gastro-jРоссийский журнал гастроэнтерологии, гепатологии, колопроктологииRussian Journal of Gastroenterology, Hepatology, Coloproctology1382-43762658-6673«Gastro» LLC10.22416/13824376-2018-28-5-35-45gastro-j-261Research ArticleОБЗОРЫREVIEWSПерспективы антиангиогенной терапии портальной гипертензии при циррозе печениProspects of Antiangiogenic Therapy for Portal Hypertension in Liver CirrhosisГарбузенкоД. В.GarbuzenkoD. V.

 доктор медицинских  наук,  профессор,  профессор  кафедры  факультетской  хирургии  Южно-Уральского  государственного  медицинского  университета.  

454092, Челябинская область, г. Челябинск, ул. Воровского, д. 64.

Dr. Sci. (Med.), Prof., Department  of Faculty Surgery, South Ural State Medical University.  

 454092, Chelyabinsk region, Chelyabinsk, Vorovskogo str., 64.

garb@inbox.ruГБОУ ВПО «Южно-Уральский государственный медицинский университет» Министерства здравоохранения Российской Федерации.РоссияSouth Ural State Medical University.Russian Federation2018111120182853545Copyright © Гарбузенко Д.В., 20182018Гарбузенко Д.В.Garbuzenko D.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gastro-j.ru/jour/article/view/261Цель обзора

Цель обзора: Представить данные литературы о роли ангиогенеза в патогенезе портальной гипертензии при циррозе печени, возможностях ее антиангиогенной терапии с описанием ингибирующих ангиогенез препаратов и механизма их действия.

Основные положения

Основные положения. Для поиска научных публикаций применяли базы данных PubMed, РИНЦ, поисковую систему Google Scholar, а также пристатейные списки литературы. Статьи, соответствующие цели обзора, отбирали за период с 2000 по 2017 г. по следующим терминам: «цирроз печени», «портальная гипертензия», «патогенез», «ангиогенез», «антиангиогенная терапия». Критерии включения ограничивались антиангиогенной терапией портальной гипертензии. Ангиогенез играет важную роль в патогенезе цирроза печени, лежит в основе развития связанной с ним портальной гипертензии и является причиной характерных для нее осложнений. Экспериментальные исследования позволили изучить механизм действия ингибирующих его препаратов и их влияние на портальную гипертензию. В настоящее время лишь ингибиторы тирозинкиназ были апробированы у больных циррозом печени в качестве антиангиогенной терапии портальной гипертензии.

Заключение

Заключение. Антиангиогенная терапия, избирательно направленная на необычно растущие вновь образованные сосуды, может быть патогенетически обоснованным методом лечения портальной гипертензии при циррозе печени в ее субклиническую стадию. 

Aim

Aim. This paper is aimed at reviewing existing literature that investigates the role of angiogenesis in portal hypertension pathogenesis in liver cirrhosis and the possibilities of its antiangiogenic therapy, along with the description of angiogenesis inhibiting drugs and their action mechanisms.

Key points

Key points. A relevant literature and reference list search was performed using PubMed and RSCI and Google Scholar, and covered the 2000–2017 period. The following keywords were used: liver cirrhosis, portal hypertension, pathogenesis, angiogenesis, antiangiogenic therapy. The inclusion criteria were limited to the antiangiogenic therapy of portal hypertension. Angiogenesis is shown to play an important role in the pathogenesis of liver cirrhosis. Angiogenesis is the basis for the development of associated portal hypertension that causes its characteristic complications. The experimental studies reviewed in this paper investigate the action mechanism of angiogenesis inhibiting drugs and their effect on portal hypertension. It is shown that, so far, only tyrosine kinase inhibitors have been tested in patients with liver cirrhosis as an antiangiogenic therapy for portal hypertension.

Conclusion

Conclusion. Antiangiogenic therapy, selectively directed at unusually growing newly-formed vessels, can be a pathogenetically justified method for treating portal hypertension in liver cirrhosis on its subclinical stage. 

цирроз печенипортальная гипертензияпатогенезангиогенезантиангиогенная терапияliver cirrhosisportal hypertensionpathogenesisangiogenesisantiangiogenic therapyReferencesИвашкин В.Т., Маевская М.В., Павлов Ч.С., Федосьина Е.А., Бессонова Е.Н., Пирогова И.Ю., Гарбузенко Д.В. Клинические рекомендации Российского общества по изучению печени и Российской гастроэнтерологической ассоциации по лечению осложнений цирроза печени. Рос журн гастроэнтерол, гепатол, колопроктол. 2016;26(4):71–102Ivashkin V.T., Mayevskaya M.V., Pavlov Ch.S., Fedosyina Ye.A., Bessonova Ye.N., Pirogova I.Yu., Garbuzenko D.V. Treatment of liver cirrhosis complications: Clinical guidelines of the Russian Scientific Liver Society and Russian gastroenterological association. Rus J gastroenterol, hepatol, coloproctol. 2016;26(4):71–102 (In Rus.).Гарбузенко Д.В. Аспекты патогенетической фармакотерапии портальной гипертензии при циррозе печени. Тер арх. 2016;88(2):101–8Garbuzenko D.V. Aspects of pathogenetic pharmacotherapy for portal hypertension in liver cirrhosis. Ter Arkh. 2016;88(2):101–8 (In Rus.).Berzigotti A., Bosch J. Pharmacologic Management of Portal Hypertension. Clin Liver Dis. 2014;18(2):303–17.Berzigotti A., Bosch J. Pharmacologic Management of Portal Hypertension. Clin Liver Dis. 2014;18(2):303–17.Coulon S., Heindryckx F., Geerts A., Van Steenkiste C., Colle I., Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int. 2011;31(2):146–62.Coulon S., Heindryckx F., Geerts A., Van Steenkiste C., Colle I., Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int. 2011;31(2):146–62.Гарбузенко Д.В. Морфофункциональная перестройка печеночного сосудистого русла в патогенезе портальной гипертензии при циррозе печени. Тер арх. 2014;86(2):90–Garbuzenko D.V. Morphofunctional rearrangement of the hepatic vasculature in the pathogenesis of portal hypertension in liver cirrhosis. Ter Arkh. 2014;86(2):90–5 (In Rus.).Гарбузенко Д.В. Механизмы адаптации сосудистого русла к гемодинамическим нарушениям при портальной гипертензии. Вестн РАМН. 2013;(1):52–7Garbuzenko D.V. The mechanisms of adaptation of the vascular bed to hemodynamic changes in portal hypertension. Vestn RAMN. 2013;(1):52–7 (In Rus.).Rosmorduc O. Antiangiogenic therapies in portal hypertension: a breakthrough in hepatology. Gastroenterol Clin Biol. 2010;34(8–9):446–9.Rosmorduc O. Antiangiogenic therapies in portal hypertension: a breakthrough in hepatology. Gastroenterol Clin Biol. 2010;34(8–9):446–9.Folkman J. Angiogenesis: an organizing principle for drug discovery?. Nat Rev Drug Discov. 2007;6(4):273–86.Folkman J. Angiogenesis: an organizing principle for drug discovery?. Nat Rev Drug Discov. 2007;6(4):273–86.Ивашкин В.Т., Павлов Ч.С. Фиброз печени. М.: ГэотарМедиа, 2011. 168 с.Ivashkin V.T., Pavlov Ch.S. Liver fibrosis. Moscow: Geotar-Media, 2011. 168 p. (In Rus.).Chaparro M., Sanz-Cameno P., Trapero-Marugan M., Garcia-Buey L., Moreno-Otero R. Mechanisms of angiogenesis in chronic inflammatory liver disease. Ann Hepatol. 2007;6(4):208–13.Chaparro M., Sanz-Cameno P., Trapero-Marugan M., Garcia-Buey L., Moreno-Otero R. Mechanisms of angiogenesis in chronic inflammatory liver disease. Ann Hepatol. 2007;6(4):208–13.Lemoinne S., Cadoret A., El Mourabit H., Thabut D., Housset C. Origins and functions of liver myofibroblasts. Biochim Biophys Acta. 2013;1832(7):948–54.Lemoinne S., Cadoret A., El Mourabit H., Thabut D., Housset C. Origins and functions of liver myofibroblasts. Biochim Biophys Acta. 2013;1832(7):948–54.Yokomori H., Oda M., Yoshimura K., Hibi T. Enhanced expressions of apelin on proliferative hepatic arterial capillaries in human cirrhotic liver. Hepatol Res. 2012;42(5):508–14.Yokomori H., Oda M., Yoshimura K., Hibi T. Enhanced expressions of apelin on proliferative hepatic arterial capillaries in human cirrhotic liver. Hepatol Res. 2012;42(5):508–14.Novo E., Povero D., Busletta C., Paternostro C., di Bonzo L.V., Cannito S., et al. The biphasic nature of hypoxiainduced directional migration of activated human hepatic stellate cells. J Pathol. 2012;226(4):588–97.Novo E., Povero D., Busletta C., Paternostro C., di Bonzo L.V., Cannito S., et al. The biphasic nature of hypoxiainduced directional migration of activated human hepatic stellate cells. J Pathol. 2012;226(4):588–97.Dufour J.F. Anti-angiogenic therapy for HCC. Minerva Gastroenterol Dietol. 2012;58(1):81–6.Dufour J.F. Anti-angiogenic therapy for HCC. Minerva Gastroenterol Dietol. 2012;58(1):81–6.Llovet J.M., Ricci S., Mazzaferro V., Hilgard P., Gane E., Blanc J.F., et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.Llovet J.M., Ricci S., Mazzaferro V., Hilgard P., Gane E., Blanc J.F., et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.Liu L., You Z., Yu H., Zhou L., Zhao H., Yan X., et al. Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis. Nat Mater. 2017;16(12):1252–61.Liu L., You Z., Yu H., Zhou L., Zhao H., Yan X., et al. Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis. Nat Mater. 2017;16(12):1252–61.Qu K., Huang Z., Lin T., Liu S., Chang H., Yan Z., et al. New Insight into the Anti-liver Fibrosis Effect of Multitargeted Tyrosine Kinase Inhibitors: From Molecular Target to Clinical Trials. Front Pharmacol. 2016;6:300.Qu K., Huang Z., Lin T., Liu S., Chang H., Yan Z., et al. New Insight into the Anti-liver Fibrosis Effect of Multitargeted Tyrosine Kinase Inhibitors: From Molecular Target to Clinical Trials. Front Pharmacol. 2016;6:300.Wang Y., Gao J., Zhang D., Zhang J., Ma J., Jiang H. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. J Hepatol. 2010;53(1):132–44.Wang Y., Gao J., Zhang D., Zhang J., Ma J., Jiang H. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. J Hepatol. 2010;53(1):132–44.Thabut D., Routray C., Lomberk G., Shergill U., Glaser K., Huebert R., et al. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology. 2011;54(2):573–85.Thabut D., Routray C., Lomberk G., Shergill U., Glaser K., Huebert R., et al. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology. 2011;54(2):573–85.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(4):1245–56.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(4):1245–56.Tugues S., Fernandez-Varo G., Muñoz-Luque J., Ros J., Arroyo V., Rodés J., et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology. 2007;46(6):1919–26.Tugues S., Fernandez-Varo G., Muñoz-Luque J., Ros J., Arroyo V., Rodés J., et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology. 2007;46(6):1919–26.Majumder S., Piguet A.C., Dufour J.F., Chatterjee S. Study of the cellular mechanism of Sunitinib mediated inactivation of activated hepatic stellate cells and its implications in angiogenesis. Eur J Pharmacol. 2013;705(1– 3):86–95.Majumder S., Piguet A.C., Dufour J.F., Chatterjee S. Study of the cellular mechanism of Sunitinib mediated inactivation of activated hepatic stellate cells and its implications in angiogenesis. Eur J Pharmacol. 2013;705(1– 3):86–95.Lin H.C., Huang Y.T., Yang Y.Y., Lee P.C., Hwang L.H., Lee W.P., et al. Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertensive rats. J Gastroenterol Hepatol. 2014;29(5):1073–82.Lin H.C., Huang Y.T., Yang Y.Y., Lee P.C., Hwang L.H., Lee W.P., et al. Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertensive rats. J Gastroenterol Hepatol. 2014;29(5):1073–82.Yang Y.Y., Liu R.S., Lee P.C., Yeh Y.C., Huang Y.T., Lee W.P., et al. Anti-VEGFR agents ameliorate hepatic venous dysregulation/microcirculatory dysfunction, splanchnic venous pooling and ascites of NASH-cirrhotic rat. Liver Int. 2014;34(4):521–34.Yang Y.Y., Liu R.S., Lee P.C., Yeh Y.C., Huang Y.T., Lee W.P., et al. Anti-VEGFR agents ameliorate hepatic venous dysregulation/microcirculatory dysfunction, splanchnic venous pooling and ascites of NASH-cirrhotic rat. Liver Int. 2014;34(4):521–34.Bieker J.J. Krüppel-like factors: three fingers in many pies. J Biol Chem. 2001;276(37):34355–8.Bieker J.J. Krüppel-like factors: three fingers in many pies. J Biol Chem. 2001;276(37):34355–8.Taniguchi H., Jacinto F.V., Villanueva A., Fernandez A.F., Yamamoto H., Carmona F.J., et al. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene. 2012;31(15):1988–94.Taniguchi H., Jacinto F.V., Villanueva A., Fernandez A.F., Yamamoto H., Carmona F.J., et al. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene. 2012;31(15):1988–94.Kawanami D., Mahabeleshwar G.H., Lin Z., Atkins G.B., Hamik A., Haldar S.M., et al. Kruppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium. J Biol Chem. 2009;284(31):20522–30.Kawanami D., Mahabeleshwar G.H., Lin Z., Atkins G.B., Hamik A., Haldar S.M., et al. Kruppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium. J Biol Chem. 2009;284(31):20522–30.Doddaballapur A., Michalik K.M., Manavski Y., Lucas T., Houtkooper R.H., You X., et al. Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3. Arterioscler Thromb Vasc Biol. 2015;35(1):137–45.Doddaballapur A., Michalik K.M., Manavski Y., Lucas T., Houtkooper R.H., You X., et al. Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3. Arterioscler Thromb Vasc Biol. 2015;35(1):137–45.Gracia-Sancho J., Russo L., García-Calderó H., GarcíaPagán J.C., García-Cardeña G., Bosch J. Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver. Gut. 2011;60(4):517–24.Gracia-Sancho J., Russo L., García-Calderó H., GarcíaPagán J.C., García-Cardeña G., Bosch J. Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver. Gut. 2011;60(4):517–24.Das A., Shergill U., Thakur L., Sinha S., Urrutia R., Mukhopadhyay D., et al. Ephrin B2/EphB4 pathway in hepatic stellate cells stimulates Erk-dependent VEGF production and sinusoidal endothelial cell recruitment. Am J Physiol Gastrointest Liver Physiol. 2010;298(6):G908–15.Das A., Shergill U., Thakur L., Sinha S., Urrutia R., Mukhopadhyay D., et al. Ephrin B2/EphB4 pathway in hepatic stellate cells stimulates Erk-dependent VEGF production and sinusoidal endothelial cell recruitment. Am J Physiol Gastrointest Liver Physiol. 2010;298(6):G908–15.Zeng X.Q., Li N., Pan D.Y., Miao Q., Ma G.F., Liu Y.M., et al. Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway. Biochem Biophys Res Commun. 2015;464(4):1241–7.Zeng X.Q., Li N., Pan D.Y., Miao Q., Ma G.F., Liu Y.M., et al. Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway. Biochem Biophys Res Commun. 2015;464(4):1241–7.Miao Q., Zeng X., Ma G., Li N., Liu Y., Luo T., et al. Simvastatin suppresses the proangiogenic microenvironment of human hepatic stellate cells via the Kruppel-like factor 2 pathway. Rev Esp Enferm Dig. 2015;107(2):63–71.Miao Q., Zeng X., Ma G., Li N., Liu Y., Luo T., et al. Simvastatin suppresses the proangiogenic microenvironment of human hepatic stellate cells via the Kruppel-like factor 2 pathway. Rev Esp Enferm Dig. 2015;107(2):63–71.Marrone G., Russo L., Rosado E., Hide D., GarcíaCardeña G., García-Pagán J.C., et al. The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. J Hepatol. 2013;58(1):98–103.Marrone G., Russo L., Rosado E., Hide D., GarcíaCardeña G., García-Pagán J.C., et al. The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. J Hepatol. 2013;58(1):98–103.Гарбузенко Д.В., Микуров А.А. Роль эндотоксемии в развитии кровотечений из варикозно-расширенных вен пищевода у больных циррозом печени. Рос мед журн. 2011;(6):47–9Garbuzenko D.V., Mikurov A.A. The role of endotoxemia in the development of the bleeding esophageal varices in patients with liver cirrhosis. Ros med zhurn. 2011;(6):47–9 (In Rus.).Jagavelu K., Routray C. Shergill U., O’Hara S.P., Faubion W., Shah V.H. Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology. 2010;52(2):590–601.Jagavelu K., Routray C. Shergill U., O’Hara S.P., Faubion W., Shah V.H. Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology. 2010;52(2):590–601.Zhu Q., Zou L., Jagavelu K., Simonetto D.A., Huebert R.C., Jiang Z.D., et al. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol. 2012;56(4):893–9.Zhu Q., Zou L., Jagavelu K., Simonetto D.A., Huebert R.C., Jiang Z.D., et al. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol. 2012;56(4):893–9.DuPont H.L. Biologic properties and clinical uses of rifaximin. Expert Opin Pharmacother. 2011;12(2):293–302.DuPont H.L. Biologic properties and clinical uses of rifaximin. Expert Opin Pharmacother. 2011;12(2):293–302.Liu Y., Salvador L.A., Byeon S., Ying Y., Kwan J.C., Law B.K., et al. Anticolon cancer activity of largazole, a marine-derived tunable histone deacetylase inhibitor. J Pharmacol Exp Ther. 2010;335(2):351–61.Liu Y., Salvador L.A., Byeon S., Ying Y., Kwan J.C., Law B.K., et al. Anticolon cancer activity of largazole, a marine-derived tunable histone deacetylase inhibitor. J Pharmacol Exp Ther. 2010;335(2):351–61.Liu Y., Wang Z., Wang J., Lam W., Kwong S., Li F., et al. A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling. Liver Int. 2013;33(4):504–15.Liu Y., Wang Z., Wang J., Lam W., Kwong S., Li F., et al. A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling. Liver Int. 2013;33(4):504–15.Fontaine H., Vallet-Pichard A., Equi-Andrade C., Nalpas B., Verkarre V., Chaix M.L., et al. Histopathologic efficacy of ribavirin monotherapy in kidney allograft recipients with chronic hepatitis C. Transplantation. 2004;78(6):853–7.Fontaine H., Vallet-Pichard A., Equi-Andrade C., Nalpas B., Verkarre V., Chaix M.L., et al. Histopathologic efficacy of ribavirin monotherapy in kidney allograft recipients with chronic hepatitis C. Transplantation. 2004;78(6):853–7.Michaelis M., Michaelis R., Suhan T., Schmidt H., Mohamed A., Doerr H.W., et al. Ribavirin inhibits angiogenesis by tetrahydrobiopterin depletion. FASEB J. 2007;21(1):81–7.Michaelis M., Michaelis R., Suhan T., Schmidt H., Mohamed A., Doerr H.W., et al. Ribavirin inhibits angiogenesis by tetrahydrobiopterin depletion. FASEB J. 2007;21(1):81–7.Bosch J., Groszmann R.J., Shah V.H. 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(1 Suppl):S121–30.Bosch J., Groszmann R.J., Shah V.H. 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(1 Suppl):S121–30.Fernandez M., Vizzutti F., Garcia-Pagan J.C., Rodes J., Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology. 2004;126(3):886–94.Fernandez M., Vizzutti F., Garcia-Pagan J.C., Rodes J., Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology. 2004;126(3):886–94.Fernandez M., Mejias M., Angermayr B., Garcia-Pagan J.C., Rodés 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(1):98–103.Fernandez M., Mejias M., Angermayr B., Garcia-Pagan J.C., Rodés 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(1):98–103.Angermayr B., Fernandez M., Mejias M., Gracia-Sancho J., Garcia-Pagan J.C., Bosch J. NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats. Gut. 2007;56(4):560–4.Angermayr B., Fernandez M., Mejias M., Gracia-Sancho J., Garcia-Pagan J.C., Bosch J. NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats. Gut. 2007;56(4):560–4.Fernández M., Semela D., Bruix J., Colle I., Pinzani M., Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50(3):604–20.Fernández M., Semela D., Bruix J., Colle I., Pinzani M., Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50(3):604–20.Fernandez M., Mejias M., Garcia-Pras E., Mendez R., Garcia-Pagan J.C., 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(4):1208–17.Fernandez M., Mejias M., Garcia-Pras E., Mendez R., Garcia-Pagan J.C., 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(4):1208–17.D’Amico M., Mejías M., García-Pras E., Abraldes J.G., García-Pagán J.C., Fernández M., et al. Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol. 2012;302(10):1191–8.D’Amico M., Mejías M., García-Pras E., Abraldes J.G., García-Pagán J.C., Fernández M., et al. Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol. 2012;302(10):1191–8.Гарбузенко Д.В. Лечение больных циррозом печени с кровотечением из варикозно-расширенных вен пищевода. Врач. 2015;(10):15–21Garbuzenko D.V. Treatment of patients with liver cirrhosis with bleeding from esophageal varices. Vrach. 2014;(1):17–20 (In Rus.).Woltering E.A. Development of targeted somatostatinbased antiangiogenic therapy: a review and future perspectives. Cancer Biother Radiopharm. 2003;18(4):601–9.Woltering E.A. Development of targeted somatostatinbased antiangiogenic therapy: a review and future perspectives. Cancer Biother Radiopharm. 2003;18(4):601–9.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(5A):1690–9.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(5A):1690–9.Гарбузенко Д.В. Принципы ведения больных циррозом печени, осложненным асцитом. Клин мед. 2017;95(9):789–96Garbuzenko D.V. The principles of management of patients with liver cirrhosis comlicated by ascites. Klin med. 2017;95(9):789–96 (In Rus.).Michel F., Ambroisine M.L., Duriez M., Delcayre C., Levy B.I., Silvestre J.S. Aldosterone enhances ischemiainduced neovascularization through angiotensin II-dependent pathway. Circulation. 2004;109(16):1933–7.Michel F., Ambroisine M.L., Duriez M., Delcayre C., Levy B.I., Silvestre J.S. Aldosterone enhances ischemiainduced neovascularization through angiotensin II-dependent pathway. Circulation. 2004;109(16):1933–7.Wilkinson-Berka J.L., Tan G., Jaworski K., Miller A.G. Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology. Circ Res. 2009;104(1):124–33.Wilkinson-Berka J.L., Tan G., Jaworski K., Miller A.G. Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology. Circ Res. 2009;104(1):124–33.Gravez B., Tarjus A., Pelloux V., Ouvrard-Pascaud A., Delcayre C., Samuel J., et al. Aldosterone promotes cardiac endothelial cell proliferation in vivo. J Am Heart Assoc. 2015;4(1):e001266.Gravez B., Tarjus A., Pelloux V., Ouvrard-Pascaud A., Delcayre C., Samuel J., et al. Aldosterone promotes cardiac endothelial cell proliferation in vivo. J Am Heart Assoc. 2015;4(1):e001266.Miternique-Grosse A., Griffon C., Siegel L., Neuville A., Weltin D., Stephan D. Antiangiogenic effects of spironolactone and other potassium-sparing diuretics in human umbilical vein endothelial cells and in fibrin gel chambers implanted in rats. J Hypertens. 2006;24(11):2207–13.Miternique-Grosse A., Griffon C., Siegel L., Neuville A., Weltin D., Stephan D. Antiangiogenic effects of spironolactone and other potassium-sparing diuretics in human umbilical vein endothelial cells and in fibrin gel chambers implanted in rats. J Hypertens. 2006;24(11):2207–13.Hsu S.J., Wang S.S., Huo T.I., Lee F.Y., Huang H.C., Chang C.C., et al. The Impact of Spironolactone on the Severity of Portal-Systemic Collaterals and Hepatic Encephalopathy in Cirrhotic Rats. J Pharmacol Exp Ther. 2015;355(1):117–24.Hsu S.J., Wang S.S., Huo T.I., Lee F.Y., Huang H.C., Chang C.C., et al. The Impact of Spironolactone on the Severity of Portal-Systemic Collaterals and Hepatic Encephalopathy in Cirrhotic Rats. J Pharmacol Exp Ther. 2015;355(1):117–24.Чикина С.Ю. Антиоксидантные эффекты N-ацетилцистеина в современной клинической практике. Эффективная фармакотерапия. 2011;(32):19–24Chikina S.Yu. Antioxidant effects of N-acetylcysteine in modern clinical practice. Jeffektivnaja farmakoterapija. 2011;(32):19–24 (In Rus.).Lee P.C., Yang Y.Y., Huang C.S., Hsieh S.L., Lee K.C., Hsieh Y.C., et al. Concomitant inhibition of oxidative stress and angiogenesis by chronic hydrogen-rich saline and N-acetylcysteine treatments improves systemic, splanchnic and hepatic hemodynamics of cirrhotic rats. Hepatol Res. 2015;45(5):578–88.Lee P.C., Yang Y.Y., Huang C.S., Hsieh S.L., Lee K.C., Hsieh Y.C., et al. Concomitant inhibition of oxidative stress and angiogenesis by chronic hydrogen-rich saline and N-acetylcysteine treatments improves systemic, splanchnic and hepatic hemodynamics of cirrhotic rats. Hepatol Res. 2015;45(5):578–88.Гарбузенко Д.В. Патофизиологические механизмы и новые направления терапии портальной гипертензии при циррозе печени. Клин персп гастроэнтерол гепатол. 2010;(6):11–20Garbuzenko D.V. Pathophysiological mechanisms and new directions of therapy of portal hypertension at liver cirrhosis. Klin persp gastrojenterol gepatol. 2010;(6):11–20 (In Rus.).Salani D., Taraboletti G., Rosanò L., Di Castro V., Borsotti P., Giavazzi R., et al. Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol. 2000;157(5):1703–11.Salani D., Taraboletti G., Rosanò L., Di Castro V., Borsotti P., Giavazzi R., et al. Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol. 2000;157(5):1703–11.Hsu S.J., Lin T.Y., Wang S.S., Chuang C.L., Lee F.Y., Huang H.C., et al. Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats. Eur J Clin Invest. 2016;46(6):572–80.Hsu S.J., Lin T.Y., Wang S.S., Chuang C.L., Lee F.Y., Huang H.C., et al. Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats. Eur J Clin Invest. 2016;46(6):572–80.Герасименко Н.Д., Дегтярь Н.И., Расин М.С. Системное воспаление и старение: роль ядерных транскрипционных факторов и терапевтические возможности (Обзор литературы). Пробл старения и долголетия. 2016;25(4):554–61Gerasimenko N.D., Degtyar N.I., Racin M.S. Systemic inflammation and aging: the role of nuclear transcription factors and therapeutic possibilities (Review of the literature). Probl starenija i dolgoletija. 2016;25(4):554–61 (In Rus.).Dana N., Javanmard S.H., Rafiee L. Role of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract. Iran J Basic Med Sci. 2016;19(1):106–10.Dana N., Javanmard S.H., Rafiee L. Role of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract. Iran J Basic Med Sci. 2016;19(1):106–10.Schwabl P., Payer B.A., 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):1135–42.Schwabl P., Payer B.A., 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):1135–42.Enomoto N., Takei Y., Hirose M., Ikejima K., Miwa H., Kitamura T., et al. Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-α production. Gastroenterology. 2002;123(1):291–300. 67. Li T.H., Huang C.C., Yang Y.Y., Lee K.C., Hsieh S.L., Hsieh Y.C., 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(1):e0147212.Enomoto N., Takei Y., Hirose M., Ikejima K., Miwa H., Kitamura T., et al. Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-α production. Gastroenterology. 2002;123(1):291–300.Hsu S.J., Wang S.S., Hsin I.F., Lee F.Y., Huang H.C., Huo T.I., et al. Green tea polyphenol decreases the severity of portosystemic collaterals and mesenteric angiogenesis in rats with liver cirrhosis. Clin Sci (Lond). 2014;126(9):633–44.Li T.H., Huang C.C., Yang Y.Y., Lee K.C., Hsieh S.L., Hsieh Y.C., 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(1):e0147212.Hsin I.F., Lee J.Y., Huo T.I., Lee F.Y., Huang H.C., Hsu S.J., et al. 2’-Hydroxyflavanone ameliorates mesenteric angiogenesis and portal-systemic collaterals in rats with liver fibrosis. J Gastroenterol Hepatol. 2016;31(5):1045–51.Hsu S.J., Wang S.S., Hsin I.F., Lee F.Y., Huang H.C., Huo T.I., et al. Green tea polyphenol decreases the severity of portosystemic collaterals and mesenteric angiogenesis in rats with liver cirrhosis. Clin Sci (Lond). 2014;126(9):633–44.Hsu S.J., Lee J.Y., Lin T.Y., Hsieh Y.H., Huang H.C., Lee F.Y., et al. The beneficial effects of curcumin in cirrhotic rats with portal hypertension. Biosci Rep. 2017;37(6):1–13.Hsin I.F., Lee J.Y., Huo T.I., Lee F.Y., Huang H.C., Hsu S.J., et al. 2’-Hydroxyflavanone ameliorates mesenteric angiogenesis and portal-systemic collaterals in rats with liver fibrosis. J Gastroenterol Hepatol. 2016;31(5):1045–51.Coriat R., Gouya H., Mir O., Ropert S., Vignaux O., Chaussade S., et al. Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib. PLoS One. 2011;6(2):e16978.Hsu S.J., Lee J.Y., Lin T.Y., Hsieh Y.H., Huang H.C., Lee F.Y., et al. The beneficial effects of curcumin in cirrhotic rats with portal hypertension. Biosci Rep. 2017;37(6):1–13.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(1):83–91.Coriat R., Gouya H., Mir O., Ropert S., Vignaux O., Chaussade S., et al. Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib. PLoS One. 2011;6(2):e16978.Garcia-Tsao G., Fallon M., Reddy K., Loo N., Bari K., Augustin S., et al. Placebo-controlled, randomized, pilot study of the effect of sorafenib on portal pressure in patients with cirrhosis, portal hypertension and ablated hepatocellular carcinoma (HCC). Hepatology. 2015;62(Suppl S1):580A.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(1):83–91.Garcia-Tsao G., Fallon M., Reddy K., Loo N., Bari K., Augustin S., et al. Placebo-controlled, randomized, pilot study of the effect of sorafenib on portal pressure in patients with cirrhosis, portal hypertension and ablated hepatocellular carcinoma (HCC). Hepatology. 2015;62(Suppl S1):580A.Garcia-Tsao G., Fallon M., Reddy K., Loo N., Bari K., Augustin S., et al. Placebo-controlled, randomized, pilot study of the effect of sorafenib on portal pressure in patients with cirrhosis, portal hypertension and ablated hepatocellular carcinoma (HCC). Hepatology. 2015;62(Suppl S1):580A.

The authors declare that there are no conflicts of interest present.