Ester García-Pras

Universitat de Barcelona

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Mercedes Fernández

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Marc Mejías

Hospital General Universitario de Ciudad Real

Javier González Gallego

Universidad de León

Sofía Pérez‐del‐Pulgar

Hospital Clínic de Barcelona

Jaime Bosch

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Xavier Forns

Universitat de Barcelona

Sabela Lens

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Raúl Méndez

Institute for Research in Biomedicine

Mireia García‐López

Universitat de Barcelona

Thais Leonel

Universitat de Barcelona

Cooperative Institutions

European Foundation for the Study of Chronic Liver Failure

199

Universitat de Barcelona

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Hospital Clínic de Barcelona

Centro de Investigación Biomédica en Red

Instituto de Salud Carlos III

Universitat Autònoma de Barcelona

Centre for Biomedical Network Research on Rare Diseases

University College London

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The somatostatin analogue octreotide inhibits angiogenesis in the earliest, but not in advanced, stages of portal hypertension in rats

Journal of Cellular and Molecular Medicine (2008)

Marc Mejías Ester García-Pras Carolina Tiani Jaime Bosch Mercedes Fernández

Abstract Background: Angiogenesis is an important determinant of the pathophysiology of portal hypertension contributing to the formation of portosystemic collateral vessels and the hyperdynamic splanchnic circulation associated to this syndrome. Somatostatin and its analogues, like octreotide, have been shown to be powerful inhibitors of experimental angiogenesis. Aim: To determine whether octreotide has angioinhibitory effects in portal hypertensive rats. Methods: Partial portal vein‐ligated (PPVL) rats were treated with octreotide or vehicle during 4 or 7 days. Splanchnic neovascularization and VEGF expression were determined by histological analysis and western blotting. Expression of the somatostatin receptor subtype 2 (SSTR2), which mediates the anti‐angiogenic effects of octreotide, was also analyzed. Formation of portosystemic collaterals (radioactive microspheres) and hemodynamic parameters were also measured. Results: Octreotide treatment during 4 days markedly and significantly decreased splanchnic neovascularization, VEGF expression by 63% and portal pressure by 15%, whereas portosystemic collateralization and splanchnic blood flow were not modified. After 1 week of octreotide injection, portal pressure was reduced by 20%, but inhibition of angiogenesis escaped from octreotide therapy, a phenomenon that could be related to the finding that expression of SSTR2 receptor decreased progressively (up to 78% reduction) during the evolution of portal hypertension. Conclusion: This study provides the first experimental evidence showing that octreotide may be an effective anti‐angiogenic therapy early after induction of portal hypertension, but not in advanced stages most likely due to SSTR2 down‐regulation during the progression of portal hypertension in rats. These findings shed light on new mechanisms of action of octreotide in portal hypertension.

Somatostatin Analogue

10.1111/j.1582-4934.2008.00218.x

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Citations (29)

Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension

Journal of Hepatology (2010)

Marc Mejías Ester García-Pras Javier González Gallego Raúl Méndez Jaime Bosch

Pathophysiology

Relevance

Clinical Significance

10.1016/j.jhep.2010.01.004

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Citations (98)

39 BONE MORPHOGENETIC PROTEINS (BMP) AND BMP SIGNALLING ARE SIGNIFICANTLY INCREASED IN EXPERIMENTAL MODELS OF CIRRHOSIS AND PORTAL HYPERTENSION

Journal of Hepatology (2009)

Andrea De Gottardi Marc Mejías Ester García-Pras Aina Rodríguez‐Vilarrupla Juan Carlos Garcı́a-Pagán

BMPR2

10.1016/s0168-8278(09)60041-6

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Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats

AJP Gastrointestinal and Liver Physiology (2012)

Michele D’Amico Marc Mejías Ester García-Pras Juan G. Abraldeṣ Juan Carlos Garcı́a-Pagán

Low doses of sorafenib have been shown to decrease portal pressure (PP), portal-systemic shunts, and liver fibrosis in cirrhotic rats. Nonselective beta blockers (NSBB) are the only drugs recommended for the treatment of portal hypertension. The aim of our study was to explore whether the combination of propranolol and sorafenib might show an additive effect reducing PP in cirrhotic rats. Groups of common bile duct-ligated cirrhotic rats (CBDL) and sham-operated control rats were treated by gavage with vehicle, propranolol (30 mg·kg −1 ·day −1 ), sorafenib (1 mg·kg −1 ·day −1 ), or propranolol+sorafenib. Treatment began 2 wk after the CBDL or sham operation. Hemodynamic evaluation was performed after 2 wk of treatment. In cirrhotic rats, propranolol and sorafenib produced a significant ( P < 0.001) and similar reduction in PP (−19 and −15%, respectively). This was achieved through different mechanisms: whereas propranolol decreased PP by reducing portal blood flow (−35%; P = 0.03), sorafenib decreased PP without decreasing portal flow indicating decreased hepatic resistance. After propranolol+sorafenib, the fall in PP was significantly greater (−30%; P < 0.001) than with either drug alone, demonstrating an additive effect. However, the reduction in portal flow (−39%) under combined therapy was not significantly greater than after propranolol alone. Sorafenib, alone or in combination with propranolol, produced significant reduction in portal-systemic shunting (−25 and −33%, respectively), splanchnic vascularization (−37 and −41%, respectively), liver fibrosis (38%), and hepatic neovascularization (−42 and −51%, respectively). These effects were not observed after propranolol alone. In conclusion, the combination of propranolol+sorafenib causes a greater reduction in PP than either drug alone and decreases markedly the extent of portal-systemic shunting, splanchnic and hepatic neovascularization, and liver fibrosis, suggesting that this drug combination is a potentially useful strategy in the treatment of portal hypertension.

10.1152/ajpgi.00252.2011

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Citations (38)

Silencing HBV expression using LNA gapmers: preliminary data of a new promising strategy

Journal of Hepatology (2020)

María Francesca Cortese Rosario Casillas Ester García-Pras Mireia García‐López Rosa López-Martínez

10.1016/s0168-8278(20)32190-5

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Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats

Hepatology (2008)

Marc Mejías Ester García-Pras Carolina Tiani Rosa Miquel Jaime Bosch

Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs.Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension.

Hyperdynamic circulation

Collateral circulation

Splanchnic Circulation

10.1002/hep.22758

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Citations (289)

Increased lymphocyte trafficking and myeloid activation in patients with chronic hepatitis delta

Journal of Hepatology (2022)

Ester García-Pras Thais Leonel Sergio Rodríguez‐Tajes Mireia García‐López Sabela Lens

HEPATITIS DELTA

10.1016/s0168-8278(22)00896-0

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Role and therapeutic potential of vascular stem/progenitor cells in pathological neovascularisation during chronic portal hypertension

Gut (2016)

Ester García-Pras Javier González Gallego Laura Coch Marc Mejías Gonzalo Fernández‐Miranda

Objective Pathological neovascularisation is intimately involved in portal hypertension (PH). Here, we determined the contribution of vascular stem/progenitor cells (VSPCs) to neovessel growth in PH and whether the RNA-binding protein cytoplasmic polyadenylation element binding protein-4 (CPEB4) was behind the mechanism controlling VSPC function. Design To identify and monitor VSPCs in PH rats (portal vein-ligated), we used a combinatorial approach, including sphere-forming assay, assessment of self-renewal, 5-bromo-2′-desoxyuridine label retention technique, in vitro and in vivo stem/progenitor cell (SPC) differentiation and vasculogenic capability, cell sorting, as well as immunohistochemistry, immunofluorescence and confocal microscopy expression analysis. We also determined the role of CPEB4 on VSPC proliferation using genetically engineered mouse models. Results We demonstrated the existence in the mesenteric vascular bed of VSPCs displaying capability to form cellular spheres in suspension culture, self-renewal ability, expression of molecules commonly found in SPCs, slow-cycling features, in addition to other cardinal properties exhibited by SPCs, like capacity to differentiate into endothelial cells and pericytes with remarkable vasculogenic activity. Such VSPCs showed, after PH induction, an early switch in proliferation, and differentiated in vivo into endothelial cells and pericytes, contributing, structurally and functionally, to abnormal neovessel formation. Quantification of VSPC-dependent neovessel formation in PH further illustrated the key role played by VSPCs. We also demonstrated that CPEB4 regulates the proliferation of the activated VSPC progeny upon PH induction. Conclusions These findings demonstrate that VSPC-derived neovessel growth (ie, vasculogenesis) and angiogenesis cooperatively stimulate mesenteric neovascularisation in PH and identify VSPC and CPEB4 as potential therapeutic targets.

Vasculogenesis

Matrigel

Cell Sorting

10.1136/gutjnl-2015-311157

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Citations (13)

Decreased Expression of Thrombospondin-1 in Failing Hearts May Favor Ventricular Remodeling

Transplantation Proceedings (2009)

Montserrat Batlle Fèlix Pérez-Villa A. Lázaro Ester García-Pras I. Vallejos

Ventricular remodeling

Thrombospondin 1

10.1016/j.transproceed.2009.06.009

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Citations (22)

Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats

Hepatology (2014)

Laura Coch Marc Mejías Annalisa Berzigotti Ester García-Pras Javier González Gallego

Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular homeostasis but not pathological angiogenesis. Conclusion : Our study provides evidence that vasohibin-1 regulates portal hypertension-associated pathological angiogenesis and highlights that increasing vasohibin-1 might be a promising novel therapeutic strategy for portal hypertension and cirrhosis. (Hepatology 2014;60:633–647)

10.1002/hep.26995

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Citations (47)