Angiogenesis and portal-systemic collaterals in portal hypertension. , 2016; 15 (3): 303-313 303 CONCISE REVIEW May-June, Vol. 15 No. 3, 2016: 303-313 The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver Angiogenesis and portal-systemic collaterals in portal hypertension Juan Cristóbal Gana,* Carolina A. Serrano,* Simon C. Ling** *Department of Pediatric Gastroenterology & Nutrition, Division of Pediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile. Chile. **Division of Gastroenterology, Hepatology & Nutrition, Department of Paediatrics, University of Toronto, and The Hospital for Sick Children, Toronto, Canada. ABSTRACT In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gas- trointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogen- esis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of an- imal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An im- proved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile. Key words. Angiogenesis. Portal hypertension. VEGF. Systemic collaterals. INTRODUCTION Prevention and improved management of portal hyper- tension and its complications are therefore important Portal hypertension and the formation of portal-sys- goals. In general, advances will be best achieved by future temic collaterals are common features of advanced liver developments in two areas; firstly, the discovery and im- disease and give rise to many severe and life-threatening plementation of preventative and curative therapies for the complications, including circulatory disturbance, gas- underlying liver diseases that cause portal hypertension, trointestinal hemorrhage, hepatic encephalopathy and as- and secondly the development of targeted therapies arising cites. Up to 1% of adults in developed countries have from an improved understanding of the mechanisms by cirrhosis,1,2 among whom the complications of portal hy- which portal hypertension causes its complications. pertension are leading causes of death or liver transplanta- Portal hypertension results from increased resistance to tion. Gastroesophageal varices are present in up to 50% of portal blood flow through the cirrhotic liver caused by the adults with cirrhosis3 and if bleeding occurs, up to 20% distortion of the liver architecture (secondary to fibrosis, of the initial bleeding episodes are fatal. Recurrent bleeding nodule formation and vascular changes) and by alterations is common in the absence of secondary prophylactic to hepatic sinusoidal cells and stellate cells that result in therapy.4-6 Variceal hemorrhage also occurs commonly in constriction of the hepatic sinusoids. Secondarily, a pro- children with chronic liver disease or portal vein obstruc- gressive splanchnic vasodilatation increases flow into the tion.7-14 In children with biliary atresia, the incidence of portal vein and further aggravates the portal hypertension.16 variceal hemorrhage ranges from 17 to 29% over a five to In the last decade, evidence has accumulated for the 10 year period9,10 and is 50% in children who survive more pivotal role of angiogenesis in the formation of portal-sys- than 10 years without liver transplantation.15 temic shunts from pre-existing vasculature. Angiogenesis Manuscript received: October 21, 2015. Manuscript accepted: January 08, 2016. DOI:10.5604/16652681.1198799. 304 Gana JC, et al. , 2016; 15 (3): 303-313 ANGIOGENESIS Fibrogenesis Within liver: VEGF, Ang-1, PDGF, PEDF, Apelin, Vasohiibin-1 Hepatic stellate cells Hepatic endothelial dysfunction ↓No In splanchnic circulation: VEGF, PIGF, PDGF, Splanchnic endothelial Ang-2, HIFs, NFKB, dysfunction EGR-1, AP-1, ICAM-1, ↑No VCAM-1, MCP-1 RAA system, Splanchnic insulin resistance, neovascularization ROS, NADPH, Apelin Portosystemic Portal hypertension collaterals Figure 1. Role of angiogenesis in portal Variceal hemorrhage hypertension. The development of porto-sys- Hepatic encephalopathy temic collaterals in portal hypertension occurs Hepatopulmonary syndrome amidst a complex interplay of pathogenic Sepsis mechanisms in the liver and in the splanchnic circulation. has also been linked with the progression of inflammation When NO availability is reduced, HSC become acti- and fibrosis (Figure 1). In this review we will describe the vated and develop a myofibroblast-like phenotype with knowledge gained from animal studies showing the im- a contractile response to vasoconstrictor molecules and portance of angiogenic mechanisms in the development of diminished response to vasodilators.20,21 As cirrhosis portal-systemic collaterals. We will summarize clinical develops, HSC proliferate and lay down extracellular studies of circulating concentrations of locally acting matrix components, including collagen and proteogly- mediators of angiogenesis and their role in prediction of cans. HSC are key players in portal hypertension and clinically relevant outcomes. Finally, we will suggest fu- they express several angiogenic mediators, including ture areas for translational research to generate improve- VEGF, Ang-1, and their receptors VEGFR-1, VEGFR-2 ments in clinical care. and Tie-2.22 Thus changes in sinusoidal and stellate cells contribute to the increase in hepatic vascular re- KEY PLAYERS IN PORTAL HYPERTENSION sistance and the modulation of angiogenesis and fibro- genesis. Sinusoidal and stellate cells Hepatic fibrosis The liver parenchyma possesses two different types of microvascular structure. Firstly, branches of the large ves- In the liver, angiogenesis is postulated to contribute to sels such as the portal vein are lined by a continuous layer portal hypertension by promoting fibrogenesis. Indeed, of endothelial cells lying on a basement membrane. Sec- angiogenesis and fibrosis develop in parallel in a number ondly, liver sinusoids are lined by fenestrated and discon- of organ beds including the kidney and the lung.23 In the tinuous endothelial cells. When the sinusoidal lining cells liver, neovasculature and overexpression of pro-angiogen- face an injury, they lose their vasoprotective phenotype, ic molecules have been detected in biopsies of patients becoming vasoconstrictor, proinflammatory and pro- with chronic viral infection, primary biliary cirrhosis and thrombotic.17 The capillarization of the sinusoids in auto-immune hepatitis.24,25 response to injury is associated with production of Vascular structural changes within the liver are well es- less nitric oxide and significantly more vasoconstrictor tablished pathological hallmarks of chronic cirrhosis26,27 prostanoids.18,19 and may be reversible determinants of resistance and Angiogenesis and portal-systemic collaterals in portal hypertension. , 2016; 15 (3): 303-313 305 pressure regulation. In this context, studies in experimen- Mechanism of tal models of cirrhosis have shown that liver fibrosis is de- new blood vessel formation creased by treatment with inhibitors of angiogenic mediators such as VEGFR, PDGF and Ang-1.28,29 Moreo- Angiogenesis is the formation of new blood vessels. It ver, in human liver samples, expression of angiogenic is an active process, dependent on growth factors, that markers like Ang-1 and endothelial markers such as CD31 takes place during growth and repair of injured tissues, but and von Willebrand factor correlate with the degree of he- also in pathologic situations like tumour progression and patic fibrosis and presence of collagen 15A1.28,30 Similar in different inflammatory, fibro-proliferative and ischemic findings were observed in animal studies using comple- diseases.40 mentary models of liver fibrosis where fibrogenesis and There are two main drivers of angiogenesis in all tis- angiogenesis develop in parallel during progression to- sues: inflammation and hypoxia.41 During chronic tissue wards cirrhosis.29,31 damage, the immune response leads to activation of endothelial cells, increased vascular permeability and pro- FORMATION OF duction of chemokines that recruit more inflammatory PORTAL-SYSTEMIC COLLATERALS cells.42-44 Local tissue hypoxia occurs due to altered blood flow in the setting of fibrosis and inflammation. Hypoxia The clinical manifestations of portal hypertension have activates angiogenesis through the actions of hypoxia-in- a complex pathogenesis which includes splanchnic va- ducible factors (HIFs).45,46 sodilatation, increased portal venous inflow, increased he- Angiogenesis is mediated by complex interactions that patic resistance to portal venous flow, and the formation can be divided into 4 steps:41 of portal-systemic collaterals.32,33 Collaterals contribute to the hemodynamic changes of portal hypertension that ex- • Sprouting and budding of endothelial cells. acerbate fluid and salt retention and the formation of as- • Extracellular matrix degradation and endothelial cell cites; they allow the development