Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya31471Editorial articleПередовая статьяReview ArticleMorphofunctional rearrangement of the hepatic vasculature in the pathogenesis of portal hypertension in liver cirrhosisМорфофункциональная перестройка печеночного сосудистого русла в патогенезе портальной гипертензии при циррозе печениGarbuzenkoD VГарбузенкоД Вgarb@inbox.ruЮжно-Уральский государственный медицинский университет Минздрава России, Челябинск15022014862VOL 86, NO2 ()ТОМ 86, №2 (2014)909510042020Copyright ©; 2014, Consilium MedicumCopyright ©; 2014, ООО "Консилиум Медикум"2014Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/31471

The paper presents an update on the mechanisms for enhanced hepatic vascular resistance to the portal circulation underlying the pathogenesis of portal hypertension in liver cirrhosis. In addition to gross hepatic structural disorders related to diffuse fibrosis and formation of regenerative nodules, the morphofunctional rearrangement of the hepatic vasculature is shown to play an important role in this process. It is characterized by endothelial dysfunction and impaired paracrine interaction between activated stellate hepatocytes and sinusoidal endotheliocytes, sinusoidal remodeling and capillarization, as well as intrahepatic angiogenesis.

Аннотация. Представлены современные данные о механизмах повышения печеночного сосудистого сопротивления портальному кровотоку, лежащему в основе патогенеза портальной гипертензии при циррозе печени. Показано, что, помимо грубых структурных нарушений в печени, связанных с диффузным фиброзом и формированием узлов регенерации, важную роль в этом процессе играет морфофункциональная перестройка печеночного сосудистого русла. Она характеризуется дисфункцией эндотелия и расстройством паракринного взаимодействия между активированными звездчатыми клетками печени и синусоидальными эндотелиальными клетками, ремоделированием и капилляризацией синусоидов, а также развитием внутрипеченочного ангиогенеза.

liver cirrhosisportal hypertensionpathogenesisendothelial dysfunctionsinusoidal remodelingangiogenesisцирроз печенипортальная гипертензияпатогенездисфункция эндотелияремоделирование синусоидовангиогенезГарбузенко Д.В. Механизмы адаптации сосудистого русла к гемодинамическим нарушениям при портальной гипертензии. Вестн РАМН 2013; 1: 52-57.Garcia-Pagan J.C., Gracia-Sancho J., Bosch J. Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J Hepatol 2012; 57 (2): 458-461.Hu L.S., George J., Wang J.H. Current concepts on the role of nitric oxide in portal hypertension. World J Gastroenterol 2013; 19 (11): 1707-1717.Hellerbrand C. Hepatic stellate cells-the pericytes in the liver. Pflugers Arch 2013; 465 (6): 775-778.Ueno T., Bioulac-Sage P., Balabaud C., Rosenbaum J. Innervation of the sinusoidal wall: regulation of the sinusoidal diameter. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (1): 868-873.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 (6): 1010-1021.Takashimizu S., Kojima S., Nishizaki Y. et al. Effect of endothelin A receptor antagonist on hepatic hemodynamics in cirrhotic rats. Implications for endothelin-1 in portal hypertension. Tokai J Exp Clin Med 2011; 36 (2): 37-43.Lugo-Baruqui A., Muñoz-Valle J.F., Arévalo-Gallegos S., Armendáriz-Borunda J. Role of angiotensin II in liver fibrosis-induced portal hypertension and therapeutic implications. Hepatol Res 2010; 40 (1): 95-104.Reynaert H., Urbain D., Geerts A. Regulation of sinusoidal perfusion in portal hypertension. Anat Rec 2008; 291 (6): 693-698.Lee J.S., Semela D., Iredale J., Shah V.H. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Hepatology 2007; 45 (3): 817-825.Lee J.S., Decker N.K., Chatterjee S. et al. Mechanismus of nitric oxide interplay with Rho GTFase famely members in modulation of actinmembrane dynamics in pericytes and fibroblasts. Am J Pathol 2005; 166 (6): 1861-1870.Semela D., Das A., Langer D. et al. Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology 2008; 135 (2): 671-679.Pinzani M. PDGF and signal transduction in hepatic stellate cells. Front Biosci 2002; 7: 1720-1726.Cao S., Yaqoob U., Das A. et al. Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells. J Clin Invest 2010; 120 (7): 2379-2394.Friedman S.L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88 (1): 125-172.Яковенко Э.П., Яковенко А.В., Иванов А.Н. и др. Фиброз печени: механизмы развития и вопросы терапии. Фарматека 2011; 225 (12): 16-22.Svegliati-Baroni G., De Minicis S., Marzioni M. Hepatic fibrogenesis in response to chronic liver injury: novel insights on the role of cell-to-cell interaction and transition. Liver Int 2008; 28 (8): 1052-1064.Rappaport A.M., MacPhee P.J., Fisher M.M., Phillips M.J. The scarring of the liver acini (Cirrhosis). Tridimensional and microcirculatory considerations. Virchows Arch A Pathol Anat Histopathol 1983; 402 (2): 107-137.Lemos Q.T., Andrade Z.A. Angiogenesis and experimental hepatic fibrosis. Mem. Inst. Oswaldo Cruz 2010; 105 (5): 611-614.Medina J., Arroyo A.G., Sanchez-Madrid F., Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease. Hepatology 2004; 39 (5): 1185-1195.Ciupińska-Kajor M., Hartleb M., Kajor M. et al. Hepatic angiogenesis and fibrosis are common features in morbidly obese patients. Hepatol Int 2013; 7 (1): 233-240.Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007; 6 (4): 273-286.Skuli N., Majmundar A.J., Krock B.L. et al. Endothelial HIF-2a regulates murine pathological angiogenesis and revascularization processes. J Clin Invest 2012; 122 (4): 1427-1443.Brandes R.P., Miller F.J., Beer S. et al. The vascular NADPH oxidase subunit p47phox is involved in redox-mediated gene expression. Free Radic Biol Med 2002; 32 (11): 1116-1122.Chen Z., Lai T.C., Jan Y.H. et al. Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis. J Clin Invest 2013; 123 (3): 1057-167.Carmeliet P. Manipulating angiogenesis in medicine. J Intern Med 2004; 255 (5): 538-561.Klein S., Roghani M., Rifkin D.B. Fibroblast growth factors as angiogenesis factors: new insights into their mechanism of action. EXS 1997; 79: 159-192.Hellberg C., Ostman A., Heldin C.H. PDGF and vessel maturation. Recent Results Cancer Res 2010; 180: 103-114.Chen J.X., Zeng H., Lawrence M.L. et al. Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase. Am J Physiol Heart Circ Physiol 2006; 291 (4): 1563-1572.Ramsauer M., D'Amore P.A. Contextual role for angiopoietins and TGFΒ1 in blood vessel stabilization. J Cell Sci 2007; 120 (Pt 10): 1810-1817.Patsenker E., Popov Y., Stickel F. et al. Pharmacological inhibition of integrin αvΒ3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 2009; 50 (5): 1501-1511.Kevil C.G., Payne D.K., Mire E., Alexander J.S. Vascular permeability factor/vascular endothelial cell growth factor-mediated permeability occurs through disorganization of endothelial junctional proteins. J Biol Chem 1998; 273 (24): 15099-15103.Elpek G.O., Gokhan G.A., Bozova S. Trombospondin-1 expression correlates with angiogenesis in experimental cirrhosis. World J Gastroenterol 2008; 14 (14): 2213-2217.Eriksson K., Magnusson P., Dixelius J. et al. Angiostatin and endostatin inhibit endothelial cell migration in response to FGF and VEGF without interfering with specific intracellular signal transduction pathways. FEBS Lett 2003; 536 (1-3): 19-24.Jagavelu K., Routray C., Shergill U. et al. Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology 2010; 52 (2): 590-601.Melgar-Lesmes P., Pauta M., Reichenbach V. et al. Hypoxia and proinflammatory factors upregulate apelin receptor expression in human stellate cells and hepatocytes. Gut 2011; 60 (10): 1404-1411.Huebert R.C., Jagavelu K., Hendrickson H.I. et al. Aquaporin-1 promotes angiogenesis, fibrosis, and portal hypertension through mechanisms dependent on osmotically sensitive microRNAs. Am J Pathol 2011; 179 (4): 1851-1860.Sahin H., Borkham-Kamphorst E., Kuppe C. et al. Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology 2012; 55 (5): 1610-1619.Staton C., Kumar I., Reed M., Brown N. Neuropilins in physiological and pathological angiogenesis. J Pathol 2007; 212 (3): 237-248.Fernandez M., Semela D., Bruix J. et al. Angiogenesis in liver disease. J Hepatol 2009; 50 (3): 604-620.Chaparro M., Sanz-Cameno P., Trapero-Marugan M. et al. Mechanisms of angiogenesis in chronic inflammatory liver disease. Ann Hepatol 2007; 6 (4): 208-213.Steib C.J. Kupffer cell activation and portal hypertension. Gut 2011; 60 (10): 1307-1308.Lochhead P.A., Gilley R., Cook S.J. ERK5 and its role in tumour development. Biochem Soc Trans 2012; 40 (1): 251-256.Dewhirst M.W., Cao Y., Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 2008; 8 (6): 425-437.Ko H.M., Seo K.H., Han S.J. et al. Nuclear factor kappaB dependency of platelet-activating factor-induced angiogenesis. Cancer Res 2002; 62 (6): 1809-1814.Franceschini B., Ceva-Grimaldi G., Russo C. et al. The complex functions of mast cells in chronic human liver diseases. Dig Dis Sci 2006; 51 (12): 2248-2256.Marra F. Chemokines in liver inflammation and fibrosis. Front Biosci 2002; 1 (7): 1899-1914.Copple B.L., Bai S., Burgoon L.D., Moon J.O. Hypoxia-inducible factor-1α regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis. Liver Int 2011; 31 (2): 230-244.Lemoinne S., Cadoret A., Mourabit H.E. et al. Origins and functions of liver myofibroblasts. Biochim Biophys Acta 2013; 1832 (7): 948-954.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): 508-514.Coulon S., Heindryckx F., Geerts A. et al. Angiogenesis in chronic liver disease and its complications. Liver Int 2011; 31 (2): 146-162.Novo E., Povero D., Busletta C. et al. The biphasic nature of hypoxia-induced directional migration of activated human hepatic stellate cells. J Pathol 2012; 226 (4): 588-597.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 (6): 1942-1953.Vanheule E., Geerts A.M., Van Huysse J. et al. An intravital microscopic study of the hepatic microcirculation in cirrhotic mice models: relationship between fibrosis and angiogenesis. Int J Exp Pathol 2008; 89 (6): 419-432.Kaur S., Tripathi D., Dongre K. et al. Increased number and function of endothelial progenitor cells stimulate angiogenesis by resident liver sinusoidal endothelial cells (SECs) in cirrhosis through paracrine factors. J Hepatol 2012; 57 (6): 1193-1198.Chen C.H., Chang L.T., Tung W.C. et al. Levels and values of circulating endothelial progenitor cells, soluble angiogenic factors, and mononuclear cell apoptosis in liver cirrhosis patients. J Biomed Sci 2012; 19: 66.