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REVIEW ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 1  |  Page : 1-5

Angiogenesis in liver cirrhosis


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Shobrahor Central Hospital, Sinblawin, Egypt

Date of Submission07-Mar-2015
Date of Acceptance17-May-2015
Date of Web Publication25-Jul-2017

Correspondence Address:
Osama I Oaf
Salah Atia Street, Sinblawin, Dakahlia Governorate, 35511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_120_15

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  Abstract 


The present work aimed at discussing the association between angiogenesis and development of liver cirrhosis. They included medical textbooks, medical journals, and medical websites with updated information. Systematic reviews that addressed angiogenesis and studies that addressed the association of angiogenesis with the development of both cirrhosis and associated complications and the benefit of inhibition of angiogenesis in treatment of complications were included. Web search was performed on the PubMed medical databases, and the full text of the relevant paper was critically analyzed and interpreted. The researcher reviewed each study independently and rebuilt obtained data in his own language according to his needs to know the role of angiogenesis in the development of liver cirrhosis through the article. Angiogenesis and related changes in the angioarchitecture have been proposed to potentiate fibrosis progression toward cirrhosis. The association of fibrogenesis and angiogenesis should be regarded as crucial in the modern evaluation of liver disease progression and in the search for therapeutic targets.

Keywords: chronic liver diseases, liver cirrhosis, portal hypertension, vascular remodeling


How to cite this article:
Boghdadi IM, Koraha TE, Dala AG, Oaf OI. Angiogenesis in liver cirrhosis. Menoufia Med J 2017;30:1-5

How to cite this URL:
Boghdadi IM, Koraha TE, Dala AG, Oaf OI. Angiogenesis in liver cirrhosis. Menoufia Med J [serial online] 2017 [cited 2017 Oct 22];30:1-5. Available from: http://www.mmj.eg.net/text.asp?2017/30/1/1/211478




  Introduction Top


Angiogenesis can be defined as a dynamic, hypoxia-stimulated and growth-factor-dependent ubiquitous process leading to the formation of new vessels from pre-existing blood vessels. It occurs virtually in almost all organs and tissues and is considered a critical step in either physiological conditions or in tissue repair and growth in several pathophysiological conditions [1], including chronic liver diseases (CLDs) [2].

Where the liver is concerned, physiological and pathological angiogenesis can occur during liver regeneration (after acute liver injury or after partial hepatectomy), in ischemic conditions, during chronic inflammatory and fibrogenic liver diseases, as well as in hepatocellular carcinoma and in metastatic liver cancers [2].

The steps and mechanisms of hepatic angiogenesis mostly overlap with those described in other organs, but a number of liver parenchyma peculiarities are likely to make the overall scenario more complex [3]. These include the existence of two different kinds of microvascular structures (portal vessels and liver sinusoids, lined by continuous or fenestrated and discontinuous endothelium, respectively), the expression of a liver-specific angiopoietin-like peptide defined as ANGPTL3 [4], and, most relevant, the functional role of hepatic stellate cells (HSCs) that, although regarded as liver-specific pericytes in normal liver, also represent the most relevant profibrogenic cell lineage in CLDs [5].


  Pathological Angiogenesis and Proangiogenic Cytokines in Liver Cirrhosis and Chronic Liver Diseases Top


Current evidence suggests that angiogenesis and fibrogenesis are detectable and develop in parallel in any clinical condition of CLDs that can progress toward the end point of cirrhosis [5]. Similar data have been reported for the most widely used experimental animal models of CLDs that angiogenesis and fibrogenesis develop in parallel during progression toward cirrhosis [6].

DNA array analysis of differential gene expression in human cirrhotic livers from patients with chronic hepatitis C, autoimmune hepatitis, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis showed overexpression of many of the key genes involved in the different phases of angiogenesis compared with nondiseased liver tissue: growth factors and their receptors – for example vascular endothelial growth factor (VEGF), hepatocyte growth factor, fibroblast growth factor-8, and fibroblast growth factor receptor-1; cell–cell and cell–matrix adhesion molecules – for example integrins and β-catenin; matrix remodeling molecules; molecules involved in vascular differentiation and polarity (ephrins); and many others [7].

Where clinical data are concerned, best relationships between angiogenesis and the pattern of fibrosis (i.e., bridging fibrosis) [8] are usually found during chronic viral infection by either HBV or HCV. This is documented by either the abundant presence of endothelial cells (ECs) and neovessels/capillary structures found in inflamed portal tracts [3] or by the overexpression of major proangiogenic molecules, including VEGF and angiopoietin 1 (Ang-1), as well as their related receptors (VEGF receptor type 2, Tie2) and hepatocyte growth factor [9]. In addition, selected viral proteins may have a multiple proangiogenic role such as HBV-related X protein [10].

Angiogenesis has also been detected in biopsies from patients affected by either PBC or autoimmune hepatitis as the formation of neovessels by ECs and vascular endothelial cadherin [3]. These neovessels were located, particularly in PBC, mainly in portal areas in association with inflammatory infiltrate [11]. Angiogenesis has also been observed in experimental biliary cirrhosis: following administration of diethylnitrosamine to rats, the progression of liver fibrosis was seen to be associated with hepatocellular hypoxia and angiogenesis, and hepatic VEGF expression was increased and correlated with microvessel density. The activation of HSCs played a central role in this setting, through the enhanced expression and secretion of both proangiogenic and fibrogenic factors [12].


  Angiogenesis in Cirrhotic Liver Top


In cirrhosis, it is postulated that angiogenesis may be stimulated by tissue hypoxia. Hypoxia stimulates the production of VEGF, which is one of the most important angiogenic growth factors, through a pathway that involves hypoxia-inducible factor 1 α. Although VEGF production is most prominent from hepatocytes, HSCs may also produce angiogenic molecules, and recent studies have also identified an important autocrine VEGF signaling loop within ECs themselves [12]. The mechanism of hypoxia in the cirrhotic liver has been studied extensively at the level of the hepatocytes with a focus on metabolic changes, but it could also occur in response to structural changes in the sinusoids including basement membrane deposition and loss of sinusoidal endothelial cells (SECs) fenestrae (also referred to as 'capillarization'), which in turn could lead to impaired oxygen diffusion from the sinusoids to the parenchyma. It is likely that capillarization of sinusoids has different origins in different forms of CLD and is probably just one component of the broader sinusoidal changes that are occurring in CLD because of overavailability of angiogenic factors that accompany the chronic wound-healing process [13].

Although SECs are the most recognized cell type that participate in angiogenesis, recent advances suggest that pericytes such as HSCs are also major contributors to angiogenesis. This may occur through direct and indirect mechanisms. Direct mechanisms include the ability of HSCs to stabilize the new vessels and provide durability to the vessels that cannot be achieved by SECs alone in the absence of mural cells such as HSCs [14]. Indirect mechanisms are also important and include the ability of HSCs to secrete angiogenic molecules that recruit and stimulate SECs thereby promoting a 'proangiogenic sinusoidal matrix' [15]. For example, recent studies show that activated HSCs secrete VEGF and Ang-1, the molecules that promote angiogenesis [9]. In response, SECs synthesize platelet-derived growth factor (PDGF) and transforming growth factor-β, thereby stimulating HSC migration and recruitment to vessels. Therefore, pericytes may contribute to angiogenesis through multiple mechanisms [15].


  Relationship between Liver Angiogenesis and Portal Hypertension Top


Portal hypertension is a pathologic increase in the portal venous pressure gradient between the portal vein and the inferior vena cava. It results from changes in the portal resistance together with changes in the portal inflow. The mechanism of the increase in portal pressure depends on the site and the cause of portal hypertension, cirrhosis being the most common cause in the western world [16].

In the liver, angiogenesis is postulated to contribute to portal hypertension by promoting fibrogenesis. Indeed, angiogenesis and fibrosis develop in parallel in a number of organ beds including the kidney and the lung [17]. Angiogenesis appears to be a typical feature of liver fibrosis. For example, neovasculature and overexpression of proangiogenic molecules have been detected in liver biopsies of patients with chronic viral infection, PBC, and autoimmune hepatitis [3]. Moreover, in human liver samples, angiogenesis directly correlates with the degree of hepatic fibrosis. Similar findings were observed in animal studies using complementary models of liver fibrosis where fibrogenesis and angiogenesis develop in parallel during progression toward cirrhosis [17]. Furthermore, pharmacologic interventions that inhibit angiogenesis, especially the use of receptor tyrosine-kinase inhibitors such as sorafenib or sunitinib, decrease hepatic fibrosis. Nevertheless, these specific agents may also inhibit PDGF receptor β, which is not only an effector for HSC angiogenesis but also a factor that influences other aspects of the HSC activation process. However, the drugs that specifically inhibit angiogenesis by targeting molecules not involved in the HSC fibrogenic pathway, such as VEGF receptor type 2, also induce a decrease in hepatic fibrosis, providing further evidence for the importance of angiogenesis in the process of fibrogenesis [18].

Although these data suggest that angiogenesis may be a requisite step that promotes fibrogenesis, it is possible that vascular changes occur in a passive manner, secondary to fibrosis. Furthermore, there is some evidence that an inhibition of angiogenesis can even worsen fibrosis [19]. For example, in a recent study performed in two complementary models of cirrhosis, the administration of cilengitide, an inhibitor of the vitronectin receptor integrin that plays an important role in liver angiogenesis, promoted hepatic fibrosis and inflammation despite its antiangiogenic effects [20].


  Pathological Sinusoidal Remodeling in Cirrhosis and Portal Hypertension Top


Activated HSCs are probably the most profibrogenic cells in the liver. However, in parallel to this important role, HSCs also make an important contribution to the vascular structural changes in cirrhosis. For example, in addition to their supportive role in angiogenesis, HSCs also play a dominant role in sinusoidal vessel structural changes in cirrhosis, a process referred to as pathological sinusoidal remodeling. Prior work has highlighted the role of sinusoidal vasoconstriction in the genesis of portal hypertension, where HSCs operate as contractile machinery in response to vasoconstrictors such as endothelin and also relax in response to vasodilators such as nitric oxide [21]. Building on this concept, recent studies suggest that the mural coverage of sinusoidal vessels is enhanced by HSCs in cirrhosis, and that because of the contractile nature of HSCs this process of 'pathological sinusoidal remodeling' contributes further to a high-resistance, constricted sinusoidal vessel. Indeed, HSCs have the ability to align themselves in an effective way around the vessel lumen to achieve these structural changes [14]. This sinusoidal remodeling requires the recruitment of 'angiogenic' stellate cells to the vascular wall or the activation of local HSCs with extension of tentacle-like structures that encircle the vessel lumen and adjacent SECs [15].

A number of growth factors and signaling pathways mediate HSC proliferation, migration, motility, and recruitment to vessels in the process of sinusoidal remodeling, including PDGF/PDGF receptor and VEGF/VEGF receptor [9]. However, PDGF may be the most critical of these molecules based not only on work in the liver but also in broader studies examining the mechanisms of pericyte recruitment to vessels [14]. Interestingly, the inhibition of the PDGF signaling pathway by the receptor tyrosine-kinase inhibitor imatinib reduced portal pressure in an animal model of cirrhosis through effects on sinusoidal remodeling and impaired HSC coverage of sinusoids with less consequential effects on fibrogenesis [14]. This is an important point because one may have predicted that HSC mass would correlate directly with the degree of fibrosis. However, it is becoming increasingly recognized that there are heterogeneous subpopulations of myofibroblasts in the liver, including those derived from HSCs, periportal fibroblasts, bone-marrow-derived cells, and the epithelial-to-mesenchymal transition [22]. Thus, it is probable that all myofibroblasts do not have identical angiogenic capacities and indeed it has been suggested recently that HSCs may display more angiogenic features than portal myofibroblasts. In total, these findings highlight the role of pathological sinusoidal remodeling in the process of increased intrahepatic vascular resistance and portal hypertension and in turn also highlight the possibility that targeting HSC motility and reversion of pathological remodeling could have therapeutic benefits [23].

In addition to the HSC-driven sinusoidal remodeling that is described above, other forms of vascular remodeling are also occurring within the cirrhotic liver, in SECs there is lose of fenestra SECs which lose their fenestra, become associated with a basement membrane, and undergo a number of other phenotypic changes which seem to go hand-in-hand with 'endothelial dysfunction' and probably contribute to enhanced HSC activation, proliferation, migration, and sinusoidal coverage as suggested in recent studies. Thus, HSC activation is promoted not only by changes in the extracellular matrix, inflammatory cytokines, and oxidative stress, but also secondary to changes in the SEC phenotype. For example, recent studies in aggregate suggest that functional endothelium with an adequate NO generation could participate in maintaining HSCs in a quiescent state but that deficient NO generation that is associated with cirrhosis allows unchecked HSC activation [24].

Vascular remodeling also occurs outside the sinusoids in cirrhosis. For example, in their pioneering studies, Rappaport et al. [25] showed that the development of a scar in the cirrhotic liver was invariably accompanied by an intense vascular proliferation including the presence of 'scar vessels'. Indeed, it has been proposed that vascular structural changes may limit potential efficiencies of antifibrotic therapies, suggesting a clinical prognostic relevance to such vascular changes [26].


  Are Angiogenesis and Sinusoidal Remodeling Therapeutic Targets in Humans? Top


Investigators have administered antiangiogenic drugs in animal models of cirrhosis with the aim of decreasing portal hypertension. The previously discussed beneficial effects of imatinib in portal hypertension is one example [14]. Moreover, sorafenib, a multitarget receptor tyrosine-kinase inhibitor approved in the treatment of unresectable hepatocellular carcinoma, has shown beneficial effects in a model of secondary bile duct ligation-induced cirrhosis that is independent of its beneficial effects of decreasing splanchnic neovascularization and portosystemic collateral circulation. Indeed, sorafenib treatment induced a decrease of portal hypertension, as well as a reduction in intrahepatic fibrosis, intrahepatic inflammatory infiltrate, and intrahepatic neovascularization [18]. Moreover, the administration of another antiangiogenic drug, that is, sunitinib, a multitarget receptor tyrosine-kinase inhibitor, in a carbon tetrachloride rat model of cirrhosis also resulted in a decrease in portal pressure, along with a decrease in inflammatory infiltrate, angiogenesis, and HSC activation/matrix deposition. Therefore, small-molecule inhibitors of receptor tyrosine kinases that target the growth factor pathways leading to angiogenesis and sinusoidal remodeling (i.e., VEGF, PDGF, Ang-1) are capable of lowering PHT, probably through a dual and converging antifibrogenic and antiangiogenic role of action that affects both HSCs and SECs [27].

However, the story could be more complex. If lowering angiogenesis in animal models of prehepatic portal hypertension decreases portal pressure by decreasing splanchnic neovascularization and venous collaterals, one might question whether decreasing intrahepatic collaterals may be detrimental, as these vessels could theoretically act as portal hypertension decompressing shunts. Furthermore, the beneficial role of angiogenesis in tissue regeneration and repair should not be underestimated. Last, some antiangiogenic interventions provide evidence for the detrimental effects in preclinical models [19].

In conclusion, angiogenesis and sinusoidal remodeling in liver occur concurrently with cirrhosis and portal hypertension, and a number of experimental evidence support a causative role for these vascular changes in the genesis of fibrosis and portal hypertension in animal models. However, animal models do not always faithfully recapitulate the human state. Clearly we need to pursue human investigations with all proper safety measures in place. A good starting point may be a more in-depth analysis of the effects of sorafenib on portal pressure and fibrosis in nontumorous fibrotic tissues obtained in previously completed clinical studies. Undoubtedly, new studies in angiogenesis, fibrosis, and portal hypertension will be forthcoming and will clarify our clinical options in humans with advanced liver disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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