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• W2023250239 abstract "Angiogenesis and disruption of liver vascular architecture have been linked to progression to cirrhosis and liver cancer (HCC) in chronic liver diseases, which contributes both to increased hepatic vascular resistance and portal hypertension and to decreased hepatocyte perfusion. On the other hand, recent evidence shows that angiogenesis modulates the formation of portal-systemic collaterals and the increased splanchnic blood flow which are involved in the life threatening complications of cirrhosis. Finally, angiogenesis plays a key role in the growth of tumours, suggesting that interference with angiogenesis may prevent or delay the development of HCC. This review summarizes current knowledge on the molecular mechanisms of liver angiogenesis and on the consequences of angiogenesis in chronic liver disease. On the other hand, it presents the different strategies that have been used in experimental models to counteract excessive angiogenesis and its potential role in preventing transition to cirrhosis, development of portal hypertension and its consequences, and its application in the treatment of hepatocellular carcinoma. Angiogenesis and disruption of liver vascular architecture have been linked to progression to cirrhosis and liver cancer (HCC) in chronic liver diseases, which contributes both to increased hepatic vascular resistance and portal hypertension and to decreased hepatocyte perfusion. On the other hand, recent evidence shows that angiogenesis modulates the formation of portal-systemic collaterals and the increased splanchnic blood flow which are involved in the life threatening complications of cirrhosis. Finally, angiogenesis plays a key role in the growth of tumours, suggesting that interference with angiogenesis may prevent or delay the development of HCC. This review summarizes current knowledge on the molecular mechanisms of liver angiogenesis and on the consequences of angiogenesis in chronic liver disease. On the other hand, it presents the different strategies that have been used in experimental models to counteract excessive angiogenesis and its potential role in preventing transition to cirrhosis, development of portal hypertension and its consequences, and its application in the treatment of hepatocellular carcinoma. Cirrhosis and hepatocellular carcinoma (HCC) are common lethal diseases in European countries, together representing the third cause of death in adults over 50 years old, as well as the indication for over 90% of the 5.000 liver transplants that are performed every year within the EU. These features are increasing due to the consequences of the hepatitis C epidemic in the 70’s. Thus, its socioeconomic impact is extraordinary. The formation of new vessels (angiogenesis) and the establishment of an abnormal angioarchitecture of the liver is a process strictly related to the progressive fibrogenesis leading to cirrhosis and liver cancer. Investigation into these aspects is complex and certainly requires a joint effort of a multidisciplinary team of basic investigators, pathologists, and hepatologists in the areas of liver fibrosis, hepatic circulation, and portal hypertension and its complications. Established evidence clearly indicates that chronic liver diseases are characterized by intrahepatic vascular remodelling with capillarization of sinusoids, fibrogenesis and development of intrahepatic shunts, which would lead to increased hepatic resistance (and hence to increased portal pressure) and decreased effective hepatocyte perfusion (and hence to liver failure). In addition, new original data obtained by the authors of this review suggest that vascular endothelial growth factor (VEGF)/ platelet-derived growth factor (PDGF) driven angiogenesis is of paramount importance in the formation of portal-systemic collaterals and of the hyperdynamic circulation which are responsible for the main complications of cirrhosis often leading to death: gastroesophageal varices, massive upper gastrointestinal bleeding, ascites, spontaneous bacterial peritonitis and hepatic encephalopathy. Finally, angiogenesis is known to play a critical role in the growth of tumours, which makes it plausible to hypothesize that early interference with angiogenesis signalling may prevent the transition from hepatic dysplasia to HCC. This article reviews the translational research effort that has been made recently on both the molecular mechanisms and signal transduction cascade of liver angiogenesis, and the consequences of angiogenesis in chronic liver disease, emphasizing studies exploring different strategies to counteract excessive angiogenesis to prevent progression of liver fibrosis and transition to cirrhosis in chronic hepatitis, to prevent the development of portal hypertension and its consequences, and finally to prevent the formation and growth of hepatocellular carcinoma often occurring in patients with cirrhosis. Pathological angiogenesis, irrespective of the aetiology, has been indeed extensively described in chronic liver diseases (CLDs) characterized by an extensive and prolonged necro-inflammatory and fibrogenic process, including chronic HBV, HCV and autoimmune hepatitis [1Garcia-Monzon C. Sanchez-Madrid F. Garcia-Buey L. Garcia-Arroyo A. Garcia-Sanchez A. Moreno-Otero R. Vascular adhesion molecule expression in viral chronic hepatitis: evidence of neoangiogenesis in portal tracts.Gastroenterology. 1995; 108: 231-241Abstract Full Text PDF PubMed Scopus (112) Google Scholar, 2Medina J. Arroyo A.G. Sanchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (139) Google Scholar], and primary biliary cirrhosis [[3]Medina J. Sanz-Cameno P. Garcia-Buey L. Martin-Vilchez S. Lopez-Cabrera M. Moreno-Otero R. Evidence of angiogenesis in primary biliary cirrhosis: an immunohistochemical descriptive study.J Hepatol. 2005; 42: 124-131Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. The formation of new vessels, which is closely associated with the pattern of fibrosis development typical of the different CLDs [[4]Pinzani M. Rombouts K. Liver fibrosis: from the bench to clinical targets.Dig Liver Dis. 2004; 36: 231-242Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar], leads to the progressive formation of the abnormal angio-architecture distinctive of cirrhosis, i.e. the common end-point of fibrogenic CLDs. Accordingly, the association of fibrogenesis and angiogenesis should be regarded as crucial in the modern evaluation of disease progression and in the search for therapeutic targets. In addition, depending on the different pattern of fibrogenic evolution (i.e. post-necrotic, biliary, centrolobular, pericellular/perisinusoidal), the extent of neo-angiogenesis may have profound consequences on the rate of disease progression to cirrhosis and represents a key determinant affecting reversibility of fibrosis (Table 1).Table 1Reversibility of liver fibrosis according to the pattern.Fibrosis patternEarly portal to central septaNeo angiogenesisReversibilityPost-necrotic+++++++++Biliary+++++++Centrolobular−±++++Pericellular-perisinusoidal−+++++ Open table in a new tab From a mechanistic point of view, angiogenesis in fibrogenic CLDs can be interpreted according to two main pathways. First, the process of liver chronic wound healing typical of fibrogenic CLDs is characterized by an over-expression of several growth factors, cytokines and metalloproteinases (MMPs) with an inherent pro-angiogenic action [[5]Pinzani M. Marra F. Cytokine receptors and signalling in hepatic stellate cells.Semin Liver Dis. 2001; 21: 397-416Crossref PubMed Scopus (316) Google Scholar]. In particular, platelet-derived growth factor (PDGF), transforming growth factor-β1 (TGF-β1), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been shown to exert a potent pro-fibrogenic and pro-angiogenic role. In addition, an increased gene expression of integrins, β-catenin, ephrins, and other adhesion molecules involved in extra-cellular matrix (ECM) remodelling and angiogenesis has been clearly demonstrated in CLDs [6Shackel N.A. McGuinness P.H. Abbott C.A. Gorrell M.D. McCaughan G.W. Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression.Am J Pathol. 2002; 160: 641-654Abstract Full Text Full Text PDF PubMed Google Scholar, 7Shackel N.A. McGuinness P.H. Abbott C.A. Gorrell M.D. McCaughan G.W. Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression.Gut. 2001; 49: 565-576Crossref PubMed Scopus (96) Google Scholar]. Second, neo-angiogenesis is stimulated in hepatic tissue by the progressive increase of tissue hypoxia. This mechanism is strictly linked to the anatomical modifications following the establishment of periportal fibrosis with an increased contribution of the hepatic artery to the formation of sinusoidal blood [[8]Hoofring A. Boitnott J. Torbenson M. Three-dimensional reconstruction of hepatic bridging fibrosis in chronic hepatitis C viral infection.J Hepatol. 2003; 39: 738-741Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Accordingly, sinusoidal blood flow becomes increasingly arterialized with hepatocytes adjusting to an abnormally high oxygen concentration. Subsequently, the progressive capillarization of sinusoids leads to an impairment of oxygen diffusion from the sinusoids to hepatocytes with the consequent up-regulation of pro-angiogenic pathways [9Corpechot 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: 1010-1021Crossref PubMed Scopus (248) Google Scholar, 10DeLeve L.D. Hepatic microvasculature in liver injury.Semin Liver Dis. 2007; 27: 390-400Crossref PubMed Scopus (75) Google Scholar, 11Rosmorduc 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: 1065-1073Abstract Full Text Full Text PDF PubMed Google Scholar]. Although neo-angiogenesis is a common feature of most chronic inflammatory and fibrogenic disorders [12Carmeliet P. Jain R.K. Angiogenesis in cancer and other diseases.Nature. 2000; 407: 249-257Crossref PubMed Scopus (4735) Google Scholar, 13Carmeliet P. Angiogenesis in life, disease and medicine.Nature. 2005; 438: 932-936Crossref PubMed Scopus (1629) Google Scholar], hepatic angiogenesis may substantially differ from homologous processes in other organs or tissue on the basis of: (a) the rather unique phenotypic profile and functional role of activated hepatic stellate cells (HSC) and of other liver myofibroblasts (MFs) [14Cassiman D. Libbrecht L. Desmet V. Denef C. Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers.J Hepatol. 2002; 36: 200-209Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 15Friedman S.L. Liver fibrosis – from bench to bedside.J Hepatol. 2003; 38: S38-S53Abstract Full Text Full Text PDF PubMed Google Scholar, 16Lee J.S. Semela D. Iredale J. Shah V.H. Sinusoidal remodelling and angiogenesis: a new function for the liver-specific pericyte?.Hepatology. 2007; 45: 817-825Crossref PubMed Scopus (122) Google Scholar, 17Novo E. Cannito S. Zamara E. Valfre di B.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: 1942-1953Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 18Parola M. Marra F. Pinzani M. Myofibroblast – like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario.Mol Aspects Med. 2008; 29: 58-66Crossref PubMed Scopus (84) Google Scholar, 19Ramadori G. Saile B. Mesenchymal cells in the liver – one cell type or two?.Liver. 2002; 22: 283-294Crossref PubMed Scopus (84) Google Scholar, 20Bataller R. Brenner D.A. Liver fibrosis.J Clin Invest. 2005; 115: 209-218Crossref PubMed Google Scholar] (b) the presence of two different microvascular structures described (i.e., sinusoids lined by fenestrated endothelium versus large vessels lined by a continuous one); (c) the existence of ANGPTL3, a liver specific angiogenic factor [[21]Camenisch G. Pisabarro M.T. Sherman D. Kowalski J. Nagel M. Hass P. et al.ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo.J Biol Chem. 2002; 277: 17281-17290Crossref PubMed Scopus (106) Google Scholar]. Evidence obtained from morphological studies suggests that angiogenesis occurring in hepatic tissue undergoing chronic wound healing is characterized by branching of neo-vessels from the existing vasculature. The large majority of these neo-vessels originate from the fine portal vein branches and tend to establish a connection between the portal system and the hepatic veins [8Hoofring A. Boitnott J. Torbenson M. Three-dimensional reconstruction of hepatic bridging fibrosis in chronic hepatitis C viral infection.J Hepatol. 2003; 39: 738-741Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 22Onori P. Morini S. Franchitto A. Sferra R. Alvaro D. Gaudio E. Hepatic microvascular features in experimental cirrhosis: a structural and morphometrical study in CCl4-treated rats.J Hepatol. 2000; 33: 555-563Abstract Full Text Full Text PDF PubMed Google Scholar]. The role of bone marrow-derived endothelial precursors (vasculogenesis) in hepatic angiogenesis has been suggested by studies employing animal models of hepatic fibrogenesis [23Jin Y.L. Enzan H. Kuroda N. Hayashi Y. Toi M. Miyazaki E. et al.Vascularization in tissue remodelling after rat hepatic necrosis induced by dimethylnitrosamine.Med Mol Morphol. 2006; 39: 33-43Crossref PubMed Scopus (11) Google Scholar, 24Nakamura 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: 91-107Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar] and needs to be substantiated in human CLDs. A key area in the study of the cellular and molecular relationships existing between fibrogenesis and angiogenesis concerns the pro-angiogenic role of activated HSC and other ECM-producing cells such as portal fibroblasts and myofibroblasts. Hypoxic conditions, through the involvement of the transcription factor HIF-1α, are able to up-regulate expression of VEGF [2Medina J. Arroyo A.G. Sanchez-Madrid F. Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease.Hepatology. 2004; 39: 1185-1195Crossref PubMed Scopus (139) Google Scholar, 17Novo E. Cannito S. Zamara E. Valfre di B.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: 1942-1953Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 25Ankoma-Sey V. Matli M. Chang K.B. Lalazar A. Donner D.B. Wong L. et al.Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing.Oncogene. 1998; 17: 115-121Crossref PubMed Google Scholar, 26Aleffi S. Petrai I. Bertolani C. Parola M. Colombatto S. Novo E. et al.Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells.Hepatology. 2005; 42: 1339-1348Crossref PubMed Scopus (189) Google Scholar, 27Wang Y.Q. Luk J.M. Ikeda K. Man K. Chu A.C. Kaneda K. et al.Regulatory role of vHL/HIF-1alpha in hypoxia-induced VEGF production in hepatic stellate cells.Biochem Biophys Res Commun. 2004; 317: 358-362Crossref PubMed Scopus (55) Google Scholar] and angiopoietin I [17Novo E. Cannito S. Zamara E. Valfre di B.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: 1942-1953Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 26Aleffi S. Petrai I. Bertolani C. Parola M. Colombatto S. Novo E. et al.Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells.Hepatology. 2005; 42: 1339-1348Crossref PubMed Scopus (189) Google Scholar] in rat or human HSC. Moreover, exposure to hypoxia results in up-regulation of VEGF receptors type I (Flt-1) and type II (Flk-1) as well as of Tie-2 (i.e., the receptor for angiopoietin I) in the same cell type [11Rosmorduc 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: 1065-1073Abstract Full Text Full Text PDF PubMed Google Scholar, 17Novo E. Cannito S. Zamara E. Valfre di B.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: 1942-1953Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 25Ankoma-Sey V. Matli M. Chang K.B. Lalazar A. Donner D.B. Wong L. et al.Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing.Oncogene. 1998; 17: 115-121Crossref PubMed Google Scholar]. Hypoxia-dependent up-regulation and release of VEGF by human HSC/MFs can stimulate, in a paracrine and/or autocrine manner, non-oriented migration and chemotaxis of human HSC/MFs [[17]Novo E. Cannito S. Zamara E. Valfre di B.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: 1942-1953Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. This feature depends mainly on the interaction between VEGF and Flk-1 and may explain the significant “in vivo” anti-fibrotic effect reported in an experimental model in which animals were treated with neutralizing anti-Flk-1 antibodies [[28]Yoshiji H. Kuriyama S. Yoshii J. Ikenaka Y. Noguchi R. Hicklin D.J. et al.Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis.Gut. 2003; 52: 1347-1354Crossref PubMed Scopus (159) Google Scholar]. Recent “in vivo” data obtained in human and rat fibrotic/cirrhotic livers, indicate that α-SMA-positive cells (i.e., myofibroblast-like phenotype) expressing VEGF, Ang-1 or the related receptors Flk-1 and Tie-2, are consistently localized at the leading edge of tiny and incomplete developing septa, but not in larger bridging septa [[17]Novo E. Cannito S. Zamara E. Valfre di B.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: 1942-1953Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. This distribution may reflect two different phases of angiogenic process during chronic wound healing: an early phase, occurring in developing septa, in which fibrogenesis and angiogenesis may be driven/modulated by ECM-producing cells, and a later phase occurring in larger and more mature fibrotic septa where the chronic wound healing is less active and fibrogenic transformation more established. In this latter setting pro-angiogenic factors are expressed only by endothelial cells, a scenario that is likely to favour the stabilization of the newly formed vessels. In this context, it is relevant that the promotion of a pro-angiogenic phenotype in activated HSC is stimulated also by non-hypoxic conditions and particularly by the exposure to the pro-fibrogenic adipokine leptin [[26]Aleffi S. Petrai I. Bertolani C. Parola M. Colombatto S. Novo E. et al.Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells.Hepatology. 2005; 42: 1339-1348Crossref PubMed Scopus (189) Google Scholar]. An elegant and convincing demonstration of the interplay between inflammatory response, angiogenesis, and fibrogenesis has been recently provided by an experimental study in which all these features have been significantly reduced by the treatment with the multitargeted receptor tyrosine kinase inhibitor sunitinib [[29]Tugues S. Fernandez-Varo G. Munoz-Luque J. Ros J. Arroyo V. Rodes J. et al.Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats.Hepatology. 2007; 46: 1919-1926Crossref PubMed Scopus (142) Google Scholar]. This study is of relevance because it provides evidence for a possible dual and converging pharmacological action (i.e. anti-fibrogenic and anti-angiogenic) able to interfere directly with liver myofibroblasts, presumably by negatively affecting PDGF-dependent signalling. Portal hypertension is a major complication of cirrhosis of the liver, which represents a leading cause of death and liver transplantation [30Bosch J. Pizcueta P. Feu F. Fernandez M. Garcia-Pagan J.C. Pathophysiology of portal hypertension.Gastroenterol Clin North Am. 1992; 21: 1-14PubMed Google Scholar, 31Bosch J. Garcia-Pagan J.C. The splanchnic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. 2nd ed. Blackwell Publishing, Oxford2005: 125-136Crossref Google Scholar, 32Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. A salient feature of portal hypertension is the formation of an extensive network of portosystemic collateral vessels, which include the oesophageal and gastric varices, responsible for variceal bleeding, associated with a high mortality rate [30Bosch J. Pizcueta P. Feu F. Fernandez M. Garcia-Pagan J.C. Pathophysiology of portal hypertension.Gastroenterol Clin North Am. 1992; 21: 1-14PubMed Google Scholar, 31Bosch J. Garcia-Pagan J.C. The splanchnic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. 2nd ed. Blackwell Publishing, Oxford2005: 125-136Crossref Google Scholar, 32Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. In addition, collateral vessels result in shunting of portal blood into the systemic circulation, causing high systemic concentrations of several substances normally metabolized by the liver, such as drugs, toxins, hormones, and bacteria. These in turn contribute to severe complications of cirrhosis, including portosystemic encephalopathy and sepsis [30Bosch J. Pizcueta P. Feu F. Fernandez M. Garcia-Pagan J.C. Pathophysiology of portal hypertension.Gastroenterol Clin North Am. 1992; 21: 1-14PubMed Google Scholar, 31Bosch J. Garcia-Pagan J.C. The splanchnic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. 2nd ed. Blackwell Publishing, Oxford2005: 125-136Crossref Google Scholar, 32Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. Therefore, successful design of medical treatment for portal hypertension requires a better understanding of the mechanisms underlying the formation of portosystemic collateral vessels, an issue that has remained largely unexplored. Traditionally, formation of collaterals was considered to be a mechanical consequence of the increased portal pressure that will result in the opening of these vascular channels. Accordingly, therapeutic strategies are mainly aimed at decreasing portal pressure [30Bosch J. Pizcueta P. Feu F. Fernandez M. Garcia-Pagan J.C. Pathophysiology of portal hypertension.Gastroenterol Clin North Am. 1992; 21: 1-14PubMed Google Scholar, 31Bosch J. Garcia-Pagan J.C. The splanchnic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. 2nd ed. Blackwell Publishing, Oxford2005: 125-136Crossref Google Scholar, 32Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. However, as discussed in this article, recent studies have examined another approach, based on the potential involvement of angiogenesis in the development of these collateral vessels. Another characteristic feature of the portal hypertensive syndrome is the development of a hyperdynamic circulatory state, with an increase in blood flow in splanchnic organs draining into the portal vein and a subsequent increase in portal venous inflow [30Bosch J. Pizcueta P. Feu F. Fernandez M. Garcia-Pagan J.C. Pathophysiology of portal hypertension.Gastroenterol Clin North Am. 1992; 21: 1-14PubMed Google Scholar, 31Bosch J. Garcia-Pagan J.C. The splanchnic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. 2nd ed. Blackwell Publishing, Oxford2005: 125-136Crossref Google Scholar, 32Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. Such an increased portal venous inflow represents a significant factor maintaining and worsening portal hypertension [30Bosch J. Pizcueta P. Feu F. Fernandez M. Garcia-Pagan J.C. Pathophysiology of portal hypertension.Gastroenterol Clin North Am. 1992; 21: 1-14PubMed Google Scholar, 31Bosch J. Garcia-Pagan J.C. The splanchnic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. 2nd ed. Blackwell Publishing, Oxford2005: 125-136Crossref Google Scholar, 32Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. The mechanisms underlying this splanchnic hyperemia are not fully understood, but involve overproduction of endogenous vasodilators and decreased vascular reactivity to vasoconstrictors [30Bosch J. Pizcueta P. Feu F. Fernandez M. Garcia-Pagan J.C. Pathophysiology of portal hypertension.Gastroenterol Clin North Am. 1992; 21: 1-14PubMed Google Scholar, 31Bosch J. Garcia-Pagan J.C. The splanchnic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. 2nd ed. Blackwell Publishing, Oxford2005: 125-136Crossref Google Scholar, 32Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. An intriguing possibility is that an increased formation of splanchnic blood vessels through active angiogenesis could also be involved in the maintenance of a hyperdynamic splanchnic circulation in portal hypertension. In the last few years, these possibilities have been addressed by studying the effects of different anti-angiogenic strategies aimed at inhibiting the signalling pathways of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and placental growth factor (PLGF), which are essential mediators of angiogenesis [33Carmeliet P. 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• W2023250239 title "Angiogenesis in liver disease" @default.
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