Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Hepatology International
Published in: Hepatology International 4/2013

01-10-2013 | Review Article

Angiogenesis in liver regeneration and fibrosis: “a double-edged sword”

Authors: Savneet Kaur, K. Anita

Published in: Hepatology International | Issue 4/2013

Login to get access

Abstract

Angiogenesis, defined as the formation of new microvasculature from preexisting blood vessels and mature endothelial cells, plays a major role in wound healing and scar formation, and it is associated with inflammatory responses. Angiogenesis can occur in physiological conditions, such as during liver regeneration, and in pathological situations, such as during the progression of fibrosis to cirrhosis and also during tumor angiogenesis. Cellular cross-talk among liver sinusoidal endothelial cells (LSECs), hepatic stellate cells and hepatocytes is believed to play an important role in the angiogenesis process during both liver regeneration and development of cirrhosis. In addition to mature endothelial cells, bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) have been recently identified for their contribution to post-natal vasculogenesis/angiogenesis. In vivo, EPCs are mobilized into the peripheral blood in response to tissue ischemia or traumatic injury, migrate to the sites of injured endothelium and differentiate into mature endothelial cells. In our recent studies, we have explored the role of EPC-mediated angiogenesis in liver regeneration and/or cirrhosis. Results have demonstrated significantly increased endogenous levels of circulating EPCs in cirrhotic patients in comparison to the controls. Also, EPCs from cirrhotic patients have been observed to stimulate substantial angiogenesis by resident LSECs in vitro via paracrine factors such as vascular endothelial growth factor and platelet-derived growth factor. This review gives an overview of the angiogenesis process in liver regeneration and disease and discusses a new mechanism for intrahepatic angiogenesis mediated by BM-derived EPCs.
Literature
1.
2.
Michalopoulos GK. Liver regeneration: alternative epithelial pathways. Int J Biochem Cell Biol 2011;43:173–179PubMedCrossRef
3.
Drixler TA, Vogten MJ, Ritchie ED, van Vroonhoven TJ, Gebbink MF, Voest EE, et al. Liver regeneration is an angiogenesis-associated phenomenon. Ann Surg 2002;236:703–711PubMedCrossRef
4.
Vanheule E, Geerts AM, Van Huysse J, Schelfhout D, Praet M, Van Vlierberghe H, et al. An intravital microscopic study of the hepatic microcirculation in cirrhotic mice models: relationship between fibrosis and angiogenesis. Int J Exp Pathol 2008;89:419–432PubMedCrossRef
5.
6.
7.
Kaur S, Jayakumar K, Kartha CC. The potential of circulating endothelial progenitor cells to form colonies is inversely proportional to total vascular risk score in patients with coronary artery disease. Indian Heart J 2007;59:475–481PubMed
8.
Kaur S, Tripathi D, Dongre K, Garg V, Rooge S, Mukopadhyay A, 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;57:1193–1198PubMedCrossRef
9.
Kmieć Z. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 2001;61:1–151
10.
Sakamoto T, Liu Z, Murase N, Ezure T, Yokomuro S, Poli V, et al. Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy. Hepatology 1999;29:403–411PubMedCrossRef
11.
Rabes HM. Kinetics of hepatocellular proliferation as a function of the microvascular structure and functional state of the liver. Ciba Found Symp 1977;55:31–53PubMed
12.
Webber EM, Bruix J, Pierce RH, Fausto N. Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology 1998;28:1226–1234PubMedCrossRef
13.
Van Sweringen HL, Sakai N, Tevar AD, Burns JM, Edwards MJ, Lentsch AB. CXC chemokine signaling in the liver: impact on repair and regeneration. Hepatology 2011;54:1445–1453PubMedCrossRef
14.
Wisse E, De Zanger RB, Charels K, Van Der Smissen P, McCuskey RS. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 1985;5:683–692PubMedCrossRef
15.
Martinez-Hernandez A, Amenta PS. The extracellular matrix in hepatic regeneration. FASEB J 1995;9:1401–410PubMed
16.
Wack KE, Ross MA, Zegarra V, Sysko LR, Watkins SC, Stolz DB. Sinusoidal ultrastructure evaluated during the revascularization of regenerating rat liver. Hepatology 2001;33:363–378PubMedCrossRef
17.
Ross MA, Sander CM, Kleeb TB, Watkins SC, Stolz DB. Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver. Hepatology 2001;34:1135–1148PubMedCrossRef
18.
Maeno H, Ono T, Dhar DK, Sato T, Yamanoi A, Nagasue N. Expression of hypoxia inducible factor-1alpha during liver regeneration induced by partial hepatectomy in rats. Liver Int 2005;25:1002–1009PubMedCrossRef
19.
Redaelli CA, Semela D, Carrick FE, Ledermann M, Candinas D, Sauter B, et al. Effect of vascular endothelial growth factor on functional recovery after hepatectomy in lean and obese mice. J Hepatol 2004;40:305–312PubMedCrossRef
20.
Taniguchi E, Sakisaka S, Matsuo K, Tanikawa K, Sata M. Expression and role of vascular endothelial growth factor in liver regeneration after partial hepatectomy in rats. J Histochem Cytochem 2001;49:121–130PubMedCrossRef
21.
Shimizu H, Miyazaki M, Wakabayashi Y, Mitsuhashi N, Kato A, Ito H, et al. Vascular endothelial growth factor secreted by replicating hepatocytes induces sinusoidal endothelial cell proliferation during regeneration after partial hepatectomy in rats. J Hepatol 2001;34:683–689PubMedCrossRef
22.
Yokomori H, Oda M, Yoshimura K, Nagai T, Ogi M, Nomura M, et al. Vascular endothelial growth factor increases fenestral permeability in hepatic sinusoidal endothelial cells. Liver Int 2003;23:467–475PubMedCrossRef
23.
Ding BS, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 2010;468:310–315PubMedCrossRef
24.
LeCouter J, Moritz DR, Li B, Phillips GL, Liang XH, Gerber HP, et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003;299:890–893PubMedCrossRef
25.
Balabaud C, Bioulac-Sage P, Desmouliere A. The role of hepatic stellate cells in liver regeneration. J Hepatol 2004;40:1023–1026PubMedCrossRef
26.
Budny T, Palmes D, Stratmann U, Minin E, Herbst H, Spiegel HU. Morphologic features in the regenerating liver—a comparative intravital, lightmicroscopical and ultrastructural analysis with focus on hepatic stellate cells. Virchows Arch 2007;451:781–791PubMedCrossRef
27.
Neufeld G, Kessler O, Herzog Y. The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors for VEGF. Adv Exp Med Biol 2002;515:81–90PubMed
28.
Unemori EN, Ferrara N, Bauer EA, Amento EP. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 1992;153:557–562PubMedCrossRef
29.
Zucker S, Mirza H, Conner CE, Lorenz AF, Drews MH, Bahou WF, et al. Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Int J Cancer 1998;75:780–786PubMedCrossRef
30.
Pepper MS, Ferrara N, Orci L, Montesano R. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 1991;181:902–906PubMedCrossRef
31.
Sato T, El-Assal ON, Ono T, Yamanoi A, Dhar DK, Nagasue N. Sinusoidal endothelial cell proliferation and expression of angiopoietin/Tie family in regenerating rat liver. J Hepatol 2001;34:690–698PubMedCrossRef
32.
Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1995;376:70–74PubMedCrossRef
33.
Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997;277:55–60PubMedCrossRef
34.
Holash J, Wiegand SJ, Yancopoulos GD. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 1999;18:5356–5362PubMedCrossRef
35.
Greene AK, Wiener S, Puder M, Yoshida A, Shi B, Perez-Atayde AR, et al. Endothelial-directed hepatic regeneration after partial hepatectomy. Ann Surg 2003;237:530–535PubMed
36.
Boulton R, Woodman A, Calnan D, Selden C, Tam F, Hodgson H. Nonparenchymal cells from regenerating rat liver generates interleukin-1alpha and -1beta: a mechanism of negative regulation of hepatocyte proliferation. Hepatology 1997;26:49–58PubMed
37.
Oe S, Lemmer ER, Conner EA, Factor VM, Levéen P, Larsson J, et al. Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice. Hepatology 2004;40:1098–1105PubMedCrossRef
38.
Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009;50:604–620PubMedCrossRef
39.
Rosmorduc O, Wendum D, Corpechot C, Galy B, Sebbagh N, Raleigh J, et al. Hepatocellular hypoxia induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am J Pathol 1999;155:1065–1073PubMedCrossRef
40.
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
41.
Taura K, De Minicis S, Seki E, Hatano E, Iwaisako K, Osterreicher CH, et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 2008;135:1729–1738PubMedCrossRef
42.
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
43.
Ankoma-Sey V, Wang Y, Dai Z. Hypoxic stimulation of vascular endothelial growth factor expression in activated rat hepatic stellate cells. Hepatology 2000;31:141–148PubMedCrossRef
44.
Novo E, Cannito S, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cravanzola C, et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 2007;170:1942–1953PubMedCrossRef
45.
Moon JO, Welch TP, Gonzalez FJ, Copple BL. Reduced liver fibrosis in hypoxia-inducible factor-1alpha-deficient mice. Am J Physiol Gastrointest Liver Physiol 2009;296:G582–G592PubMedCrossRef
46.
Copple BL, Kaska S, Wentling C. Hypoxia-inducible factor activation in myeloid cells contributes to the development of liver fibrosis in cholestatic mice. J Pharmacol Exp Ther 2012;341:307–316PubMedCrossRef
47.
48.
Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodes J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol 2005;43:98–103PubMedCrossRef
49.
Cejudo-Martin P, Ros J, Navasa M, Fernandez J, Fernandez-Varo G, Ruiz-del-Arbol L, et al. Increased production of vascular endothelial growth factor in peritoneal macrophages of cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2001;34:487–493PubMedCrossRef
50.
Tsugawa K, Hashizume M, Tomikawa M, Migou S, Kawanaka H, Shiraishi S, et al. Immunohistochemical localization of vascular endothelial growth factor in the rat portal hypertensive gastropathy. J Gastroenterol Hepatol 2001;16:429–437PubMedCrossRef
51.
Cha C, Dematteo RP. Molecular mechanisms in hepatocellular carcinoma development. Best Pract Res Clin Gastroenterol 2005;19:25–37PubMedCrossRef
52.
Pang R, Poon RT. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett 2006;242:151–167PubMedCrossRef
53.
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;46:1919–1926PubMedCrossRef
54.
Rosmorduc O. Antiangiogenic therapies in portal hypertension: a breakthrough in hepatology. Gastroenterol Clin Biol 2010;34:446–449PubMedCrossRef
55.
Patsenker E, Popov Y, Stickel F, Schneider V, Ledermann M, Sägesser H, et al. Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 2009;50:1501–1511PubMedCrossRef
56.
Parlakgumus A, Colakoglu T, Kayaselcuk F, Colakoglu S, Ezer A, Calıskan K, et al. Two drugs with paradoxical effects on liver regeneration through antiangiogenesis and antifibrosis: Losartan and Spironolactone: a pharmacologic dilemma on hepatocyte proliferation. J Surg Res 2013;179:60–65PubMedCrossRef
57.
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–967PubMedCrossRef
58.
Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A, et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 1998;92:362–367PubMed
59.
Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999;5:434–438PubMedCrossRef
60.
Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 2001;103:634–637PubMedCrossRef
61.
Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000;97:3422–3427PubMedCrossRef
62.
Fan CL, Gao PJ, Che ZQ, Liu JJ, Wei J, Zhu DL. Therapeutic neovascularization by autologous transplantation with expanded endothelial progenitor cells from peripheral blood into ischemic hind limbs. Acta Pharmacol Sin 2005;26:1069–1075PubMedCrossRef
63.
Nakamura T, Torimura T, Sakamoto M, Hashimoto O, Taniguchi E, Inoue K, et al. Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model. Gastroenterology 2007;133:91–107PubMedCrossRef
64.
Nakamura T, Torimura T, Iwamoto H, Masuda H, Naitou M, Koga H, et al. Prevention of liver fibrosis and liver reconstitution of DMN-treated rat liver by transplanted EPCs. Eur J Clin Invest 2012;42:717–728PubMedCrossRef
65.
Sakamoto M, Nakamura T, Torimura T, Iwamoto H, Masuda H, Koga H, et al. Transplantation of endothelial progenitor cells ameliorates vascular dysfunction and portal hypertension in carbon tetrachloride-induced rat liver cirrhotic model. J Gastroenterol Hepatol 2013;28:168–178PubMedCrossRef
66.
Wang L, Wang X, Xie G, Wang L, Hill CK, DeLeve LD. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J Clin Invest 2012;122:1567–1573PubMedCrossRef
67.
Ho JW, Pang RW, Lau C, Sun CK, Yu WC, Fan ST, et al. Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. Hepatology 2006;44:836–843PubMedCrossRef
68.
Yu D, Sun X, Qiu Y, Zhou J, Wu Y, Zhuang L, et al. Identification and clinical significance of mobilized endothelial progenitor cells in tumor vasculogenesis of hepatocellular carcinoma. Clin Cancer Res 2007;13:3814–3824PubMedCrossRef
69.
Yu DC, Chen J, Sun XT, Zhuang LY, Jiang CP, Ding YT. Mechanism of endothelial progenitor cell recruitment into neo-vessels in adjacent non-tumor tissues in hepatocellular carcinoma. BMC Cancer 2010;10:435PubMedCrossRef
70.
Yu DC, Chen J, Ding YT. Hypoxic and highly angiogenic non-tumor tissues surrounding hepatocellular carcinoma: the ‘niche’ of endothelial progenitor cells. Int J Mol Sci 2010;11:2901–2909PubMedCrossRef
71.
Abdelmoneim SS, Talwalkar J, Sethi S, Kamath P, Fathalla MM, Kipp BR, et al. A prospective pilot study of circulating endothelial cells as a potential new biomarker in portal hypertension. Liver Int 2010;30:191–197PubMedCrossRef
72.
Rautou PE. Endothelial progenitor cells in cirrhosis: The more, the merrier? J Hepatol 2012;57:1163–1165PubMedCrossRef
73.
Kaur S, Kumar TR, Uruno A, Sugawara A, Jayakumar K, Kartha CC. Genetic engineering with endothelial nitric oxide synthase improves functional properties of endothelial progenitor cells from patients with coronary artery disease: an in vitro study. Basic Res Cardiol 2009;104:739–749PubMedCrossRef
74.
Kaur S, Harikrishnan VS, Shenoy SJ, Radhakrishnan NS, Uruno A, Sugawara A, et al. Transfection of endothelial nitric oxide synthase gene improves angiogenic efficacy of endothelial progenitor cells in rabbits with hindlimb ischemia. J Clin Exp Cardiol 2011;2:140
Metadata
Title
Angiogenesis in liver regeneration and fibrosis: “a double-edged sword”
Authors
Savneet Kaur
K. Anita
Publication date
01-10-2013
Publisher
Springer India
Published in
Hepatology International / Issue 4/2013
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-013-9483-7

Other articles of this Issue 4/2013

Hepatology International 4/2013 Go to the issue

Original Article

Multiple courses of G-CSF in patients with decompensated cirrhosis: consistent mobilization of immature cells expressing hepatocyte markers and exploratory clinical evaluation

Original Article

HBsAg, HBeAg and HBV DNA level changes and precore/basal core promoter mutations in the natural history of chronic hepatitis B in Indonesian patients

Original Article

The virological response in Koreans infected with HCV genotype 1 did not differ between groups treated with a full dose or reduced dose (≥80 % full dose) of peginterferon alfa-2a: a prospective randomized multicenter trial

Editorial

The prediction of immunological dysfunction during antiviral therapy for HCV after liver transplantation: can we improve outcomes?

Original Article

Incidence and risk factors for surveillance failure in patients with regular hepatocellular carcinoma surveillance

Editorial

Viral factors and outcome of chronic hepatitis B revisited
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits