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Hepatology International
Published in: Hepatology International 1/2018

01-02-2018 | Special Issue - Portal Hypertension

Biology of portal hypertension

Authors: Matthew McConnell, Yasuko Iwakiri

Published in: Hepatology International | Special Issue 1/2018

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Abstract

Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.
Literature
1.
Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis—current status and future directions. J Hepatol 2014;61:912–924PubMedPubMedCentralCrossRef
2.
Bosch J, Groszmann RJ, Shah VH. Evolution in the understanding of the pathophysiological basis of portal hypertension: how changes in paradigm are leading to successful new treatments. J Hepatol 2015;62:S121–S130PubMedPubMedCentralCrossRef
3.
Iwakiri Y. The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol 2007;41(Suppl 3):S288–S294PubMedCrossRef
4.
5.
Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:S121–S131PubMedCrossRef
6.
Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver Int 2012;32:199–213PubMedCrossRef
7.
Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol 2007;46:927–934PubMedCrossRef
8.
Tetangco EP, Silva R, Lerma E. Portal hypertension: etiology, evaluation, and management. Dis Mon 2016;62(12):411–426PubMedCrossRef
9.
Cavallin M, Fasolato S, Marenco S, Piano S, Tonon M, Angeli P. The treatment of hepatorenal syndrome. Dig Dis 2015;33:548–554PubMedCrossRef
10.
Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2017;65:310–335PubMedCrossRef
11.
Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325–337PubMedCrossRef
12.
13.
Trautwein C, Friedman SL, Schuppan D, Pinzani M. Hepatic fibrosis: concept to treatment. J Hepatol 2015;62:S15–S24PubMedCrossRef
14.
15.
16.
Franco M, Roswall P, Cortez E, Hanahan D, Pietras K. Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression. Blood 2011;118:2906–2917PubMedPubMedCentralCrossRef
17.
LaBarbera KE, Hyldahl RD, O’Fallon KS, Clarkson PM, Witkowski S. Pericyte NF-kappaB activation enhances endothelial cell proliferation and proangiogenic cytokine secretion in vitro. Physiol Rep 2015;3(4):e12309PubMedPubMedCentralCrossRef
18.
Rockey DC, Boyles JK, Gabbiani G, Friedman SL. Rat hepatic lipocytes express smooth muscle actin upon activation in vivo and in culture. J Submicrosc Cytol Pathol 1992;24:193–203PubMed
19.
Rockey DC, Housset CN, Friedman SL. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 1993;92:1795–1804PubMedPubMedCentralCrossRef
20.
21.
Rockey DC, Fouassier L, Chung JJ, Carayon A, Vallee P, Rey C, et al. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 1998;27:472–480PubMedCrossRef
22.
Shao R, Yan W, Rockey DC. Regulation of endothelin-1 synthesis by endothelin-converting enzyme-1 during wound healing. J Biol Chem 1999;274:3228–3234PubMedCrossRef
23.
Rothermund L, Leggewie S, Schwarz A, Thone-Reinecke C, Cho JJ, Bauer C, et al. Regulation of the hepatic endothelin system in advanced biliary fibrosis in rats. Clin Chem Lab Med 2000;38:507–512PubMedCrossRef
24.
Yokomori H, Oda M, Ogi M, Kamegaya Y, Tsukada N, Nakamura M, et al. Enhanced expression of endothelin receptor subtypes in cirrhotic rat liver. Liver 2001;21:114–122PubMedCrossRef
25.
Zhang JX, Pegoli W Jr, Clemens MG. Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol 1994;266:G624–G632PubMedCrossRef
26.
Feng HQ, Weymouth ND, Rockey DC. Endothelin antagonism in portal hypertensive mice: implications for endothelin receptor-specific signaling in liver disease. Am J Physiol Gastrointest Liver Physiol 2009;297:G27–G33PubMedPubMedCentralCrossRef
27.
Iizuka M, Murata T, Hori M, Ozaki H. Increased contractility of hepatic stellate cells in cirrhosis is mediated by enhanced Ca2+-dependent and Ca2+-sensitization pathways. Am J Physiol Gastrointest Liver Physiol 2011;300:G1010–G1021PubMedCrossRef
28.
Saiman Y, Agarwal R, Hickman DA, Fausther M, El-Shamy A, Dranoff JA, et al. CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway. Am J Physiol Gastrointest Liver Physiol 2013;305:G375–G382PubMedPubMedCentralCrossRef
29.
Jalan R, De Chiara F, Balasubramaniyan V, Andreola F, Khetan V, Malago M, et al. Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension. J Hepatol 2016;64:823–833PubMedCrossRef
30.
Fallowfield JA, Hayden AL, Snowdon VK, Aucott RL, Stutchfield BM, Mole DJ, et al. Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo. Hepatology 2014;59:1492–1504PubMedCrossRef
31.
Schwabl P, Hambruch E, Seeland BA, Hayden H, Wagner M, Garnys L, et al. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 2017;66(4):724–33
32.
Wisse E. An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids. J Ultrastruct Res 1970;31:125–150PubMedCrossRef
33.
Bhunchet E, Fujieda K. Capillarization and venularization of hepatic sinusoids in porcine serum-induced rat liver fibrosis: a mechanism to maintain liver blood flow. Hepatology 1993;18:1450–1458PubMedCrossRef
34.
Horn T, Christoffersen P, Henriksen JH. Alcoholic liver injury: defenestration in noncirrhotic livers–a scanning electron microscopic study. Hepatology 1987;7:77–82PubMedCrossRef
35.
Funyu J, Mochida S, Inao M, Matsui A, Fujiwara K. VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells. Biochem Biophys Res Commun 2001;280:481–485PubMedCrossRef
36.
DeLeve LD, Wang X, Hu L, McCuskey MK, McCuskey RS. Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Am J Physiol Gastrointest Liver Physiol 2004;287:G757–G763PubMedCrossRef
37.
May D, Djonov V, Zamir G, Bala M, Safadi R, Sklair-Levy M, et al. A transgenic model for conditional induction and rescue of portal hypertension reveals a role of VEGF-mediated regulation of sinusoidal fenestrations. PLoS ONE 2011;6:e21478PubMedPubMedCentralCrossRef
38.
McGuire RF, Bissell DM, Boyles J, Roll FJ. Role of extracellular matrix in regulating fenestrations of sinusoidal endothelial cells isolated from normal rat liver. Hepatology 1992;15:989–997PubMedCrossRef
39.
Svistounov D, Warren A, McNerney GP, Owen DM, Zencak D, Zykova SN, et al. The relationship between fenestrations, sieve plates and rafts in liver sinusoidal endothelial cells. PLoS ONE 2012;7:e46134PubMedPubMedCentralCrossRef
40.
41.
Jarnagin WR, Rockey DC, Koteliansky VE, Wang SS, Bissell DM. Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol 1994;127:2037–2048PubMedCrossRef
42.
Olsen AL, Sackey BK, Marcinkiewicz C, Boettiger D, Wells RG. Fibronectin extra domain-A promotes hepatic stellate cell motility but not differentiation into myofibroblasts. Gastroenterology 2012;142(928–937):e923
43.
Wang R, Ding Q, Yaqoob U, de Assuncao TM, Verma VK, Hirsova P, et al. Exosome adherence and internalization by hepatic stellate cells triggers sphingosine 1-phosphate-dependent migration. J Biol Chem 2015;290:30684–30696PubMedPubMedCentralCrossRef
44.
Marrone G, Russo L, Rosado E, Hide D, Garcia-Cardena G, Garcia-Pagan JC, et al. The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. J Hepatol 2013;58:98–103PubMedCrossRef
45.
Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 2008;48:920–930PubMedPubMedCentralCrossRef
46.
Failli P, De FR, Caligiuri A, Gentilini A, Romanelli RG, Marra F, et al. Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells. Gastroenterology 2000;119:479–492PubMedCrossRef
47.
Routray C, Liu C, Yaqoob U, Billadeau DD, Bloch KD, Kaibuchi K, et al. Protein kinase G signaling disrupts Rac1-dependent focal adhesion assembly in liver specific pericytes. Am J Physiol Cell Physiol 2011;301:C66–C74PubMedPubMedCentralCrossRef
48.
Lee JS, Kang Decker N, Chatterjee S, Yao J, Friedman S, Shah V. Mechanisms of nitric oxide interplay with Rho GTPase family members in modulation of actin membrane dynamics in pericytes and fibroblasts. Am J Pathol 2005;166:1861–1870PubMedPubMedCentralCrossRef
49.
Langer DA, Das A, Semela D, Kang-Decker N, Hendrickson H, Bronk SF, et al. Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species. Hepatology 2008;47:1983–1993PubMedPubMedCentralCrossRef
50.
Mittal MK, Gupta TK, Lee FY, Sieber CC, Groszmann RJ. Nitric oxide modulates hepatic vascular tone in normal rat liver. Am J Physiol 1994;267:G416–G422PubMed
51.
Shah V, Haddad FG, Garcia-Cardena G, Frangos JA, Mennone A, Groszmann RJ. Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. J Clin Invest 1997;100:2923–2930PubMedPubMedCentralCrossRef
52.
Abraldes JG, Iwakiri Y, Loureiro-Silva M, Haq O, Sessa WC, Groszmann RJ. 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–G987PubMedCrossRef
53.
Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998;114:344–351PubMedCrossRef
54.
Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K, et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 1999;117:1222–1228PubMedCrossRef
55.
Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999;399:597–601PubMedPubMedCentralCrossRef
56.
Liu S, Premont RT, Rockey DC. G-protein-coupled receptor kinase interactor-1 (GIT1) is a new endothelial nitric-oxide synthase (eNOS) interactor with functional effects on vascular homeostasis. J Biol Chem 2012;287:12309–12320PubMedPubMedCentralCrossRef
57.
Liu S, Premont RT, Rockey DC. Endothelial nitric-oxide synthase (eNOS) is activated through G-protein-coupled receptor kinase-interacting protein 1 (GIT1) tyrosine phosphorylation and Src protein. J Biol Chem 2014;289:18163–18174PubMedPubMedCentralCrossRef
58.
Michel JB, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem 1997;272:15583–15586PubMedCrossRef
59.
Abraldes JG, Albillos A, Banares R, Turnes J, Gonzalez R, Garcia-Pagan JC, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009;136:1651–1658PubMedCrossRef
60.
Abraldes JG, Rodriguez-Vilarrupla A, Graupera M, Zafra C, Garcia-Caldero H, Garcia-Pagan JC, et al. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. J Hepatol 2007;46:1040–1046PubMedCrossRef
61.
Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, Schepke M, et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007;46:242–253PubMedCrossRef
62.
Ming XF, Viswambharan H, Barandier C, Ruffieux J, Kaibuchi K, Rusconi S, et al. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol 2002;22:8467–8477PubMedPubMedCentralCrossRef
63.
Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998;273:24266–24271PubMedCrossRef
64.
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;49:1245–1256PubMedCrossRef
65.
Reiberger T, Angermayr B, Schwabl P, Rohr-Udilova N, Mitterhauser M, Gangl A, et al. Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats. J Hepatol 2009;51:865–873PubMedCrossRef
66.
Tugues S, Fernandez-Varo G, Munoz-Luque J, Ros J, Arroyo V, Rodes J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007;46:1919–1926PubMedCrossRef
67.
Semela D, Das A, Langer D, Kang N, Leof E, Shah V. Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology 2008;135:671–679PubMedPubMedCentralCrossRef
68.
Schwabl P, Payer BA, Grahovac J, Klein S, Horvatits T, Mitterhauser M, et al. Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats. J Hepatol 2014;60(6):1135–1142PubMedCrossRef
69.
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;46:1208–1217PubMedCrossRef
70.
Dill MT, Rothweiler S, Djonov V, Hlushchuk R, Tornillo L, Terracciano L, et al. Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterology 2012;142(967–977):e962
71.
Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R, et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 2002;35:1010–1021PubMedCrossRef
72.
Ehling J, Bartneck M, Wei X, Gremse F, Fech V, Mockel D, et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014;63:1960–1971PubMedPubMedCentralCrossRef
73.
Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol 2010;53:976–980PubMedCrossRef
74.
Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995;21:1238–1247PubMed
75.
76.
De Pietri L, Bianchini M, Montalti R, De Maria N, Di Maira T, Begliomini B, et al. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: a randomized, controlled trial. Hepatology 2016;63:566–573PubMedCrossRef
77.
Levy GA, MacPhee PJ, Fung LS, Fisher MM, Rappaport AM. The effect of mouse hepatitis virus infection on the microcirculation of the liver. Hepatology 1983;3:964–973PubMedCrossRef
78.
MacPhee PJ, Schmidt EE, Keown PA, Groom AC. Microcirculatory changes in livers of mice infected with murine hepatitis virus. Evidence from microcorrosion casts and measurements of red cell velocity. Microvasc Res 1988;36:140–149PubMedCrossRef
79.
Neubauer K, Knittel T, Armbrust T, Ramadori G. Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver injury. Gastroenterology 1995;108:1124–1135PubMedCrossRef
80.
81.
Marsden PA, Ning Q, Fung LS, Luo X, Chen Y, Mendicino M, et al. The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis. J Clin Invest 2003;112:58–66PubMedPubMedCentralCrossRef
82.
Abdel-Salam OM, Baiuomy AR, Ameen A, Hassan NS. A study of unfractionated and low molecular weight heparins in a model of cholestatic liver injury in the rat. Pharmacol Res 2005;51:59–67PubMedCrossRef
83.
Assy N, Hussein O, Khalil A, Luder A, Szvalb S, Paizi M, et al. The beneficial effect of aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of cirrhosis. Dig Dis Sci 2007;52:1187–1193PubMedCrossRef
84.
Abe W, Ikejima K, Lang T, Okumura K, Enomoto N, Kitamura T, et al. Low molecular weight heparin prevents hepatic fibrogenesis caused by carbon tetrachloride in the rat. J Hepatol 2007;46:286–294PubMedCrossRef
85.
Anstee QM, Goldin RD, Wright M, Martinelli A, Cox R, Thursz MR. Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies. J Thromb Haemost 2008;6:1336–1343PubMedCrossRef
86.
Simonetto DA, Yang HY, Yin M, de Assuncao TM, Kwon JH, Hilscher M, et al. Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces. Hepatology 2015;61:648–659PubMedPubMedCentralCrossRef
87.
Cerini F, Vilaseca M, Lafoz E, Garcia-Irigoyen O, Garcia-Caldero H, Tripathi DM, et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2016;64:834–842PubMedCrossRef
88.
Vilaseca M, Garcia-Caldero H, Lafoz E, Garcia-Irigoyen O, Avila M, Reverter JC, et al. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017;65(6):2031–2044PubMedCrossRef
89.
Ordinas A, Escolar G, Cirera I, Vinas M, Cobo F, Bosch J, et al. Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: studies under flow conditions. Hepatology 1996;24:1137–1142PubMedCrossRef
90.
Rubin MH, Weston MJ, Langley PG, White Y, Williams R. Platelet function in chronic liver disease: relationship to disease severity. Dig Dis Sci 1979;24:197–202PubMedCrossRef
91.
Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006;44:53–61PubMedCrossRef
92.
Raparelli V, Basili S, Carnevale R, Napoleone L, Del Ben M, Nocella C, et al. Low-grade endotoxemia and platelet activation in cirrhosis. Hepatology 2017;65(2):571–81
93.
Potze W, Siddiqui MS, Boyett SL, Adelmeijer J, Daita K, Sanyal AJ, et al. Preserved hemostatic status in patients with non-alcoholic fatty liver disease. J Hepatol 2016;65:980–987PubMedCrossRef
94.
95.
Lang PA, Contaldo C, Georgiev P, El-Badry AM, Recher M, Kurrer M, et al. Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med 2008;14:756–761PubMedCrossRef
96.
Ruddell RG, Mann DA, Ramm GA. The function of serotonin within the liver. J Hepatol 2008;48:666–675PubMedCrossRef
97.
Cummings JL, Cilento EV, Reilly FD. Hepatic microvascular regulatory mechanisms. XII. Effects of 5-HT2-receptor blockade on serotonin-induced intralobular hypoperfusion. Int J Microcirc Clin Exp 1993;13:99–112PubMed
98.
Brauneis U, Gatmaitan Z, Arias IM. Serotonin stimulates a Ca2+ permeant nonspecific cation channel in hepatic endothelial cells. Biochem Biophys Res Commun 1992;186:1560–1556PubMedCrossRef
99.
Gatmaitan Z, Varticovski L, Ling L, Mikkelsen R, Steffan AM, Arias IM. Studies on fenestral contraction in rat liver endothelial cells in culture. Am J Pathol 1996;148:2027–2041PubMedPubMedCentral
100.
Park KS, Sin PJ, Lee DH, Cha SK, Kim MJ, Kim NH, et al. Switching-on of serotonergic calcium signaling in activated hepatic stellate cells. World J Gastroenterol 2011;17:164–173PubMedPubMedCentralCrossRef
101.
Kim DC, Jun DW, Kwon YI, Lee KN, Lee HL, Lee OY, et al. 5-HT2A receptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis. Liver Int 2013;33:535–543PubMedCrossRef
102.
Morange PE, Alessi MC. Thrombosis in central obesity and metabolic syndrome: mechanisms and epidemiology. Thromb Haemost 2013;110:669–680PubMedCrossRef
103.
Committee ASoP, Acosta RD, Abraham NS, Chandrasekhara V, Chathadi KV, Early DS, et al. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc 2016;83:3–16CrossRef
104.
Fujita K, Nozaki Y, Wada K, Yoneda M, Endo H, Takahashi H, et al. Effectiveness of antiplatelet drugs against experimental non-alcoholic fatty liver disease. Gut 2008;57:1583–1591PubMedCrossRef
105.
Groszmann R, Kotelanski B, Cohn JN, Khatri IM. Quantitation of portasystemic shunting from the splenic and mesenteric beds in alcoholic liver disease. Am J Med 1972;53:715–722PubMedCrossRef
106.
Kotelanski B, Groszmann R, Cohn JN. Circulation times in the splanchnic and hepatic beds in alcoholic liver disease. Gastroenterology 1972;63:102–111PubMed
107.
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–G1051PubMed
108.
Iwakiri Y, Tsai MH, McCabe TJ, Gratton JP, Fulton D, Groszmann RJ, et al. Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension. Am J Physiol Heart Circ Physiol 2002;282:H2084–H2090PubMedCrossRef
109.
Grace JA, Klein S, Herath CB, Granzow M, Schierwagen R, Masing N, et al. Activation of the MAS receptor by angiotensin-(1–7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology 2013;145(874–884):e875
110.
Fernandez-Varo G, Ros J, Morales-Ruiz M, Cejudo-Martin P, Arroyo V, Sole M, et al. Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis. Am J Pathol 2003;162:1985–1993PubMedPubMedCentralCrossRef
111.
Heinemann A, Wachter CH, Fickert P, Trauner M, Stauber RE. Vasopressin reverses mesenteric hyperemia and vasoconstrictor hyporesponsiveness in anesthetized portal hypertensive rats. Hepatology 1998;28:646–654PubMedCrossRef
112.
Song D, Liu H, Sharkey KA, Lee SS. Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression. Hepatology 2002;35:159–166PubMedCrossRef
113.
Moleda L, Trebicka J, Dietrich P, Gabele E, Hellerbrand C, Straub RH, et al. Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction. Gut 2011;60:1122–1132PubMedCrossRef
114.
Ezkurdia N, Coll M, Raurell I, Rodriguez S, Cuenca S, Gonzalez A, et al. Blockage of the afferent sensitive pathway prevents sympathetic atrophy and hemodynamic alterations in rat portal hypertension. Liver Int 2012;32:1295–1305PubMedCrossRef
115.
Ezkurdia N, Raurell I, Rodriguez S, Gonzalez A, Esteban R, Genesca J, et al. Inhibition of neuronal apoptosis and axonal regression ameliorates sympathetic atrophy and hemodynamic alterations in portal hypertensive rats. PLoS ONE 2014;9:e84374PubMedPubMedCentralCrossRef
116.
Dietrich P, Moleda L, Kees F, Muller M, Straub RH, Hellerbrand C, et al. Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: impact of exogenous neuropeptide Y. J Hepatol 2013;58:254–261PubMedCrossRef
117.
Hartl J, Dietrich P, Moleda L, Muller-Schilling M, Wiest R. Neuropeptide Y restores non-receptor-mediated vasoconstrictive action in superior mesenteric arteries in portal hypertension. Liver Int 2015;35:2556–2563PubMedCrossRef
118.
Li TH, Huang CC, Yang YY, Lee KC, Hsieh SL, Hsieh YC, et al. Thalidomide improves the intestinal mucosal injury and suppresses mesenteric angiogenesis and vasodilatation by down-regulating inflammasomes-related cascades in cirrhotic rats. PLoS ONE 2016;11:e0147212PubMedPubMedCentralCrossRef
119.
Fernandez-Varo G, Oro D, Cable EE, Reichenbach V, Carvajal S, de la Presa BG, et al. Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats. Hepatology 2016;63:207–216PubMedCrossRef
120.
Yada A, Iimuro Y, Uyama N, Uda Y, Okada T, Fujimoto J. Splenectomy attenuates murine liver fibrosis with hypersplenism stimulating hepatic accumulation of Ly-6C(lo) macrophages. J Hepatol 2015;63:905–916PubMedCrossRef
121.
Kajita M, Murata T, Horiguchi K, Iizuka M, Hori M, Ozaki H. iNOS expression in vascular resident macrophages contributes to circulatory dysfunction of splanchnic vascular smooth muscle contractions in portal hypertensive rats. Am J Physiol Heart Circ Physiol 2011;300:H1021–H1031PubMedCrossRef
122.
123.
Caldwell S, Lisman T. The cirrhotic platelet: shedding light on an enigma. Hepatology 2017;65:407–410PubMedCrossRef
124.
125.
126.
Kawasaki T, Murata S, Takahashi K, Nozaki R, Ohshiro Y, Ikeda N, et al. Activation of human liver sinusoidal endothelial cell by human platelets induces hepatocyte proliferation. J Hepatol 2010;53:648–654PubMedCrossRef
127.
Chen PY, Qin L, Barnes C, Charisse K, Yi T, Zhang X, et al. FGF regulates TGF-beta signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA expression. Cell Rep 2012;2:1684–1696PubMedPubMedCentralCrossRef
128.
129.
130.
131.
Tanaka M, Iwakiri Y. The hepatic lymphatic vascular system: structure, function, markers, and lymphangiogenesis. Cell Mol Gastroenterol Hepatol 2016;2:733–749PubMedPubMedCentralCrossRef
132.
Rautou PE, Tatsumi K, Antoniak S, Owens AP 3rd, Sparkenbaugh E, Holle LA, et al. Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury. J Hepatol 2016;64:53–59PubMedCrossRef
133.
Gonzalez-Reimers E, Quintero-Platt G, Martin-Gonzalez C, Perez-Hernandez O, Romero-Acevedo L, Santolaria-Fernandez F. Thrombin activation and liver inflammation in advanced hepatitis C virus infection. World J Gastroenterol 2016;22:4427–4437PubMedPubMedCentralCrossRef
134.
Fiorucci S, Antonelli E, Distrutti E, Severino B, Fiorentina R, Baldoni M, et al. PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation. Hepatology 2004;39:365–375PubMedCrossRef
135.
Violi F, Basili S, Raparelli V, Chowdary P, Gatt A, Burroughs AK. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction? J Hepatol 2011;55:1415–1427PubMedCrossRef
136.
Lalor PF, Herbert J, Bicknell R, Adams DH. Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leukocyte recruitment. Am J Physiol Gastrointest Liver Physiol 2013;304:G469–G478PubMedCrossRef
137.
Yoshida S, Ikenaga N, Liu SB, Peng ZW, Chung J, Sverdlov DY, et al. Extrahepatic platelet-derived growth factor-beta, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology 2014;147:1378–1392PubMedCrossRef
Metadata
Title
Biology of portal hypertension
Authors
Matthew McConnell
Yasuko Iwakiri
Publication date
01-02-2018
Publisher
Springer India
Published in
Hepatology International / Issue Special Issue 1/2018
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-017-9826-x

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