; 35: 478-491Crossref PubMed Scopus (370) Google Scholar]. Different studies have shown that interventions that increase eNOS activity improve liver endothelial dysfunction and reduce portal pressure in experimental models of cirrhosis. Statin administration probably represents the most promising therapeutic option; indeed, the beneficial effects of statin administration reducing portal pressure have been already confirmed in patients with cirrhosis in a recent double-blind study [[7]Abraldes J.G. Albillos A. Banares R. Turnes J. Gonzalez R. Garcia-Pagan J.C. et al.Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial.Gastroenterology. 2009; 136: 1651-1658Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar].Increased superoxide levels in cirrhotic livers result from increased production and diminished elimination by superoxide dismutase (SOD) [[8]Gracia-Sancho J. Lavina B. Rodriguez-Vilarrupla A. Garcia-Caldero H. Fernandez M. Bosch J. et al.Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability.Hepatology. 2008; 47: 1248-1256Crossref PubMed Scopus (109) Google Scholar]. Superoxide reacts with NO leading to formation of peroxynitrite, a powerful pro-fibrogenic agent, and decreases NO availability. This is especially relevant in an infection situation, where increased inducible NOS (iNOS) overproduces NO that reacts with superoxide to form high levels of peroxynitrite [[9]Thabut D. Tazi K.A. Bonnefont-Rousselot D. Aller M. Farges O. Guimont M.C. et al.High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats.Hepatology. 2007; 46: 1893-1906Crossref PubMed Scopus (54) Google Scholar]. In addition, superoxide can oxidize and therefore inactivate BH4 further reducing NO bioavailability by decreasing eNOS activity. SOD supplementation reduces intrahepatic superoxide, increases NO, improves endothelial function and reduces portal pressure. In addition, peroxynitrite is also reduced, which may explain our recent finding of decreased liver fibrosis after SOD treatment (unpublished observation).In addition to these mechanisms related to endothelial dysfunction, alterations in the contractile cells have also been described. HSC have been shown to hyperreact in response to vasoconstrictor stimuli. The RhoA/Rho-kinase pathway is essential for contraction of vascular smooth muscle cells and its upregulation in cirrhotic livers contributes to increase HVR by increasing the sensitivity of the hepatic vasculature to vasoconstrictors [[10]Zhou Q. Hennenberg M. Trebicka J. et upregulation of and contributes to increased hepatic vascular resistance in with PubMed Scopus Google vascular vasodilators NO, and have been in the splanchnic vasodilatation of liver cirrhosis (Fig. In addition, and in to is in the liver, a in the RhoA/Rho-kinase pathway has been in the systemic that this may contribute to vascular and vasodilatation M. Trebicka J. J. of in portal 2008; PubMed Scopus Google Scholar]. that splanchnic also a in the development and of splanchnic in portal hypertension [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. The mechanisms for this are but several factors that increase such as or in portal blockade of decreases splanchnic and portal in models of portal hypertension M. M. B. Garcia-Pagan J.C. J. Bosch J. of decreases the development of splanchnic and in portal hypertensive Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar]. The increased portal can be by of splanchnic vasoconstrictors such as and its and its and the other splanchnic vasodilatation to decreased which promotes the activation of endogenous and of the by an increase in the that in turn contributes to further increase splanchnic blood and portal pressure and to the development of and dysfunction Y. Groszmann R.J. The of chronic liver from the to the PubMed Scopus Google is that the and the hepatic vascular share alterations in the vasoactive are in an vascular tone due to decreased vasodilators and increased vasoconstrictors the primary factors in the intrahepatic the vascular bed an response characterized by of and a response to to be new strategies to portal vasodilators to reduce the increased intrahepatic vascular tone a further increase in splanchnic and systemic vasoconstrictors to reduce splanchnic and systemic vasodilatation may the enhanced intrahepatic vascular tone [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google by and and has a from is by the of that not have to or of with to this Portal hypertension is a severe and frequent complication of chronic liver disease. Its consequences, bleeding from gastro-esophageal varices and portal hypertensive gastropathy, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary/portopulmonary syndromes, and hepatic encephalopathy, represent the first cause of death and liver transplantation in patients with cirrhosis. The primary factor in the development of portal hypertension is a marked increase in hepatic vascular resistance (HVR) to portal blood flow, which was classically attributed to distortion of the liver architecture inherent to cirrhosis. However, over the past 20 years, a better understanding of the liver microcirculation has demonstrated that a dynamic component due to an increased hepatic vascular tone further contributes to augment HVR. Secondarily to the increased HVR, there is a progressive splanchnic vasodilatation that increments portal blood flow, which aggravates and perpetuates the portal hypertension syndrome [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar] (Fig. vascular regulationThe analysis of the structural factors (fibrosis, vascular remodeling, vascular occlusion, nodule formation) contributing to increase HVR is out of the scope of this review that will focus on the dynamic component of the increased HVR.During progression to cirrhosis, sinusoidal endothelial cells (SEC) become dysfunctional and among other features acquire a vasoconstrictor phenotype, characterized by elevated production of vasoconstrictors and reduced release of vasodilators. The resulting imbalance promotes the contraction of different cells of the cirrhotic liver, such as hepatic stellate cells (HSC), portal myofibroblasts and vascular smooth muscle cells that lead to increased hepatic vascular tone and portal pressure. HSC in turn also experience a profound phenotypical transformation, with morphologic and functional consequences: loss of vitamin A droplets, alpha-smooth muscle actin overexpression, hyper-response to vasoconstrictors and enhanced proliferative and fibrogenic activity. Interestingly, in experimental models of cirrhosis, strategies aimed at improving the hepatic vascular tone by targeting SEC have also been shown to improve liver fibrosis. This may be due to the fact that cellular phenotype alterations share pathophysiological mechanisms, but also because SEC phenotype amelioration positively affects HSC phenotype [[2]DeLeve L.D. Wang X. Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence.Hepatology. 2008; 48: 920-930Crossref PubMed Scopus (245) Google Scholar].Increase of vasoconstrictors in the liverIncreased activity of several endogenous vasoconstrictors, such as endothelin, norepinephrine, angiotensin II, vasopressin, leukotrienes, and thromboxane A2 has been demonstrated in the cirrhotic liver (Fig. 2). Additionally, there is an increased vasoconstrictive response of the hepatic vascular bed to these vasoconstrictors. Although all these systems are potential targets to decrease HVR in cirrhosis, the phospholipase A2 – cycloxygenase-1 – thromboxane A2 pathway has been one of the most extensively studied. This system has been shown to be upregulated in cirrhotic SEC and Kupffer cells [3Gracia-Sancho J. Lavina B. Rodriguez-Vilarrupla A. Garcia-Caldero H. Bosch J. Garcia-Pagan J.C. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers.J Hepatol. 2007; 47: 220-227Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 4Steib C.J. Gerbes A.L. Bystron M. Op d.W. Hartl J. Roggel F. et al.Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A(2).J Hepatol. 2007; 47: 228-238Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar], and its blockade significantly improves endothelial dysfunction and reduces HVR in the cirrhotic liver [[5]Graupera M. Garcia-Pagan J.C. Pares M. Abraldes J.G. Rosello J. Bosch J. et al.Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers.J Hepatol. 2003; 39: 515-521Abstract Full Text Full Text PDF PubMed Scopus (64) Google bioavailability of intrahepatic vasodilatorsNitric oxide (NO) is probably the most important vasodilator involved in the regulation of hepatic vascular tone. Cirrhotic livers exhibit reduced NO availability, which is due both to decreased endothelial Nitric Oxide Synthase (eNOS) activity and to increased NO scavenging by elevated oxidative stress (Fig. 2).Reduced eNOS activity is attributed to several alterations in its post-translational regulation, which have been described in detail in a recent review [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. These alterations include reduced eNOS phosphorylation, low levels of its co-factor tetrahydrobiopterin (BH4), increased caveolin expression and release of asymmetric-dimethyl-arginine [[6]Wiest R. Groszmann R.J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.Hepatology. 2002; 35: 478-491Crossref PubMed Scopus (370) Google Scholar]. Different studies have shown that interventions that increase eNOS activity improve liver endothelial dysfunction and reduce portal pressure in experimental models of cirrhosis. Statin administration probably represents the most promising therapeutic option; indeed, the beneficial effects of statin administration reducing portal pressure have been already confirmed in patients with cirrhosis in a recent double-blind study [[7]Abraldes J.G. Albillos A. Banares R. Turnes J. Gonzalez R. Garcia-Pagan J.C. et al.Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial.Gastroenterology. 2009; 136: 1651-1658Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar].Increased superoxide levels in cirrhotic livers result from increased production and diminished elimination by superoxide dismutase (SOD) [[8]Gracia-Sancho J. Lavina B. Rodriguez-Vilarrupla A. Garcia-Caldero H. Fernandez M. Bosch J. et al.Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability.Hepatology. 2008; 47: 1248-1256Crossref PubMed Scopus (109) Google Scholar]. Superoxide reacts with NO leading to formation of peroxynitrite, a powerful pro-fibrogenic agent, and decreases NO availability. This is especially relevant in an infection situation, where increased inducible NOS (iNOS) overproduces NO that reacts with superoxide to form high levels of peroxynitrite [[9]Thabut D. Tazi K.A. Bonnefont-Rousselot D. Aller M. Farges O. Guimont M.C. et al.High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats.Hepatology. 2007; 46: 1893-1906Crossref PubMed Scopus (54) Google Scholar]. In addition, superoxide can oxidize and therefore inactivate BH4 further reducing NO bioavailability by decreasing eNOS activity. SOD supplementation reduces intrahepatic superoxide, increases NO, improves endothelial function and reduces portal pressure. In addition, peroxynitrite is also reduced, which may explain our recent finding of decreased liver fibrosis after SOD treatment (unpublished observation).In addition to these mechanisms related to endothelial dysfunction, alterations in the contractile cells have also been described. HSC have been shown to hyperreact in response to vasoconstrictor stimuli. The RhoA/Rho-kinase pathway is essential for contraction of vascular smooth muscle cells and its upregulation in cirrhotic livers contributes to increase HVR by increasing the sensitivity of the hepatic vasculature to vasoconstrictors [[10]Zhou Q. Hennenberg M. Trebicka J. et upregulation of and contributes to increased hepatic vascular resistance in with PubMed Scopus Google Scholar]. The analysis of the structural factors (fibrosis, vascular remodeling, vascular occlusion, nodule formation) contributing to increase HVR is out of the scope of this review that will focus on the dynamic component of the increased HVR. progression to cirrhosis, sinusoidal endothelial cells (SEC) become dysfunctional and among other features acquire a vasoconstrictor phenotype, characterized by elevated production of vasoconstrictors and reduced release of vasodilators. The resulting imbalance promotes the contraction of different cells of the cirrhotic liver, such as hepatic stellate cells (HSC), portal myofibroblasts and vascular smooth muscle cells that lead to increased hepatic vascular tone and portal pressure. HSC in turn also experience a profound phenotypical transformation, with morphologic and functional consequences: loss of vitamin A droplets, alpha-smooth muscle actin overexpression, hyper-response to vasoconstrictors and enhanced proliferative and fibrogenic activity. Interestingly, in experimental models of cirrhosis, strategies aimed at improving the hepatic vascular tone by targeting SEC have also been shown to improve liver fibrosis. This may be due to the fact that cellular phenotype alterations share pathophysiological mechanisms, but also because SEC phenotype amelioration positively affects HSC phenotype [[2]DeLeve L.D. Wang X. Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence.Hepatology. 2008; 48: 920-930Crossref PubMed Scopus (245) Google Scholar]. of vasoconstrictors in the liverIncreased activity of several endogenous vasoconstrictors, such as endothelin, norepinephrine, angiotensin II, vasopressin, leukotrienes, and thromboxane A2 has been demonstrated in the cirrhotic liver (Fig. 2). Additionally, there is an increased vasoconstrictive response of the hepatic vascular bed to these vasoconstrictors. Although all these systems are potential targets to decrease HVR in cirrhosis, the phospholipase A2 – cycloxygenase-1 – thromboxane A2 pathway has been one of the most extensively studied. This system has been shown to be upregulated in cirrhotic SEC and Kupffer cells [3Gracia-Sancho J. Lavina B. Rodriguez-Vilarrupla A. Garcia-Caldero H. Bosch J. Garcia-Pagan J.C. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers.J Hepatol. 2007; 47: 220-227Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 4Steib C.J. Gerbes A.L. Bystron M. Op d.W. Hartl J. Roggel F. et al.Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A(2).J Hepatol. 2007; 47: 228-238Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar], and its blockade significantly improves endothelial dysfunction and reduces HVR in the cirrhotic liver [[5]Graupera M. Garcia-Pagan J.C. Pares M. Abraldes J.G. Rosello J. Bosch J. et al.Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers.J Hepatol. 2003; 39: 515-521Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. activity of several endogenous vasoconstrictors, such as endothelin, norepinephrine, angiotensin II, vasopressin, leukotrienes, and thromboxane A2 has been demonstrated in the cirrhotic liver (Fig. 2). Additionally, there is an increased vasoconstrictive response of the hepatic vascular bed to these vasoconstrictors. Although all these systems are potential targets to decrease HVR in cirrhosis, the phospholipase A2 – cycloxygenase-1 – thromboxane A2 pathway has been one of the most extensively studied. This system has been shown to be upregulated in cirrhotic SEC and Kupffer cells [3Gracia-Sancho J. Lavina B. Rodriguez-Vilarrupla A. Garcia-Caldero H. Bosch J. Garcia-Pagan J.C. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers.J Hepatol. 2007; 47: 220-227Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 4Steib C.J. Gerbes A.L. Bystron M. Op d.W. Hartl J. Roggel F. et al.Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A(2).J Hepatol. 2007; 47: 228-238Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar], and its blockade significantly improves endothelial dysfunction and reduces HVR in the cirrhotic liver [[5]Graupera M. Garcia-Pagan J.C. Pares M. Abraldes J.G. Rosello J. Bosch J. et al.Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers.J Hepatol. 2003; 39: 515-521Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. bioavailability of intrahepatic vasodilatorsNitric oxide (NO) is probably the most important vasodilator involved in the regulation of hepatic vascular tone. Cirrhotic livers exhibit reduced NO availability, which is due both to decreased endothelial Nitric Oxide Synthase (eNOS) activity and to increased NO scavenging by elevated oxidative stress (Fig. 2).Reduced eNOS activity is attributed to several alterations in its post-translational regulation, which have been described in detail in a recent review [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. These alterations include reduced eNOS phosphorylation, low levels of its co-factor tetrahydrobiopterin (BH4), increased caveolin expression and release of asymmetric-dimethyl-arginine [[6]Wiest R. Groszmann R.J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.Hepatology. 2002; 35: 478-491Crossref PubMed Scopus (370) Google Scholar]. Different studies have shown that interventions that increase eNOS activity improve liver endothelial dysfunction and reduce portal pressure in experimental models of cirrhosis. Statin administration probably represents the most promising therapeutic option; indeed, the beneficial effects of statin administration reducing portal pressure have been already confirmed in patients with cirrhosis in a recent double-blind study [[7]Abraldes J.G. Albillos A. Banares R. Turnes J. Gonzalez R. Garcia-Pagan J.C. et al.Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial.Gastroenterology. 2009; 136: 1651-1658Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar].Increased superoxide levels in cirrhotic livers result from increased production and diminished elimination by superoxide dismutase (SOD) [[8]Gracia-Sancho J. Lavina B. Rodriguez-Vilarrupla A. Garcia-Caldero H. Fernandez M. Bosch J. et al.Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability.Hepatology. 2008; 47: 1248-1256Crossref PubMed Scopus (109) Google Scholar]. Superoxide reacts with NO leading to formation of peroxynitrite, a powerful pro-fibrogenic agent, and decreases NO availability. This is especially relevant in an infection situation, where increased inducible NOS (iNOS) overproduces NO that reacts with superoxide to form high levels of peroxynitrite [[9]Thabut D. Tazi K.A. Bonnefont-Rousselot D. Aller M. Farges O. Guimont M.C. et al.High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats.Hepatology. 2007; 46: 1893-1906Crossref PubMed Scopus (54) Google Scholar]. In addition, superoxide can oxidize and therefore inactivate BH4 further reducing NO bioavailability by decreasing eNOS activity. SOD supplementation reduces intrahepatic superoxide, increases NO, improves endothelial function and reduces portal pressure. In addition, peroxynitrite is also reduced, which may explain our recent finding of decreased liver fibrosis after SOD treatment (unpublished observation).In addition to these mechanisms related to endothelial dysfunction, alterations in the contractile cells have also been described. HSC have been shown to hyperreact in response to vasoconstrictor stimuli. The RhoA/Rho-kinase pathway is essential for contraction of vascular smooth muscle cells and its upregulation in cirrhotic livers contributes to increase HVR by increasing the sensitivity of the hepatic vasculature to vasoconstrictors [[10]Zhou Q. Hennenberg M. Trebicka J. et upregulation of and contributes to increased hepatic vascular resistance in with PubMed Scopus Google Scholar]. Nitric oxide (NO) is probably the most important vasodilator involved in the regulation of hepatic vascular tone. Cirrhotic livers exhibit reduced NO availability, which is due both to decreased endothelial Nitric Oxide Synthase (eNOS) activity and to increased NO scavenging by elevated oxidative stress (Fig. 2). eNOS activity is attributed to several alterations in its post-translational regulation, which have been described in detail in a recent review [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. These alterations include reduced eNOS phosphorylation, low levels of its co-factor tetrahydrobiopterin (BH4), increased caveolin expression and release of asymmetric-dimethyl-arginine [[6]Wiest R. Groszmann R.J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.Hepatology. 2002; 35: 478-491Crossref PubMed Scopus (370) Google Scholar]. Different studies have shown that interventions that increase eNOS activity improve liver endothelial dysfunction and reduce portal pressure in experimental models of cirrhosis. Statin administration probably represents the most promising therapeutic option; indeed, the beneficial effects of statin administration reducing portal pressure have been already confirmed in patients with cirrhosis in a recent double-blind study [[7]Abraldes J.G. Albillos A. Banares R. Turnes J. Gonzalez R. Garcia-Pagan J.C. et al.Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial.Gastroenterology. 2009; 136: 1651-1658Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar]. superoxide levels in cirrhotic livers result from increased production and diminished elimination by superoxide dismutase (SOD) [[8]Gracia-Sancho J. Lavina B. Rodriguez-Vilarrupla A. Garcia-Caldero H. Fernandez M. Bosch J. et al.Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability.Hepatology. 2008; 47: 1248-1256Crossref PubMed Scopus (109) Google Scholar]. Superoxide reacts with NO leading to formation of peroxynitrite, a powerful pro-fibrogenic agent, and decreases NO availability. This is especially relevant in an infection situation, where increased inducible NOS (iNOS) overproduces NO that reacts with superoxide to form high levels of peroxynitrite [[9]Thabut D. Tazi K.A. Bonnefont-Rousselot D. Aller M. Farges O. Guimont M.C. et al.High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats.Hepatology. 2007; 46: 1893-1906Crossref PubMed Scopus (54) Google Scholar]. In addition, superoxide can oxidize and therefore inactivate BH4 further reducing NO bioavailability by decreasing eNOS activity. SOD supplementation reduces intrahepatic superoxide, increases NO, improves endothelial function and reduces portal pressure. In addition, peroxynitrite is also reduced, which may explain our recent finding of decreased liver fibrosis after SOD treatment (unpublished In addition to these mechanisms related to endothelial dysfunction, alterations in the contractile cells have also been described. HSC have been shown to hyperreact in response to vasoconstrictor stimuli. The RhoA/Rho-kinase pathway is essential for contraction of vascular smooth muscle cells and its upregulation in cirrhotic livers contributes to increase HVR by increasing the sensitivity of the hepatic vasculature to vasoconstrictors [[10]Zhou Q. Hennenberg M. Trebicka J. et upregulation of and contributes to increased hepatic vascular resistance in with PubMed Scopus Google Scholar]. vascular vasodilators NO, and have been in the splanchnic vasodilatation of liver cirrhosis (Fig. In addition, and in to is in the liver, a in the RhoA/Rho-kinase pathway has been in the systemic that this may contribute to vascular and vasodilatation M. Trebicka J. J. of in portal 2008; PubMed Scopus Google Scholar]. that splanchnic also a in the development and of splanchnic in portal hypertension [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. The mechanisms for this are but several factors that increase such as or in portal blockade of decreases splanchnic and portal in models of portal hypertension M. M. B. Garcia-Pagan J.C. J. Bosch J. of decreases the development of splanchnic and in portal hypertensive Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar]. The increased portal can be by of splanchnic vasoconstrictors such as and its and its and the other splanchnic vasodilatation to decreased which promotes the activation of endogenous and of the by an increase in the that in turn contributes to further increase splanchnic blood and portal pressure and to the development of and dysfunction Y. Groszmann R.J. The of chronic liver from the to the PubMed Scopus Google is that the and the hepatic vascular share alterations in the vasoactive are in an vascular tone due to decreased vasodilators and increased vasoconstrictors the primary factors in the intrahepatic the vascular bed an response characterized by of and a response to to be new strategies to portal vasodilators to reduce the increased intrahepatic vascular tone a further increase in splanchnic and systemic vasoconstrictors to reduce splanchnic and systemic vasodilatation may the enhanced intrahepatic vascular tone [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. vasodilators NO, and have been in the splanchnic vasodilatation of liver cirrhosis (Fig. In addition, and in to is in the liver, a in the RhoA/Rho-kinase pathway has been in the systemic that this may contribute to vascular and vasodilatation M. Trebicka J. J. of in portal 2008; PubMed Scopus Google Scholar]. that splanchnic also a in the development and of splanchnic in portal hypertension [[1]Bosch J. Abraldes J.G. Fernandez M. Garcia-Pagan J.C. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. The mechanisms for this are but several factors that increase such as or in portal blockade of decreases splanchnic and portal in models of portal hypertension M. M. B. Garcia-Pagan J.C. J. Bosch J. of decreases the development of splanchnic and in portal hypertensive Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar]. The increased portal can be by of splanchnic vasoconstrictors such as and its and its and the other splanchnic vasodilatation to decreased which promotes the activation of endogenous and of the by an increase in the that in turn contributes to further increase splanchnic blood and portal pressure and to the development of and dysfunction Y. Groszmann R.J. 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