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2016, Number 3

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Ann Hepatol 2016; 15 (3)

Angiogenesis and portal-systemic collaterals in portal hypertension

Gana JC, Serrano CA, Ling SC

Language: English
References: 96
Page: 303-313
PDF size: 169.70 Kb.


ABSTRACT

In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.


REFERENCES

  1. Quinn PG, Johnston DE. Detection of chronic liver disease: costs and benefits. Gastroenterologist 1997; 5: 58-77.

  2. Bellentani S, Tiribelli C, Saccoccio G, Sodde M, Fratti N, De Martin C, Cristianini G, et al. Prevalence of chronic liver disease in the general population of northern Italy: the Dionysos Study. Hepatology 1994; 20: 1442-9.

  3. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46: 922-38.

  4. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. N Engl J Med 1988; 319: 983-9.

  5. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001; 345: 669-81.

  6. Garcia-Tsao G, Bosch J, Groszmann RJ. Portal hypertension and variceal bleeding—unresolved issues. Summary of an American Association for the study of liver diseases and European Association for the study of the liver single-topic conference. Hepatology 2008; 47: 1764-72.

  7. Lykavieris P, Gauthier F, Hadchouel P, Duche M, Bernard O. Risk of gastrointestinal bleeding during adolescence and early adulthood in children with portal vein obstruction. J Pediatr 2000; 136: 805-8.

  8. Goncalves ME, Cardoso SR, Maksoud JG. Prophylactic sclerotherapy in children with esophageal varices: long-term results of a controlled prospective randomized trial. J Pediatr Surg 2000; 35: 401-5.

  9. Miga D, Sokol RJ, Mackenzie T, Narkewicz MR, Smith D, Karrer FM. Survival after first esophageal variceal hemorrhage in patients with biliary atresia. J Pediatr 2001; 139: 291-6.

  10. van Heurn LW, Saing H, Tam PK. Portoenterostomy for biliary atresia: Long-term survival and prognosis after esophageal variceal bleeding. J Pediatr Surg 2004; 39: 6-9.

  11. Kobayashi A, Itabashi F, Ohbe Y. Long-term prognosis in biliary atresia after hepatic portoenterostomy: analysis of 35 patients who survived beyond 5 years of age. J Pediatr 1984; 105: 243-6.

  12. Mitra SK, Kumar V, Datta DV, Rao PN, Sandhu K, Singh GK, Sodhi JS, et al. Extrahepatic portal hypertension: a review of 70 cases. J Pediatr Surg 1978; 13: 51-7.

  13. Gana JC, Turner D, Roberts EA, Ling SC. Derivation of a clinical prediction rule for the noninvasive diagnosis of varices in children. J Pediatr Gastroenterol Nutr 2010; 50: 188-93.

  14. Gana JC, Turner D, Mielivergani G, Davenport M, Miloh T, Avitzur Y, Yap J, et al. A clinical prediction rule and platelet count predict esophageal varices in children. Gastroenterology 2011; 141: 2009-16.

  15. Toyosaka A, Okamoto E, Okasora T, Nose K, Tomimoto Y. Outcome of 21 patients with biliary atresia living more than 10 years. J Pediatr Surg 1993; 28: 1498-501.

  16. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010; 362: 823-32.

  17. Gracia-Sancho J, Maeso-Díaz R, Fernández-Iglesias A, Navarro-Zornoza M, Bosch J. New cellular and molecular targets for the treatment of portal hypertension. Hepatol Int 2015; 9: 183-91.

  18. Gracia-Sancho J, Laviña B, Rodríguez-Vilarrupla A, García-Calderó H, Bosch J, García-Pagán JC. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers. J Hepatol 2007; 47: 220-7.

  19. Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998; 114: 344-51.

  20. Marra F, Pinzani M. Role of hepatic stellate cells in the pathogenesis of portal hypertension. Nefrologia 2002; 22(Suppl. 5): 34-40.

  21. Hu LS, George J, Wang JH. Current concepts on the role of nitric oxide in portal hypertension. World J. Gastroenterol 2013; 19: 170-17.

  22. Novo E, Cannito S, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 2007; 170: 1942-53.

  23. Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Hepatology 2007; 45: 817-25.

  24. Medina J, Arroyo AG, Sanchez-Madrid F, Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease. Hepatology 2004; 39: 1185-95.

  25. Pinzani M, Rombouts K. Liver fibrosis: from the bench to clinical targets. Dig Liver Dis 2004; 36: 231-42.

  26. Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009; 50: 604-20.

  27. Rappaport AM, MacPhee PJ, Fisher MM, Phillips MJ. The scarring of the liver acini (Cirrhosis). Tridimensional and microcirculatory considerations. Virchows Arch A Pathol Anat Histopathol 1983; 402: 107-37.

  28. Wang YQ, Ikeda K, Ikebe T, Hirakawa K, Sowa M, Nakatani K, Kawada N, et al. Inhibition of hepatic stellate cell proliferation and activation by the semisynthetic analogue of fumagillin TNP-470 in rats. Hepatology 2000; 32: 980-9.

  29. Taura K, De MS, Seki E, Hatano E, Iwaisako K, Osterreicher CH, Kodama Y, et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 2008; 135: 1729-38.

  30. Lemoinne S, Cadoret A, Rautou P-E, El Mourabit H, Ratziu V, Corpechot C, Rey C, et al. Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles. Hepatology 2015; 61: 1041-55.

  31. Tugues S, Fernandez-Varo G, Muñoz-Luque J, Ros J, Arroyo V, Rodés J, Friedman SL, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007; 46: 1919-26.

  32. Bosch J, D’Amico G, Garcia-Pagan JC. Portal hypertension. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff’s diseases of the liver. Philadelphia: Lippincott Williams & Wilkins; 2003, p. 429-85.

  33. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002; 35: 478-91.

  34. Riggio O, Efrati C, Catalano C, Pediconi F, Mecarelli O, Accornero N, Nicolao F, et al. High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology 2005; 42: 1158-65.

  35. Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363: 1461-8.

  36. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985; 5: 419-24.

  37. Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006; 43: S121-S131.

  38. Wiest R, Shah V, Sessa WC, Groszmann RJ. NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. Am J Physiol 1999; 276: G1043-G1051.

  39. Martell M, Coll M, Ezkurdia N, Raurell I, Genescà J. Physiopathology of splanchnic vasodilation in portal hypertension. World J Hepatol 2010; 2: 208-20.

  40. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473: 298-307.

  41. Elpek GÖ. Angiogenesis and liver fibrosis. World J Hepatol 2015; 7: 377-91.

  42. Bruno A, Pagani A, Pulze L, Albini A, Dallaglio K, Noonan DM, Mortara L. Orchestration of angiogenesis by immune cells. Front Oncol 2014; 4: 131.

  43. Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 2014; 147: 577-94.e1.

  44. Novo E, Cannito S, Paternostro C, Bocca C, Miglietta A, Parola M. Cellular and molecular mechanisms in liver fibrogenesis. Arch Biochem Biophys 2014; 548: 20-37.

  45. Sanz-Cameno P, Trapero-Marugán M, Chaparro M, Jones EA, Moreno-Otero R. Angiogenesis: from chronic liver inflammation to hepatocellular carcinoma. J Oncol 2010; 2010: 272170.

  46. Novo E, Povero D, Busletta C, Paternostro C, di Bonzo LV, Cannito S, Compagnone A, et al. The biphasic nature of hypoxia- induced directional migration of activated human hepatic stellate cells. J Pathol 2012; 226: 588-97.

  47. Helisch A, Schaper W. Arteriogenesis: the development and growth of collateral arteries. Microcirculation 2003; 10: 83-97.

  48. Unthank JL, Fath SW, Burkhart HM, Miller SC, Dalsing MC. Wall remodeling during luminal expansion of mesenteric arterial collaterals in the rat. Circ Res 1996; 79: 1015–23.

  49. Nagel T, Resnick N, Dewey Jr. CF, Gimbrone Jr. MA. Vascular endothelial cells respond to spatial gradients in fluid shear stress by enhanced activation of transcription factors. Arterioscler Thromb Vasc Biol 1999; 19: 1825-34.

  50. Walpola PL, Gotlieb AI, Cybulsky MI, Langille BL. Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress. Arterioscler Thromb Vasc Biol 1995; 15: 2-10.

  51. Cai W, Vosschulte R, fsah-Hedjri A, Koltai S, Kocsis E, Scholz D, Kostin S, et al. Altered balance between extracellular proteolysis and antiproteolysis is associated with adaptive coronary arteriogenesis. J Mol Cell Cardiol 2000; 32: 997-1011.

  52. Shyy JY, Lin MC, Han J, Lu Y, Petrime M, Chien S. The cis-acting phorbol ester "12-O-tetradecanoylphorbol 13-acetate"-responsive element is involved in shear stress-induced monocyte chemotactic protein 1 gene expression. Proc Natl Acad Sci USA 1995; 92: 8069-73.

  53. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone Jr. MA, Luster AD, et al. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 1999; 398: 718-23.

  54. Clauss M, Weich H, Breier G, Knies U, Rockl W, Waltenberger J, Risau W. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a unctional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 1996; 271: 17629-34.

  55. Heil M, Clauss M, Suzuki K, Buschmann IR, Willuweit A, Fischer S, Schaper W. Vascular endothelial growth factor (VEGF) stimulates monocyte migration through endothelial monolayers via increased integrin expression. Eur J Cell Biol 2000; 79: 8507.

  56. Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Shirai Y, Douhara A, et al. Possible involvement of angiogenesis in chronic liver diseases: interaction among renin-angiotensinaldosterone system, insulin resistance and oxidative stress. Curr Med Chem 2012; 19: 188998.

  57. Sumanovski LT, Battegay E, Stumm M, van der KM, Sieber CC. Increased angiogenesis in portal hypertensive rats: role of nitric oxide. Hepatology 1999; 29: 1044-49.

  58. Tsugawa K, Hashizume M, Tomikawa M, Migou S, Kawanaka H, Shiraishi S, Sueishi K, et al. Immunohistochemical localization of vascular endothelial growth factor in the rat portal hypertensive gastropathy. J Gastroenterol Hepatol 2001; 16: 429-37.

  59. Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R, Housset C, et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 2002; 35: 1010-21.

  60. Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portalsystemic collateral vessel formation in portal hypertensive mice. Gastroenterology 2004; 126: 886-94.

  61. Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodes J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol 2005; 43: 98-103.

  62. Angermayr B, Fernandez M, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J. NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats. Gut 2007; 56: 560-4.

  63. Reichenbach V, Fernández-Varo G, Casals G, Oró D, Ros J, Melgar-Lesmes P, Weiskirchen R, et al. Adenoviral dominantnegative soluble PDGFRα improves hepatic collagen, systemic hemodynamics, and portal pressure in fibrotic rats. J Hepatol 2012; 57: 967-73.

  64. Semela D, Das A, Langer D, Kang N, Leof E, Shah V. Plateletderived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology 2008; 135: 671-9.

  65. Principe A, Melgar-Lesmes P, Fernández-Varo G, del Arbol LR, Ros J, Morales-Ruiz M, et al. The hepatic apelin system: a new therapeutic target for liver disease. Hepatology 2008; 48: 1193-201.

  66. Tiani C, Garcia-Pras E, Mejias M, de Gottardi A, Berzigotti A, Bosch J, Fernandez M. Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension. J Hepatol 2009; 50: 296-305.

  67. Mejias M, Garcia-Pras E, Tiani C, Bosch J, Fernandez M. The somatostatin analogue octreotide inhibits angiogenesis in the earliest, but not in advanced, stages of portal hypertension in rats. J Cell Mol Med 2008; 12: 1690-9.

  68. Reiberger T, Angermayr B, Schwabl P, Rohr-Udilova N, Mitterhauser M, Gangl A, Peck-Radosavljevic M. Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats. J Hepatol 2009; 51: 865-73.

  69. Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 2009; 49: 1245-56.

  70. Thabut D, Routray C, Lomberk G, Shergill U, Glaser K, Huebert R, Patel L, et al. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 2011; 54:573-85.

  71. Pinter M, Sieghart W, Reiberger T, Rohr-Udilova N, Ferlitsch A, Peck-Radosavljevic M. The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma–a pilot study. Aliment Pharmacol Ther 2012; 35: 83-91.

  72. Shah VH, Bruix J. Antiangiogenic therapy: not just for cancer anymore? Hepatology 2009; 49: 1066-8.

  73. Van Steenkiste C, Geerts A, Vanheule E, Van Vlierberghe H, De Vos F, Olievier K, Casteleyn C, et al. Role of placental growth factor in mesenteric neoangiogenesis in a mouse model of portal hypertension. Gastroenterology 2009; 137: 2112-24.e1-6.

  74. Van Steenkiste C, Ribera J, Geerts A, Pauta M, Tugues S, Casteleyn C, Libbrecht L, et al. Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice. Hepatology 2011; 53: 1629-40.

  75. Hennenberg M, Trebicka J, Stark C, Kohistani AZ, Heller J, Sauerbruch T. Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis. Br J Pharmacol 2009; 157: 258-70.

  76. Fernandez M, Mejias M, Garcia-Pras E, Mendez R, Garcia-Pagan JC, Bosch J. 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: 1208-17.

  77. D’Amico M, Mejías M, García-Pras E, Abraldes JG, García- Pagán JC, Fernández M, Bosch J. Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 2012; 302: G1191-G1198.

  78. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Wu Y, et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 2003; 52: 1347-54.

  79. Watanabe K, Hasegawa Y, Yamashita H, Shimizu K, Ding Y, Abe M, Ohta H, et al. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J Clin Invest 2004; 114: 898-907.

  80. Coch L, Mejias M, Berzigotti A, Garcia-Pras E, Gallego J, Bosch J, Mendez R, et al. Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats. Hepatology 2014; 60: 633-47.

  81. Chatterjee S. Reversal of vasohibin-driven negative feedback loop of vascular endothelial growth factor/angiogenesis axis promises a novel antifibrotic therapeutic strategy for liver diseases. Hepatology 2014; 60: 458-60.

  82. Mejias M, Coch L, Berzigotti A, Garcia-Pras E, Gallego J, Bosch J, Fernandez M. Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile ductligated portal hypertensive rats. Gut 2015; 64: 657-66.

  83. Coriat R, Gouya H, Mir O, Ropert S, Vignaux O, Chaussade S, Sogni P, et al. Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib. PLoS One 2011; 6:e16978.

  84. Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001; 19: 1207-25.

  85. Greene AK, Wiener S, Puder M, Yoshida A, Shi B, Perez-Atayde AR, Jason Efstathiou JA, et al. Endothelial-directed hepatic regeneration after partial hepatectomy. Ann Surg 2003; 237: 530-35.

  86. LeCouter J, Moritz DR, Li B, Phillips GL, Liang XH, Gerber HP, Hillan KJ, et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003; 299: 890-93.

  87. Ward NL, Haninec AL, Van SP, Sled JG, Sturk C, Henkelman RM, Wanless IR, et al. Angiopoietin-1 causes reversible degradation of the portal microcirculation in mice: implications for treatment of liver disease. Am J Pathol 2004; 165: 889-99.

  88. Torimura T, Sata M, Ueno T, Kin M, Tsuji R, Suzaku K, Hashimoto O, et al. Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol 1998; 29: 986-91.

  89. Miyahara K, Nouso K, Tomoda T, Kobayashi S, Hagihara H, Kuwaki K, Toshimori J, et al. Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2011; 26: 1604-11.

  90. Enjoji M, Nakamuta M, Yamaguchi K, Ohta S, Kotoh K, Fukushima M, Kuniyoshi M, et al. Clinical significance of serum levels of vascular endothelial growth factor and its receptor in biliary disease and carcinoma. World J Gastroenterol 2005; 11: 1167-71.

  91. Assy N, Paizi M, Gaitini D, Baruch Y, Spira G. Clinical implication of VEGF serum levels in cirrhotic patients with or without portal hypertension. World J Gastroenterol 1999; 5: 296-300.

  92. Akiyoshi F, Sata M, Suzuki H, Uchimura Y, Mitsuyama K, Matsuo K, Tanikawa K. Serum vascular endothelial growth factor levels in various liver diseases. Dig Dis Sci 1998; 43: 41-5.

  93. Genesca J, Gonzalez A, Mujal A, Cereto F, Segura R. Vascular endothelial growth factor levels in liver cirrhosis. Dig Dis Sci 1999; 44: 1261-2.

  94. Waidmann O, Brunner F, Herrmann E, Zeuzem S, Piiper A, Kronenberger B. Macrophage activation is a prognostic parameter for variceal bleeding and overall survival in patients with liver cirrhosis. J Hepatol 2013; 58: 956-61.

  95. Grønbaek H, Sandahl TD, Mortensen C, Vilstrup H, Møller HJ, Møller S. Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis. Aliment Pharmacol Ther 2012; 36: 173-80.

  96. Yang Y-Y, Hou M-C, Lin M-W, Chen P-H, Liao W-C, Chu C-J, Lin HC. Combined platelet count with sCD163 and genetic variants optimizes esophageal varices prediction in cirrhotic patients. J Gastroenterol Hepatol 2013; 28: 112-21.




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