Pathophysiology of portal hypertension

Clinics in Liver Disease

Volumn 18, Issue 2, 2014, Pages 281-291

  Iwakiri, Yasuko ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cirrhosis; Fibrosis; Hyperdynamic circulation; Lymphatic system; Nitric oxide; Splenomegaly

Indexed keywords

ANGIOPOIETIN; ANGIOTENSIN; ANTIOXIDANT; ARACHIDONIC ACID; BRADYKININ; CHEMOKINE; CYCLOOXYGENASE 1; CYTOKINE; ENDOCANNABINOID; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENDOTHELIN 1; ENDOTHELIUM DERIVED HYPERPOLARIZING FACTOR; EPOXYICOSATRIENOIC ACID; IMATINIB; NEUROPEPTIDE Y; NITRIC OXIDE; PEROXYNITRITE; PLACENTAL GROWTH FACTOR; POTASSIUM ION; PROSTACYCLIN; PROSTAGLANDIN H2; RAPAMYCIN; RETINOL; SORAFENIB; SUPEROXIDE; THROMBOXANE A2; THROMBOXANE A2 RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; UROTENSIN II; VASCULOTROPIN;

ANGIOGENESIS; BACTERIAL TRANSLOCATION; ENDOTHELIUM CELL; HEART INDEX; HEPATIC ENCEPHALOPATHY; HUMAN; INTESTINE FLORA; LIVER BLOOD FLOW; LIVER CIRCULATION; LIVER CIRRHOSIS; LIVER FIBROSIS; LIVER SINUSOID; LYMPHATIC SYSTEM; MEAN ARTERIAL PRESSURE; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PATHOPHYSIOLOGY; PORTAL HYPERTENSION; PORTAL VEIN BLOOD FLOW; PORTAL VEIN BLOOD PRESSURE; REVIEW; SHEAR STRESS; SPLANCHNIC BLOOD FLOW; SPLENOMEGALY; STELLATE CELL; STEM CELL TRANSPLANTATION; SYSTEMIC CIRCULATION; SYSTEMIC VASCULAR RESISTANCE; VASODILATATION; COLLATERAL CIRCULATION; COMPLICATION; HYPERTENSION, PORTAL; NEOVASCULARIZATION (PATHOLOGY); PHYSIOLOGY; VASCULAR RESISTANCE; VASOCONSTRICTION;

COLLATERAL CIRCULATION; ENDOTHELIAL CELLS; HEPATIC STELLATE CELLS; HUMANS; HYPERTENSION, PORTAL; LIVER CIRCULATION; LIVER CIRRHOSIS; NEOVASCULARIZATION, PATHOLOGIC; SPLANCHNIC CIRCULATION; VASCULAR RESISTANCE; VASOCONSTRICTION; VASODILATION;

EID: 84897078974     PISSN: 10893261     EISSN: 15578224     Source Type: Journal    
DOI: 10.1016/j.cld.2013.12.001     Document Type: Review

References (86)

1. Bosch J. Vascular deterioration in cirrhosis: the big picture. JClin Gastroenterol 2007, 41(Suppl 3):S247-S253.
2. Iwakiri Y., Groszmann R.J. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006, 43:S121-S131.
3. Rockey D.C. Cell and molecular mechanisms of increased intrahepatic resistance and hemodynamic correlates 2005, Humana Press, Totowa (NJ).
4. Pinzani M., Vizzutti F. Anatomy and vascular biology of the cells in the portal circulation 2005, Humana Press, Totowa (NJ).
5. Wiest R., Groszmann R.J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002, 35:478-491.
6. Ding B.S., Nolan D.J., Butler J.M., et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 2010, 468:310-315.
7. Jagavelu K., Routray C., Shergill U., et al. Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology 2010, 52:590-601.
8. Thabut D., Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension?. JHepatol 2010, 53:976-980.
9. Iwakiri Y., Groszmann R.J. Vascular endothelial dysfunction in cirrhosis. JHepatol 2007, 46:927-934.
10. Shah V., Haddad F.G., Garcia-Cardena G., et al. Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. JClin Invest 1997, 100:2923-2930.
11. Shah V., Toruner M., Haddad F., et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 1999, 117:1222-1228.
12. Iwakiri Y. The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. JClin Gastroenterol 2007, 41:S288-S294.
13. Gracia-Sancho J., Lavina B., Rodriguez-Vilarrupla A., et al. Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 2008, 47:1248-1256.
14. Hernandez-Guerra M., Garcia-Pagan J.C., Turnes J., et al. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology 2006, 43:485-491.
15. Lavina B., Gracia-Sancho J., Rodriguez-Vilarrupla A., et al. Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension. Gut 2009, 58:118-125.
16. Radi R. Peroxynitrite, a stealthy biological oxidant. JBiol Chem 2013, 288:26464-26472.
17. Yang Y.Y., Lee T.Y., Huang Y.T., et al. Asymmetric dimethylarginine (ADMA) determines the improvement of hepatic endothelial dysfunction by vitamin E in cirrhotic rats. Liver Int 2012, 32:48-57.
18. Garcia-Caldero H., Rodriguez-Vilarrupla A., Gracia-Sancho J., et al. Tempol administration, a superoxide dismutase mimetic, reduces hepatic vascular resistance and portal pressure in cirrhotic rats. JHepatol 2011, 54:660-665.
19. Yang Y.Y., Lee K.C., Huang Y.T., et al. Effects of N-acetylcysteine administration in hepatic microcirculation of rats with biliary cirrhosis. JHepatol 2008, 49:25-33.
20. Gracia-Sancho J., Lavina B., Rodriguez-Vilarrupla A., et al. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers. JHepatol 2007, 47:220-227.
21. Graupera M., March S., Engel P., et al. Sinusoidal endothelial COX-1-derived prostanoids modulate the hepatic vascular tone of cirrhotic rat livers. Am J Physiol Gastrointest Liver Physiol 2005, 288:G763-G770.
22. Kawada N., Tran-Thi T.A., Klein H., et al. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances. Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem 1993, 213:815-823.
23. Bauer M., Bauer I., Sonin N.V., et al. Functional significance of endothelin B receptors in mediating sinusoidal and extrasinusoidal effects of endothelins in the intact rat liver. Hepatology 2000, 31:937-947.
24. Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver Int 2012, 32:199-213.
25. Kawada N., Seki S., Kuroki T., et al. ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1. Biochem Biophys Res Commun 1999, 266:296-300.
26. Pinzani M., Milani S., De Franco R., et al. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 1996, 110:534-548.
27. Rockey D.C., Weisiger R.A. Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology 1996, 24:233-240.
28. Medina J., Arroyo A.G., Sanchez-Madrid F., et al. Angiogenesis in chronic inflammatory liver disease. Hepatology 2004, 39:1185-1195.
29. Kim M.Y., Baik S.K., Lee S.S. Hemodynamic alterations in cirrhosis and portal hypertension. Korean J Hepatol 2010, 16:347-352.
30. Perri R.E., Langer D.A., Chatterjee S., et al. Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation. Am J Physiol Gastrointest Liver Physiol 2006, 290:G535-G542.
31. Rappaport A.M., MacPhee P.J., Fisher M.M., et al. The scarring of the liver acini (cirrhosis). Tridimensional and microcirculatory considerations. Virchows Arch A Pathol Anat Histopathol 1983, 402:107-137.
32. Taura K., De Minicis S., Seki E., et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 2008, 135:1729-1738.
33. Thabut D., Routray C., Lomberk G., et al. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 2011, 54:573-585.
34. Novo E., Cannito S., Zamara E., et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 2007, 170:1942-1953.
35. Nagy J.A., Morgan E.S., Herzberg K.T., et al. Pathogenesis of ascites tumor growth: angiogenesis, vascular remodeling, and stroma formation in the peritoneal lining. Cancer Res 1995, 55:376-385.
36. Dill M.T., Rothweiler S., Djonov V., et al. Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterology 2012, 142:967-977.e2.
37. Sumanovski L.T., Battegay E., Stumm M., et al. Increased angiogenesis in portal hypertensive rats: role of nitric oxide. Hepatology 1999, 29:1044-1049.
38. Sieber C.C., Sumanovski L.T., Stumm M., et al. Invivo angiogenesis in normal and portal hypertensive rats: role of basic fibroblast growth factor and nitric oxide. JHepatol 2001, 34:644-650.
39. Groszmann R.J., Kotelanski B., Cohn J.N. Different patterns of porta-systemic shunting in cirrhosis of the liver studied by an indicator dilution technique. Acta Gastroenterol Latinoam 1971, 3:111-116.
40. Bosch J., Pizcueta P., Feu F., et al. Pathophysiology of portal hypertension. Gastroenterol Clin North Am 1992, 21:1-14.
41. Abraldes J.G., Iwakiri Y., Loureiro-Silva M., et al. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 2006, 290:G980-G987.
42. Huang H.C., Haq O., Utsumi T., et al. Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure. JCell Mol Med 2012, 16:1125-1133.
43. Fernandez M., Vizzutti F., Garcia-Pagan J.C., et al. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology 2004, 126:886-894.
44. Geerts A.M., De Vriese A.S., Vanheule E., et al. Increased angiogenesis and permeability in the mesenteric microvasculature of rats with cirrhosis and portal hypertension: an invivo study. Liver Int 2006, 26:889-898.
45. Van Steenkiste C., Geerts A., Vanheule E., et al. Role of placental growth factor in mesenteric neoangiogenesis in a mouse model of portal hypertension. Gastroenterology 2009, 137:2112-2124.e1-6.
46. Fernandez M., Mejias M., Angermayr B., et al. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. JHepatol 2005, 43:98-103.
47. Fernandez M., Mejias M., Garcia-Pras E., et al. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology 2007, 46:1208-1217.
48. Tiani C., Garcia-Pras E., Mejias M., et al. Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension. JHepatol 2009, 50:296-305.
49. Mejias M., Garcia-Pras E., Tiani C., et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 2009, 49:1245-1256.
50. Reiberger T., Angermayr B., Schwabl P., et al. Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats. JHepatol 2009, 51:865-873.
51. Huang H.C., Wang S.S., Hsin I.F., et al. Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats. Hepatology 2012, 56:248-258.
52. Iwakiri Y. The systemic and splanchnic circulation. Chronic liver failure, mechanisms and management 2011, 305-320. Humana Press, New York. P. Gines, P.S. Kamath, V. Arroyo (Eds.).
53. Tsai M.H., Iwakiri Y., Cadelina G., et al. Mesenteric vasoconstriction triggers nitric oxide overproduction in the superior mesenteric artery of portal hypertensive rats. Gastroenterology 2003, 125:1452-1461.
54. Iwakiri Y., Tsai M.H., McCabe T.J., et al. Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension. Am J Physiol Heart Circ Physiol 2002, 282:H2084-H2090.
55. Moezi L., Gaskari S.A., Liu H., et al. Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors. Br J Pharmacol 2006, 149:898-908.
56. Batkai S., Jarai Z., Wagner J.A., et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001, 7:827-832.
57. Moleda L., Trebicka J., Dietrich P., et al. Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction. Gut 2011, 60(8):1122-1132.
58. Trebicka J., Leifeld L., Hennenberg M., et al. Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology 2008, 47:1264-1276.
59. Kemp W., Krum H., Colman J., et al. Urotensin II: a novel vasoactive mediator linked to chronic liver disease and portal hypertension. Liver Int 2007, 27:1232-1239.
60. Hennenberg M., Trebicka J., Kohistani A.Z., et al. Vascular hyporesponsiveness to angiotensin II in rats with CCl(4)-induced liver cirrhosis. Eur J Clin Invest 2009, 39:906-913.
61. Chu C.J., Wu S.L., Lee F.Y., et al. Splanchnic hyposensitivity to glypressin in a haemorrhage/transfused rat model of portal hypertension: role of nitric oxide and bradykinin. Clin Sci (Lond) 2000, 99:475-482.
62. Chen C.T., Chu C.J., Lee F.Y., et al. Splanchnic hyposensitivity to glypressin in a hemorrhage-transfused common bile duct-ligated rat model of portal hypertension: role of nitric oxide and bradykinin. Hepatogastroenterology 2009, 56:1261-1267.
63. Heinemann A., Wachter C.H., Fickert P., et al. Vasopressin reverses mesenteric hyperemia and vasoconstrictor hyporesponsiveness in anesthetized portal hypertensive rats. Hepatology 1998, 28:646-654.
64. Song D., Liu H., Sharkey K.A., et al. Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression. Hepatology 2002, 35:159-166.
65. Coll M., Martell M., Raurell I., et al. Atrophy of mesenteric sympathetic innervation may contribute to splanchnic vasodilation in rat portal hypertension. Liver Int 2010, 30:593-602.
66. Ezkurdia N., Coll M., Raurell I., et al. Blockage of the afferent sensitive pathway prevents sympathetic atrophy and hemodynamic alterations in rat portal hypertension. Liver Int 2012, 32:1295-1305.
67. Fernandez-Varo G., Ros J., Morales-Ruiz M., et al. Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis. Am J Pathol 2003, 162:1985-1993.
68. Fernandez-Varo G., Morales-Ruiz M., Ros J., et al. Impaired extracellular matrix degradation in aortic vessels of cirrhotic rats. JHepatol 2007, 46:440-446.
69. Seo Y.S., Shah V.H. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol 2012, 18:337-346.
70. Frances R., Chiva M., Sanchez E., et al. Bacterial translocation is downregulated by anti-TNF-alpha monoclonal antibody administration in rats with cirrhosis and ascites. JHepatol 2007, 46:797-803.
71. Terai S., Ishikawa T., Omori K., et al. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells 2006, 24:2292-2298.
72. Jang Y.O., Kim Y.J., Baik S.K., et al. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver Int 2014, 34(1):33-41.
73. Sakamoto M., Nakamura T., Torimura T., et al. Transplantation of endothelial progenitor cells ameliorates vascular dysfunction and portal hypertension in carbon tetrachloride-induced rat liver cirrhotic model. JGastroenterol Hepatol 2013, 28:168-178.
74. Sakaida I., Terai S., Yamamoto N., et al. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology 2004, 40:1304-1311.
75. Cardenas A., Bataller R., Arroyo V. Mechanisms of ascites formation. Clin Liver Dis 2000, 4:447-465.
76. Barrowman J.A., Granger D.N. Effects of experimental cirrhosis on splanchnic microvascular fluid and solute exchange in the rat. Gastroenterology 1984, 87:165-172.
77. Chung C., Iwakiri Y. The lymphatic vascular system in liver diseases: its role in ascites formation. Clin Mol Hepatol 2013, 19:99-104.
78. Ribera J., Pauta M., Melgar-Lesmes P., et al. Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats. Gut 2013, 62:138-145.
79. Takuma Y., Nouso K., Morimoto Y., et al. Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices. Gastroenterology 2013, 144:92-101.e2.
80. Colecchia A., Montrone L., Scaioli E., et al. Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis. Gastroenterology 2012, 143:646-654.
81. Berzigotti A., Seijo S., Arena U., et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 2013, 144:102-111.e1.
82. Mori K., Arai H., Abe T., et al. Spleen stiffness correlates with the presence of ascites but not esophageal varices in chronic hepatitis C patients. Biomed Res Int 2013, 2013:857862.
83. Mejias M., Garcia-Pras E., Gallego J., et al. Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension. JHepatol 2010, 52:529-539.
84. Iwakiri Y., Grisham M., Shah V. Vascular biology and pathobiology of the liver: report of a single-topic symposium. Hepatology 2008, 47:1754-1763.
85. Tashiro K., Satoh A., Utsumi T., et al. Absence of Nogo-B (reticulon 4B) facilitates hepatic stellate cell apoptosis and diminishes hepatic fibrosis in mice. Am J Pathol 2013, 182:786-795.
86. Zhang D., Utsumi T., Huang H.C., et al. Reticulon 4B (Nogo-B) is a novel regulator of hepatic fibrosis. Hepatology 2011, 53:1306-1315.