urmjУральский медицинский журналUral Medical Journal2949-4389Ural State Medical Universityurmj-56Research ArticleОБЗОР ЛИТЕРАТУРЫЭкспериментальные методы изучения ангиогенеза, ассоциированного с портальной гипертензией (обзор литературы)Portal hypertension associated angiogenesis assay in experimental studies (literature review)АрефьевН. О.ArefyevN. O.nikolai.arefyev@gmail.comГарбузенкоД. В.GarbuzenkoD. V.noemail@neicon.ruКазачковЕ. Л.KazachkovE. L.noemail@neicon.ruБордуновскийВ. Н.BordunovskiiV. N.noemail@neicon.ruФГБОУ ВО ЮУГМУ Минздрава РФRussian FederationФГБОУ ВО ЮУГМУ Минздрава РоссииRussian Federation201814042021021623Copyright © Арефьев Н.О., Гарбузенко Д.В., Казачков Е.Л., Бордуновский В.Н., 20212021Арефьев Н.О., Гарбузенко Д.В., Казачков Е.Л., Бордуновский В.Н.Arefyev N.O., Garbuzenko D.V., Kazachkov E.L., Bordunovskii V.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.umjusmu.ru/jour/article/view/56

В обзоре представлены литературные данные о современных методах изучения ангиогенеза, ассоциированного с портальной гипертензией, в эксперименте. для поиска научных статей применялись база данных PubMed, поисковая система Google Scholar, а также пристатейные списки литературы. Соответствующие цели обзора публикации отбирались за период с 1981 по 2017 год по терминам: «портальная гипертензия», «микрокт», «ангиогенез», «иммуногистохимия», «интравитальная микроскопия», «микросферы». анализ литературы показал, что современные методы изучения внутри- и внепечёночного ангиогенеза, такие как микрокомпьютерная томография in vivo и ex vivo, интравитальная микроскопия, а также эффективные средства компьютерной обработки изображений, позволяют установить его важную роль в патогенезе портальной гипертензии. разработка способов антиангиогенной терапии, избирательно направленной на новообразованные сосуды, может быть перспективным направлением в лечении портальной гипертензии и связанных с ней осложнений.

The review presents literature data on portal hypertension associated angiogenesis assay in experimental studies. The information was collected from the PubMed database, the Google Scholar retrieval system, and the reference lists from relevant publications for 1981 - 2017 using the keywords: “portal hypertension,” “jCT,” “angiogenesis,” “immunohistochemistry,” “intravital microscopy,” “microspheres.” Analysis of the literature showed that intra- and extrahepatic angiogenesis assays, such as micro-computed tomography in vivo and ex vivo, intravital microscopy, and computer image processing allow us to establish its important role in portal hypertension pathogenesis. The development of anti-angiogenic therapy, which would be focused on newly formed vessels, may be a perspective direction in the treatment of portal hypertension and its complications

портальная гипертензияангиогенезиммуногистохимические методымикроктинтравитальная микроскопиямикросферыportal hypertensionangiogenesisimmunohistochemistrymicroCTintravital microscopymicrospheresReferencesГарбузенко Д.В. Морфофункциональная перестройка печёночного сосудистого русла в патогенезе портальной гипертензии при циррозе печени. Тер арх 2014; 86 (2): 90-5.Гарбузенко Д.В. Морфофункциональная перестройка печёночного сосудистого русла в патогенезе портальной гипертензии при циррозе печени. Тер арх 2014; 86 (2): 90-5.Гарбузенко Д.В. Механизмы адаптации сосудистого русла к гемодинамическим нарушениям при портальной гипертензии. Вестн РАМН 2013; (1): 52-7.Гарбузенко Д.В. Механизмы адаптации сосудистого русла к гемодинамическим нарушениям при портальной гипертензии. Вестн РАМН 2013; (1): 52-7.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.Гарбузенко Д.В. Экспериментальные методы изучения портальной гипертензии. Рос журн гастроэнтерол гепатол колопроктол 2010; 20 (2): 4-12.Гарбузенко Д.В. Экспериментальные методы изучения портальной гипертензии. Рос журн гастроэнтерол гепатол колопроктол 2010; 20 (2): 4-12.Fernandez M., Semela D., Bruix J., Colle I., Pinzani M., Bosch J. Angiogenesis in liver disease. J Hepatol 2009; 50 (3): 604-20.Fernandez M., Semela D., Bruix J., Colle I., Pinzani M., Bosch J. Angiogenesis in liver disease. J Hepatol 2009; 50 (3): 604-20.McDonald D.M., Choyke P.L. Imaging of angiogenesis: from microscope to clinic. Nat Med 2003; 9 (6): 713-25.McDonald D.M., Choyke P.L. Imaging of angiogenesis: from microscope to clinic. Nat Med 2003; 9 (6): 713-25.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.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.Van Steenkiste C., Trachet B., Casteleyn C. et al. Vascular corrosion casting: analyzing wall shear stress in the portal vein and vascular abnormalities in portal hypertensive and cirrhotic rodents. Lab Invest 2010; 90 (11): 1558-72.Van Steenkiste C., Trachet B., Casteleyn C. et al. Vascular corrosion casting: analyzing wall shear stress in the portal vein and vascular abnormalities in portal hypertensive and cirrhotic rodents. Lab Invest 2010; 90 (11): 1558-72.Niggemann P., Murata S., Naito Z., Kumazaki T. A comparative study of the microcirculatory changes in the developing liver cirrhosis between the central and peripheral parts of the main lobe in mice. Hepatol Res 2004; 28 (1): 41-48.Niggemann P., Murata S., Naito Z., Kumazaki T. A comparative study of the microcirculatory changes in the developing liver cirrhosis between the central and peripheral parts of the main lobe in mice. Hepatol Res 2004; 28 (1): 41-48.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): 419-32.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): 419-32.Yang Y.Y., Huang Y.T., Lin H.C. Thalidomide decreases intrahepatic resistance in cirrhotic rats. Biochem Biophys Res Commun 2009; 380 (3): 666-72.Yang Y.Y., Huang Y.T., Lin H.C. Thalidomide decreases intrahepatic resistance in cirrhotic rats. Biochem Biophys Res Commun 2009; 380 (3): 666-72.Boerckel J.D., Mason D.E., McDermott A.M., Alsberg E. Microcomputed tomography: approaches and applications in bioengineering. Stem Cell Res Ther 2014; 5 (6): 144.Boerckel J.D., Mason D.E., McDermott A.M., Alsberg E. Microcomputed tomography: approaches and applications in bioengineering. Stem Cell Res Ther 2014; 5 (6): 144.Ehling J., Bartneck M., Wei X. et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014; 63 (12): 1960-71.Ehling J., Bartneck M., Wei X. et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014; 63 (12): 1960-71.Bartneck M., Fech V, Ehling J. et al. Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease. Hepatology 2016; 63 (4): 1310-24.Bartneck M., Fech V, Ehling J. et al. Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease. Hepatology 2016; 63 (4): 1310-24.Jorgensen S.M., Demirkaya O., Ritman E.L. Threedimensional imaging of vasculature and parenchyma in intact rodent organs with X-ray micro-CT. Am J Physiol 1998; 275 (3 Pt 2): H1103-14.Jorgensen S.M., Demirkaya O., Ritman E.L. Threedimensional imaging of vasculature and parenchyma in intact rodent organs with X-ray micro-CT. Am J Physiol 1998; 275 (3 Pt 2): H1103-14.Thabut D., Routray C., Lomberk G. et al. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 2011; 54 (2): 573-85.Thabut D., Routray C., Lomberk G. et al. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 2011; 54 (2): 573-85.Lin H.C., Huang Y.T., Yang Y.Y. 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. 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.Kline T.L., Knudsen B.E., Anderson J.L., Vercnocke A.J., Jorgensen S.M., Ritman E.L. Anatomy of hepatic arteriolo-portal venular shunts evaluated by 3D micro-CT imaging. J Anat 2014; 224 (6): 724-31.Kline T.L., Knudsen B.E., Anderson J.L., Vercnocke A.J., Jorgensen S.M., Ritman E.L. Anatomy of hepatic arteriolo-portal venular shunts evaluated by 3D micro-CT imaging. J Anat 2014; 224 (6): 724-31.Peeters G., Debbaut C., Laleman W. et al. A multilevel framework to reconstruct anatomical 3D models of the hepatic vasculature in rat livers. J Anat 2017; 230 (3): 471-83.Peeters G., Debbaut C., Laleman W. et al. A multilevel framework to reconstruct anatomical 3D models of the hepatic vasculature in rat livers. J Anat 2017; 230 (3): 471-83.Peeters G., Debbaut C., Friebel A. et al. Quantitative analysis of hepatic macro- and microvascular alterations during cirrhogenesis in the rat. J Anat 2017 Dec 4 [Epub ahead of print].Peeters G., Debbaut C., Friebel A. et al. Quantitative analysis of hepatic macro- and microvascular alterations during cirrhogenesis in the rat. J Anat 2017 Dec 4 [Epub ahead of print].Hsu S.J., Lee J.Y., Lin T.Y. et al. The beneficial effects of curcumin in cirrhotic rats with portal hypertension. Biosci Rep 2017; 37 (6).Hsu S.J., Lee J.Y., Lin T.Y. et al. The beneficial effects of curcumin in cirrhotic rats with portal hypertension. Biosci Rep 2017; 37 (6).Renier N., Wu Z., Simon D.J. et al. iDISCO: simple, rapid method to immunolabel large tissue samples for volume imaging. Cell 2014; 159: 896-910.Renier N., Wu Z., Simon D.J. et al. iDISCO: simple, rapid method to immunolabel large tissue samples for volume imaging. Cell 2014; 159: 896-910.Susaki E.A., Tainaka K., Perrin D. et al. Whole-brain imaging with single-cell resolution using chemical cocktails and computational analysis. Cell 2014; 157: 726-39.Susaki E.A., Tainaka K., Perrin D. et al. Whole-brain imaging with single-cell resolution using chemical cocktails and computational analysis. Cell 2014; 157: 726-39.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.Арефьев Н.О., Гарбузенко Д.В., Емельянов И.В., Хасанов Л.Р. Оценка неоангиогенеза в брыжейке тонкой кишки у крыс с моделью предпечёночной портальной гипертензии. Рос журн гастроэнтерол, гепатол, колопроктол 2017; 27 (приложение 50): 83.Арефьев Н.О., Гарбузенко Д.В., Емельянов И.В., Хасанов Л.Р. Оценка неоангиогенеза в брыжейке тонкой кишки у крыс с моделью предпечёночной портальной гипертензии. Рос журн гастроэнтерол, гепатол, колопроктол 2017; 27 (приложение 50): 83.Geerts A.M., De Vriese A.S., Vanheule E. et al. Increased angiogenesis and permeability in the mesenteric microvasculature of rats with cirrhosis and portal hypertension: an in vivo study. Liver Int 2006; 26: 889-98.Geerts A.M., De Vriese A.S., Vanheule E. et al. Increased angiogenesis and permeability in the mesenteric microvasculature of rats with cirrhosis and portal hypertension: an in vivo study. Liver Int 2006; 26: 889-98.Maksan S.M., Ryschich E., Ulger Z., Gebhard M.M., Schmidt J. Disturbance of hepatic and intestinal microcirculation in experimental liver cirrhosis. World J Gastroenterol 2005; 11 (6): 846-9.Maksan S.M., Ryschich E., Ulger Z., Gebhard M.M., Schmidt J. Disturbance of hepatic and intestinal microcirculation in experimental liver cirrhosis. World J Gastroenterol 2005; 11 (6): 846-9.Yamaki K., Lindbom L., Thorlacius H., Hedqvist P., Raud J. An approach for studies of mediator-induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery. Br J Pharmacol 1998; 123 (3): 381-9.Yamaki K., Lindbom L., Thorlacius H., Hedqvist P., Raud J. An approach for studies of mediator-induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery. Br J Pharmacol 1998; 123 (3): 381-9.Sumanovski L.T., Battegay E., Stumm M., van der Kooij M., Sieber C.C. Increased angiogenesis in portal hypertensive rats: role of nitric oxide. Hepatology 1999; 29 (4): 1044-9.Sumanovski L.T., Battegay E., Stumm M., van der Kooij M., Sieber C.C. Increased angiogenesis in portal hypertensive rats: role of nitric oxide. Hepatology 1999; 29 (4): 1044-9.Anderson C.R., Ponce A.M., Price R.J. Immunohistochemical identification of an extracellular matrix scaffold that microguides capillary sprouting in vivo. JHistochem Cytochem 2004; 52 (8): 1063-72.Anderson C.R., Ponce A.M., Price R.J. Immunohistochemical identification of an extracellular matrix scaffold that microguides capillary sprouting in vivo. JHistochem Cytochem 2004; 52 (8): 1063-72.Abraldes J.G., Iwakiri Y., Loureiro-Silva M., Haq O., Sessa W.C., Groszmann R.J. 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 (5): G980-7.Abraldes J.G., Iwakiri Y., Loureiro-Silva M., Haq O., Sessa W.C., Groszmann R.J. 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 (5): G980-7.Huang H.C., Wang S.S., Hsin I.F. Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats. Hepatology 2012; 56 (1): 248-58.Huang H.C., Wang S.S., Hsin I.F. Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats. Hepatology 2012; 56 (1): 248-58.Patsenker E., Popov Y., Stickel F. Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 2009; 50 (5): 1501-11.Patsenker E., Popov Y., Stickel F. Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 2009; 50 (5): 1501-11.Yang M., Stapor P.C., Peirce S.M., Betancourt A.M., Murfee W.L. Rat Mesentery Exteriorization: A Model for Investigating the Cellular Dynamics Involved in Angiogenesis. J Vis Exp 2012; 63: e3954.Yang M., Stapor P.C., Peirce S.M., Betancourt A.M., Murfee W.L. Rat Mesentery Exteriorization: A Model for Investigating the Cellular Dynamics Involved in Angiogenesis. J Vis Exp 2012; 63: e3954.McConnell M., Iwakiri Y. Biology of portal hypertension. Hepatol Int 2017 [Epub ahead of print].McConnell M., Iwakiri Y. Biology of portal hypertension. Hepatol Int 2017 [Epub ahead of print].Licks F., Hartmann R. M., Marques C., Schemitt E., Colares J. R., Soares M. do C. et al. N-acetylcysteine modulates angiogenesis and vasodilation in stomach such as DNA damage in blood of portal hypertensive rats. World J Gastroenterol 2015; 21 (43): 12351-60.Licks F., Hartmann R. M., Marques C., Schemitt E., Colares J. R., Soares M. do C. et al. N-acetylcysteine modulates angiogenesis and vasodilation in stomach such as DNA damage in blood of portal hypertensive rats. World J Gastroenterol 2015; 21 (43): 12351-60.De Backer D., Hollenberg S., Boerma C. et al. How to evaluate the microcirculation: report of a round table conference. Crit Care 2007; 11 (5): R101.De Backer D., Hollenberg S., Boerma C. et al. How to evaluate the microcirculation: report of a round table conference. Crit Care 2007; 11 (5): R101.De Backer D., Creteur J., Preiser J.C., Dubois M.J., Vincent J.L. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002; 166 (1): 98-104.De Backer D., Creteur J., Preiser J.C., Dubois M.J., Vincent J.L. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002; 166 (1): 98-104.Spronk P.E., Ince C., Gardien M.J., Mathura K.R., Oudemans-van Straaten H.M., Zandstra D.F. Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 2002; 360 (9343): 1395-6.Spronk P.E., Ince C., Gardien M.J., Mathura K.R., Oudemans-van Straaten H.M., Zandstra D.F. Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 2002; 360 (9343): 1395-6.Klyscz T., Jünger M., Jung F., Zeintl H. Cap image--a new kind of computer-assisted video image analysis system for dynamic capillary microscopy. Biomed Tech (Berl) 1997; 42 (6): 168-75.Klyscz T., Jünger M., Jung F., Zeintl H. Cap image--a new kind of computer-assisted video image analysis system for dynamic capillary microscopy. Biomed Tech (Berl) 1997; 42 (6): 168-75.Aperio Technologies I. Microvessel Analysis Algorithm, User’S Guide @ONLINE. 2008.Aperio Technologies I. Microvessel Analysis Algorithm, User’S Guide @ONLINE. 2008.Reyes-Aldasoro C.C., Williams L.J., Akerman S., Kanthou C., Tozer G.M. An automatic algorithm for the segmentation and morphological analysis of microvessels in immunostained histological tumour sections. JMicrosc 2011; 242 (3): 262-278.Reyes-Aldasoro C.C., Williams L.J., Akerman S., Kanthou C., Tozer G.M. An automatic algorithm for the segmentation and morphological analysis of microvessels in immunostained histological tumour sections. JMicrosc 2011; 242 (3): 262-278.Fernández-Carrobles M.M., Tadeo I., Bueno G. et al. TMA Vessel Segmentation Based on Color and Morphological Features: Application to Angiogenesis Research. The Scientific World Journal 2013; 2013: 263190.Fernández-Carrobles M.M., Tadeo I., Bueno G. et al. TMA Vessel Segmentation Based on Color and Morphological Features: Application to Angiogenesis Research. The Scientific World Journal 2013; 2013: 263190.Chojkier M., Groszmann R.J. Measurement of portal-systemic shunting in the rat by using у-labeled microspheres. Am J Physiol 1981; 240: G371-G375.Chojkier M., Groszmann R.J. Measurement of portal-systemic shunting in the rat by using у-labeled microspheres. Am J Physiol 1981; 240: G371-G375.Hodeige D., de Pauw M., Eechaute W., Weyne J., Heyndrickx, G. R. On the validity of blood flow measurement using colored microspheres. Am J Physiol 1999; 276: H1150-H1158.Hodeige D., de Pauw M., Eechaute W., Weyne J., Heyndrickx, G. R. On the validity of blood flow measurement using colored microspheres. Am J Physiol 1999; 276: H1150-H1158.Theodorakis N., Maluccio M., Skill N. Murine study of portal hypertension associated endothelin-1 hyporesponse. World J Gastroenterol 2015; 21 (16): 4817-28.Theodorakis N., Maluccio M., Skill N. Murine study of portal hypertension associated endothelin-1 hyporesponse. World J Gastroenterol 2015; 21 (16): 4817-28.Hsu S.J., Wang S.S., Hsin I.F. 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., Wang S.S., Hsin I.F. 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.Fernandez M., Vizzutti F., Garcia-Pagan J.C., Rodes J., Bosh J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology 2004; 126: 886-94.Fernandez M., Vizzutti F., Garcia-Pagan J.C., Rodes J., Bosh J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology 2004; 126: 886-94.Lee P.C., Yang Y.Y., Huang C.S. et al. Concomitant ingibition 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. et al. Concomitant ingibition 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.Van Steenkiste C., Staelens S., Deleye S. et al. Measurement of porto-systemic shunting in mice by novel three-dimensional micro-single photon emission computed tomography imaging enabling longitudinal follow-up. Liver Int 2010; 30 (8): 1211-20.Van Steenkiste C., Staelens S., Deleye S. et al. Measurement of porto-systemic shunting in mice by novel three-dimensional micro-single photon emission computed tomography imaging enabling longitudinal follow-up. Liver Int 2010; 30 (8): 1211-20.

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