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• W1874465904 abstract "Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles. Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles. SummaryPathologic angiogenesis is intrinsically associated with the fibrogenic progression of chronic liver diseases. Hypoxia, hypoxia-inducible factors, and other signals and mediators released by various cells of the liver drive and modulate the critical profibrogenic and proangiogenic role of hepatic myofibroblasts. Pathologic angiogenesis is intrinsically associated with the fibrogenic progression of chronic liver diseases. Hypoxia, hypoxia-inducible factors, and other signals and mediators released by various cells of the liver drive and modulate the critical profibrogenic and proangiogenic role of hepatic myofibroblasts. Fibrogenic progression of chronic liver diseases (CLDs), eventually leading to the development of liver cirrhosis and related complications including hepatocellular carcinoma (HCC), is intimately associated with pathologic angiogenesis and sinusoidal remodeling.1Medina J. Arroyo A.G. Sánchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (140) Google Scholar, 2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Valfrè di Bonzo L. Novo E. Cannito S. et al.Angiogenesis and liver fibrogenesis.Histol Histopathol. 2009; 23: 1324-1341Google Scholar, 5Elpek GÖ Angiogenesis and liver fibrosis.World J Hepatol. 2015; 7: 377-391Crossref PubMed Google Scholar, 6Bosch J. Abraldes J.G. Fernández M. et al.Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar This is not surprising because angiogenesis is a major feature of any wound healing response and chronic activation of wound healing is a general mechanism involved in the progression of CLDs.7Zhang D.Y. Friedman S.L. Fibrosis-dependent mechanisms of hepatocarcinogenesis.Hepatology. 2012; 56: 769-775Crossref PubMed Scopus (69) Google Scholar, 8Kocabayoglu P. Friedman S.L. Cellular basis of hepatic fibrosis and its role in inflammation and cancer.Front Biosci (Schol Ed). 2013; 5: 217-230Crossref PubMed Google Scholar, 9Parola M. Marra F. Pinzani M. Myofibroblast-like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario.Mol Asp Med. 2008; 29: 59-67Crossref Scopus (88) Google Scholar, 10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar Some researchers, including the authors of this review, go further2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Valfrè di Bonzo L. Novo E. Cannito S. et al.Angiogenesis and liver fibrogenesis.Histol Histopathol. 2009; 23: 1324-1341Google Scholar, 9Parola M. Marra F. Pinzani M. Myofibroblast-like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario.Mol Asp Med. 2008; 29: 59-67Crossref Scopus (88) Google Scholar, 10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar, 11Novo E. Cannito S. Paternostro C. et al.Cellular and molecular mechanisms in liver fibrogenesis.Arch Biochem Biophys. 2014; 548: 20-37Crossref PubMed Google Scholar, 12Cannito S. Paternostro C. Busletta C. et al.Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.Histol Histopathol. 2014; 29: 33-44PubMed Google Scholar, 13Fernandez M. Molecular pathophysiology of portal hypertension.Hepatology. 2015; 61: 1406-1415Crossref PubMed Scopus (0) Google Scholar, 14Povero D. Eguchi A. Niesman I.R. et al.Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells.Sci Signal. 2013; 6: ra88Crossref PubMed Scopus (9) Google Scholar, 15Lemoinne S. Cadoret A. Rautou P.E. et al.Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles.Hepatology. 2015; 61: 1041-1055Crossref PubMed Scopus (2) Google Scholar in suggesting additionally that 1) hypoxia (the most obvious stimulus for angiogenesis, commonly detected in progressive CLDs1Medina J. Arroyo A.G. Sánchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (140) Google Scholar, 2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Valfrè di Bonzo L. Novo E. Cannito S. et al.Angiogenesis and liver fibrogenesis.Histol Histopathol. 2009; 23: 1324-1341Google Scholar, 5Elpek GÖ Angiogenesis and liver fibrosis.World J Hepatol. 2015; 7: 377-391Crossref PubMed Google Scholar, 6Bosch J. Abraldes J.G. Fernández M. et al.Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.J Hepatol. 2010; 53: 558-567Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16Nath B. Szabo G. Hypoxia and hypoxia inducible factors: diverse roles in liver diseases.Hepatology. 2012; 55: 622-633Crossref PubMed Scopus (46) Google Scholar), hypoxia-inducible factors (HIFs), and angiogenesis may have a major role in sustaining and potentially driving liver fibrogenesis; 2) hepatic myofibroblasts (MFs), regardless of origin, are critical cells in governing and modulating the interactions between inflammation, angiogenesis, and fibrogenesis; 3) liver angiogenesis has a role in the genesis of portal hypertension and related complications in advanced stages of CLDs; and 4) microparticles/microvesicles released by either fat-laden hepatocytes or portal MFs have an emerging role in mediating angiogenesis and vascular remodeling. This review offers a synthesis of the most relevant recent data and opinions regarding the close relationship between liver angiogenesis and fibrogenesis. Established concepts about mechanisms of liver angiogenesis, liver fibrogenesis, and CLD progression will not be addressed. Moreover, in this review, the relationship between angiogenesis and portal hypertension and related complications are not discussed; readers interested in this specific topic should refer to a recent authoritative review.13Fernandez M. Molecular pathophysiology of portal hypertension.Hepatology. 2015; 61: 1406-1415Crossref PubMed Scopus (0) Google Scholar Liver angiogenesis occurs in both physiologic (ie, liver regeneration) and pathologic conditions, including ischemia, progressive CLDs, hepatocellular carcinoma, and metastatic liver cancer.1Medina J. Arroyo A.G. Sánchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (140) Google Scholar, 2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Valfrè di Bonzo L. Novo E. Cannito S. et al.Angiogenesis and liver fibrogenesis.Histol Histopathol. 2009; 23: 1324-1341Google Scholar, 5Elpek GÖ Angiogenesis and liver fibrosis.World J Hepatol. 2015; 7: 377-391Crossref PubMed Google Scholar Angiogenesis in the liver is similar to angiogenesis in other tissues and organs; however, as suggested by several groups,1Medina J. Arroyo A.G. Sánchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (140) Google Scholar, 2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Valfrè di Bonzo L. Novo E. Cannito S. et al.Angiogenesis and liver fibrogenesis.Histol Histopathol. 2009; 23: 1324-1341Google Scholar, 5Elpek GÖ Angiogenesis and liver fibrosis.World J Hepatol. 2015; 7: 377-391Crossref PubMed Google Scholar, 10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar, 11Novo E. Cannito S. Paternostro C. et al.Cellular and molecular mechanisms in liver fibrogenesis.Arch Biochem Biophys. 2014; 548: 20-37Crossref PubMed Google Scholar, 12Cannito S. Paternostro C. Busletta C. et al.Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.Histol Histopathol. 2014; 29: 33-44PubMed Google Scholar pathologic angiogenesis occurring during the progression of CLDs can be significantly affected by liver-specific events, interactions between different hepatic cell populations, and the involvement of atypical proangiogenic mediators. From a general point of view, the pattern of fibrosis that predominates in a specific CLD is relevant to angiogenesis. Although pathologic liver angiogenesis has been described in all CLDs irrespective of etiology, it is much more prominent under conditions of bridging or postnecrotic fibrosis (eg, in chronic viral infection or, to a lesser extent, in autoimmune diseases) than in conditions characterized by pericellular or perisinusoidal fibrosis (as in non-alcoholic fatty liver disease or alcoholic liver disease) or by biliary fibrosis.3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 9Parola M. Marra F. Pinzani M. Myofibroblast-like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario.Mol Asp Med. 2008; 29: 59-67Crossref Scopus (88) Google Scholar, 10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar This suggests an inverse correlation between angiogenesis and the potential for fibrosis reversibility, which is more evident in conditions characterized by pericellular or perisinusoidal fibrosis and biliary fibrosis than in those associated with bridging fibrosis.9Parola M. Marra F. Pinzani M. Myofibroblast-like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario.Mol Asp Med. 2008; 29: 59-67Crossref Scopus (88) Google Scholar This may be related to the unique tissue localization, phenotypic profile, and functional role of hepatic stellate cells (HSCs). HSCs, which in physiologic conditions synthesize extracellular matrix components in the space of Disse, store retinoids and possibly contract in response to vasoactive mediators to modulate sinusoidal blood flux, are also liver-specific pericytes. During the progression of CLDs, HSCs are the most relevant myofibroblast precursors and profibrogenic hepatic cells.2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 17Friedman S.L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.Physiol Rev. 2008; 88: 125-172Crossref PubMed Scopus (778) Google Scholar, 18Kisseleva T. Brenner D.A. The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis.J Hepatol. 2012; 56: 965-972Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 19Lee U.E. Friedman S.L. Mechanisms of hepatic fibrogenesis.Best Pract Res Clin Gastroenterol. 2011; 25: 195-206Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 20Forbes S.J. Parola M. Liver fibrogenic cells.Best Pract Res Clin Gastroenterol. 2011; 25: 207-218Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 21Mederacke I. Hsu C.C. Troeger J.S. et al.Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology.Nature Commun. 2013; 4: 2823Crossref PubMed Scopus (0) Google Scholar HSCs, particularly in their activated and MF-like phenotype (HSC/MFs), modulate angiogenesis in a way that, as we will describe, relates to the role attributed to them as microcapillary pericytes. Hepatic MFs, a heterogenous population of profibrogenic, highly proliferative, and contractile cells, can also originate from portal MFs and bone marrow-derived stem cells recruited into the injured liver, and these may also play a role in angiogenesis.17Friedman S.L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.Physiol Rev. 2008; 88: 125-172Crossref PubMed Scopus (778) Google Scholar, 18Kisseleva T. Brenner D.A. The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis.J Hepatol. 2012; 56: 965-972Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 19Lee U.E. Friedman S.L. Mechanisms of hepatic fibrogenesis.Best Pract Res Clin Gastroenterol. 2011; 25: 195-206Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 20Forbes S.J. Parola M. Liver fibrogenic cells.Best Pract Res Clin Gastroenterol. 2011; 25: 207-218Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 21Mederacke I. Hsu C.C. Troeger J.S. et al.Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology.Nature Commun. 2013; 4: 2823Crossref PubMed Scopus (0) Google Scholar, 22Dranoff J.A. Wells R.G. Portal fibroblasts: Underappreciated mediators of biliary fibrosis.Hepatology. 2010; 51: 1438-1444Crossref PubMed Scopus (94) Google Scholar The relevance of intense cross-talk between hepatic cell populations in pathologic angiogenesis is strongly supported by the knowledge that major proangiogenic mediators such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), are produced and released by several liver cell types involved in CLD progression, including hypoxic hepatocytes and hypoxia-responsive macrophages and MFs.1Medina J. Arroyo A.G. Sánchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (140) Google Scholar, 2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 9Parola M. Marra F. Pinzani M. Myofibroblast-like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario.Mol Asp Med. 2008; 29: 59-67Crossref Scopus (88) Google Scholar, 10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar, 11Novo E. Cannito S. Paternostro C. et al.Cellular and molecular mechanisms in liver fibrogenesis.Arch Biochem Biophys. 2014; 548: 20-37Crossref PubMed Google Scholar, 12Cannito S. Paternostro C. Busletta C. et al.Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.Histol Histopathol. 2014; 29: 33-44PubMed Google Scholar The role of liver-specific proangiogenic mediators such as angiopoietin-like-3 peptide (ANGPTL3)23Camenisch G. Pisabarro M.T. Sherman D. et al.ANGPTL3 stimulates endothelial cell adhesion and migration via integrin avβ3 and induces blood vessel formation in vivo.J Biol Chem. 2002; 277: 17281-17290Crossref PubMed Scopus (107) Google Scholar is controversial. ANGPTL3, which belongs to a family of mediators described as playing major roles in the trafficking and metabolism of lipids, was reported to induce haptotactic endothelial cell adhesion and migration, possibly by binding to αvβ3 integrin.23Camenisch G. Pisabarro M.T. Sherman D. et al.ANGPTL3 stimulates endothelial cell adhesion and migration via integrin avβ3 and induces blood vessel formation in vivo.J Biol Chem. 2002; 277: 17281-17290Crossref PubMed Scopus (107) Google Scholar However, no further studies have been published on the role of this mediator in either physiologic or pathologic liver angiogenesis. As we will discuss, a more interesting role is attributed to the antiangiogenic protein vasohibin, which may have a dual role in inhibiting not only angiogenesis but also fibrogenesis, likely by deactivating HSCs.24Coch L. Mejias M. Berzigotti A. et al.Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats.Hepatology. 2014; 60: 633-647Crossref PubMed Scopus (6) Google Scholar Angiogenesis is best defined as a dynamic, hypoxia-stimulated, and growth factor-dependent process leading to the formation of new blood vessels from preexisting ones.25Semenza G.L. Oxygen sensing, homeostasis and disease.N Engl J Med. 2011; 365: 537-547Crossref PubMed Scopus (246) Google Scholar, 26Semenza G.L. Hypoxia inducible factors in physiology and medicine.Cell. 2012; 148: 399-408Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar Hypoxia and HIFs are critical in sustaining the fibrogenic progression of CLDs, representing a persistent driving force able to directly affect the behavior of hepatic cell populations, including profibrogenic and proangiogenic MFs.1Medina J. Arroyo A.G. Sánchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (140) Google Scholar, 2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Valfrè di Bonzo L. Novo E. Cannito S. et al.Angiogenesis and liver fibrogenesis.Histol Histopathol. 2009; 23: 1324-1341Google Scholar, 5Elpek GÖ Angiogenesis and liver fibrosis.World J Hepatol. 2015; 7: 377-391Crossref PubMed Google Scholar, 10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar, 11Novo E. Cannito S. Paternostro C. et al.Cellular and molecular mechanisms in liver fibrogenesis.Arch Biochem Biophys. 2014; 548: 20-37Crossref PubMed Google Scholar, 12Cannito S. Paternostro C. Busletta C. et al.Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.Histol Histopathol. 2014; 29: 33-44PubMed Google Scholar, 13Fernandez M. Molecular pathophysiology of portal hypertension.Hepatology. 2015; 61: 1406-1415Crossref PubMed Scopus (0) Google Scholar, 16Nath B. Szabo G. Hypoxia and hypoxia inducible factors: diverse roles in liver diseases.Hepatology. 2012; 55: 622-633Crossref PubMed Scopus (46) Google Scholar Detection of hypoxic areas is a common finding at any stage of CLD, increasing progressively from early injury to the development of cirrhosis, with hypoxia and HIFs serving throughout as proangiogenic stimuli in the overall, etiology-independent scenario of chronic wound healing. CLD progression itself is a major contributor to hypoxia due to the formation of regenerative nodules of parenchyma surrounded by evolving fibrotic septa and vascular remodeling that, along with progressive capillarization of the sinusoids, leads to an impairment of oxygen diffusion. A vicious circle between fibrosis and pathologic angiogenesis is likely to occur10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar, 12Cannito S. Paternostro C. Busletta C. et al.Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.Histol Histopathol. 2014; 29: 33-44PubMed Google Scholar, 27Zhang Z. Zhang F. Lu Y. Zheng S. Update on implications and mechanisms of angiogenesis in liver fibrosis.Hepatol Res. 2015; 45: 162-178Crossref PubMed Google Scholar in which parenchymal hypoxia, through the action of HIFs, up-regulates expression of wound healing-related factors and mediators that should facilitate liver repair and revascularization. However, pathologic angiogenesis can be inefficient due to the immaturity and permeability of VEGF-induced neovessels and, as a result, may be unable to correct liver hypoxia. Pathologic angiogenesis and hypoxia may act synergistically in disrupting normal tissue repair, thereby promoting the development of liver fibrosis.27Zhang Z. Zhang F. Lu Y. Zheng S. Update on implications and mechanisms of angiogenesis in liver fibrosis.Hepatol Res. 2015; 45: 162-178Crossref PubMed Google Scholar The connection between pathologic angiogenesis and fibrogenesis in progressive CLDs is strongly suggested by their parallel development in all major human forms of CLD and animal models of CLDs, with several laboratories describing high numbers of endothelial cells and microvascular structures within fibrotic septae and in expanded portal areas.1Medina J. Arroyo A.G. Sánchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (140) Google Scholar, 2Lee J.S. Semela D. Iredale J. et al.Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (120) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Valfrè di Bonzo L. Novo E. Cannito S. et al.Angiogenesis and liver fibrogenesis.Histol Histopathol. 2009; 23: 1324-1341Google Scholar, 5Elpek GÖ Angiogenesis and liver fibrosis.World J Hepatol. 2015; 7: 377-391Crossref PubMed Google Scholar, 10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar, 11Novo E. Cannito S. Paternostro C. et al.Cellular and molecular mechanisms in liver fibrogenesis.Arch Biochem Biophys. 2014; 548: 20-37Crossref PubMed Google Scholar, 12Cannito S. Paternostro C. Busletta C. et al.Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.Histol Histopathol. 2014; 29: 33-44PubMed Google Scholar, 13Fernandez M. Molecular pathophysiology of portal hypertension.Hepatology. 2015; 61: 1406-1415Crossref PubMed Scopus (0) Google Scholar, 16Nath B. Szabo G. Hypoxia and hypoxia inducible factors: diverse roles in liver diseases.Hepatology. 2012; 55: 622-633Crossref PubMed Scopus (46) Google Scholar, 28Corpechot C. Barbu V. Wendum D. et al.Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis.Hepatology. 2002; 35: 1010-1021Crossref PubMed Scopus (249) Google Scholar, 29Novo 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: 1942-1953Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 30Novo 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: 588-597Crossref PubMed Scopus (20) Google Scholar The response to hypoxia and VEGF (the major proangiogenic target gene) expression can be seen in liver sinusoidal endothelial cells (LSECs) and in hepatocytes1Medina J. Arroyo A.G. Sánchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (140) Google Scholar, 3Fernández M. Semela D. Bruix J. et al.Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Valfrè di Bonzo L. Novo E. Cannito S. et al.Angiogenesis and liver fibrogenesis.Histol Histopathol. 2009; 23: 1324-1341Google Scholar, 10Rosmorduc O. Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.Semin Liver Dis. 2010; 30: 258-270Crossref PubMed Scopus (76) Google Scholar, 28Corpechot C. Barbu V. Wendum D. et al.Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis.Hepatology. 2002; 35: 1010-1021Crossref PubMed Scopus (249) Google Scholar and HSC/MFs of developing septa and at the borders of more mature and larger fibrotic septa.29Novo 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: 1942-1953Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 30Novo 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: 588-597Crossref PubMed Scopus (20) Google Scholar Studies performed in HIF-1α liver conditional knockout mice provided the first definitive in vivo evidence for hypoxia-dependent induction of fibrogenesis.31Moon J.O. Welch T.P. Gonzalez F.J. et al.Reduced liver fibrosis in hypoxia-inducible factor-1 alpha-deficient mice.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G582-G592Crossref PubMed Scopus (63) Google Scholar However, the most convincing evidence relating angiogenesis and fibrogenesis came through in vivo studies indicating that experimental antiangiogenic therapy was highly effective in significantly reducing fibrogenic progression. As summarized in Table 1, whatever the specific molecule or tool employed, experimental antiangiogenic therapy always resulted in a significant reduction not only of angiogenesis but also of the inflammatory infiltrate, the number of α-smooth muscle actin (α-SMA)-positive MFs and the extent of fibrosis.32Tugues S. Fernandez-Varo G. Muñoz-Luque J. et al.Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats.He" @default.
• W1874465904 created "2016-06-24" @default.
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• W1874465904 date "2015-09-01" @default.
• W1874465904 modified "2023-10-12" @default.
• W1874465904 title "Angiogenesis and Fibrogenesis in Chronic Liver Diseases" @default.
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