Model Of Portal Hypertension Research Articles

Letter: sorafenib in portal hypertension – authors' reply

We are thankful to Procopet et al. for their comments and for sharing their data with us.1 We are also happy to see that our results2 were confirmed by an independent series and found a similar proportion of patients responding to treatment as we did. In addition, they were able to show a long-term effect of sorafenib on portal hypertension in some patients. We were unable to do so because our patients underwent trans-arterial chemoembolisation after 2 weeks of sorafenib treatment,3 which precluded us from obtaining unbiased hepatic venous pressure gradient (HVPG)-measurements and survival data thereafter. We are not surprised to see a lack of correlation between HVPG-response and survival, considering the overall patient number was 18, 11 patients underwent repeat HVPG-measurement only, and 4 of those showed a drop in HVPG. In view of the potential confounders in cirrhotic patients with hepatocellular carcinoma (HCC) with major impact on survival (cirrhosis stage, performance status, tumour size, vascular invasion, extrahepatic spread, among others), it would be really astonishing to find a significant survival difference within such a small patient sample. However, the findings extend nicely the principle observation from animal experiments4 to the clinical setting, with about one-third of treated individuals showing an improvement in portal hypertension with sorafenib, an effect of about the same magnitude as can be expected from the treatment of portal hypertensive patients with nonselective β-blockers like propranolol or nadolol.5 We agree with Procopet et al. that for studying the antihypertensive effects of sorafenib, patients with HCC are not an ideal patient population, but for lack of other options to test the drug so far, both of our groups did resort to this group of patients to perform a proof-of-principle study on the haemodynamic effects of sorafenib in humans. In our opinion, two scenarios for the use of sorafenib for treatment of portal hypertension could be envisioned: as variceal bleeding is a major cause of death in patients with advanced stage HCC, haemodynamic responders to sorafenib might not need the addition of a nonselective β-blocker for prevention of variceal bleeding, which could help to improve their quality of life significantly. On the other hand, in cirrhotic patients without HCC and nonresponse to nonselective β-blockers, lower dose sorafenib (for safety and tolerability reasons) could be investigated as an alternative medical treatment option (albeit currently not feasible for economic reasons). We think that in view of the human data presented as well as our previous preclinical data from a model of prehepatic portal hypertension,6 a pilot trial on the effects of lower dose sorafenib on portal hypertension in patients with cirrhosis would be reasonable, in particular, in patients not responding to nonselective β-blockers. Prospective randomised trials do not seem to be warranted to date as long as we do not have data on the response in this selected and difficult to treat patient group. The authors' declarations of personal and financial interests are unchanged from those in the original article.2

Nitric oxide and prostaglandin as mediators in the pathogenesis of hyperkinetic circulatory state in a model of endotoxemia-induced portal hypertension

To evaluate the participation of nitric oxide (NO) and prostaglandin (PGI2) on hyperdynamic state in endotoxemia-induced portal hypertension (EIP) induced by chronic endotoxemia. The portal pressure (PP) and mean arterial pressure (MAP) were recorded, in vivo before and after administration of L-NAME (NOS inhibitor) and indomethacin (specific blocker of COX). The vasoactive responses to acetylcholine of thoracic rat aortic rings were studied in vitro before and after nitric oxide and cyclooxygenase blockade using multichannel organ bath. The mRNA expression for isoforms of (cyclooxygenase) COX and nitric oxide synthase (NOS) were analyzed using RT-PCR. Administration of both L-NAME and indomethacin in EIP rabbits significantly reduced (p<0.05) the PP and reversed the MAP to normal as compared to sham-operated (SO) rabbits. There was impaired vasodilatory response to acetylcholine in EIP rabbits. L-NAME caused a significant reduction in acetylcholine-induced vasorelaxation in SO rabbits than EIP due to preexisting hyperemia in EIP. Indomethacin partially restored vasoresponsiveness to acetylcholine in EIP group. The mRNA expression of eNOS (endothelial NOS) and COX-1 (constitutive COX) were significantly higher in SO than EIP rabbits. iNOS (inducible NOS) and COX-2 (inducible COX) mRNA expression was seen only in EIP rabbits. A significant component of acetylcholine-mediated vasorelaxation in EIP model is modulated by eNOS. There was increased production of contractile prostaglandin in EIP rabbits. iNOS and COX-2 play an important role in the hemodynamic abnormalities of PHT. This novel model of PHT produced by chronic splanchnic endotoxemia in rabbit, mimics impaired vasodilation and vasoreactivity akin to other models of PHT.

Investigating the Efficacy of Subharmonic Aided Pressure Estimation for Portal Vein Pressures and Portal Hypertension Monitoring

The efficacy of using subharmonic emissions from Sonazoid microbubbles (GE Healthcare, Oslo, Norway) to track portal vein pressures and pressure changes was investigated in 14 canines using either slow- or high-flow models of portal hypertension (PH). A modified Logiq 9 scanner (GE Healthcare, Milwaukee, WI, USA) operating in subharmonic mode (ftransmit: 2.5 MHz, freceive: 1.25 MHz) was used to collect radiofrequency data at 10–40% incident acoustic power levels with 2–4 transmit cycles (in triplicate) before and after inducing PH. A pressure catheter (Millar Instruments, Inc., Houston, TX, USA) provided reference portal vein pressures. At optimum insonification, subharmonic signal amplitude changes correlated with portal vein pressure changes; r ranged from −0.82 to −0.94 and from −0.70 to −0.73 for PH models considered separately or together, respectively. The subharmonic signal amplitudes correlated with absolute portal vein pressures (r: −0.71 to −0.79). Statistically significant differences between subharmonic amplitudes, before and after inducing PH, were noted (p ≤ 0.01). Portal vein pressures estimated using subharmonic aided pressure estimation did not reveal significant differences (p > 0.05) with respect to the pressures obtained using the Millar pressure catheter. Subharmonic-aided pressure estimation may be useful clinically for portal vein pressure monitoring.

Comparison of endothelin receptors in normal versus cirrhotic human liver and in the liver from endothelial cell-specific ETB knockout mice

AimsEndothelin (ET) antagonists show promise in animal models of cirrhosis and portal hypertension. The aim was to pharmacologically characterise the expression of endothelin receptors in human liver, hepatic artery and portal vein. Main methodsImmunofluorescence staining, receptor autoradiography and competition binding assays were used to localise and quantify ET receptors on hepatic parenchyma, hepatic artery and portal vein in human cirrhotic or normal liver. Additional experiments were performed to determine the affinity and selectivity of ET antagonists for liver ET endothelin receptors. An endothelial cell ETB knockout murine model was used to examine the function of sinusoid endothelial ETB receptors. Key findingsETB receptors predominated in normal human liver and displayed the highest ratio (ETB:ETA 63:47) compared with other peripheral tissues. In two patients examined, liver ETB expression was up-regulated in cirrhosis (ETB:ETA 83:17). Both sub-types localised to the media of normal portal vein but ETB receptors were downregulated fivefold in the media of cirrhotic portal vein. Sinusoid diameter was fourfold smaller in endothelial cell ETB knockout mice. The liver morphology of ETB knockout mice was markedly different to normal murine liver, with loss of the wide spread sinusoidal pattern. In the knockout mice, sinusoids were reduced in both number and absolute diameter, while large intrahepatic veins were congested with red blood cells. SignificanceThese data support a role for the ET system in cirrhosis of the liver and suggest that endothelial ETB blockade may cause sinusoidal constriction which may contribute to hepatotoxicity associated with some endothelin antagonists.

Intestinal bacterial translocation in rats with cirrhosis is related to compromised paneth cell antimicrobial host defense

Liver cirrhosis is associated with bacterial translocation (BT) and endotoxemia. Most translocating bacteria belong to the common intestinal microbiota, suggesting a breakdown of intestinal barrier function. We hypothesized that diminished mucosal antimicrobial host defense could predispose to BT. Two rodent models of portal hypertension with increased BT were used, CCl(4)-induced ascitic cirrhosis and 2-day portal vein-ligated (PVL) animals. BT was assessed by standard microbiological techniques on mesenteric lymph nodes. Total RNA was isolated systematically throughout the intestinal tract, and expression of Paneth cell α-cryptdins and β-defensins was determined by real-time quantitative polymerase chain reaction (qPCR). To determine functional consequences, mucosal antimicrobial activity was assessed with a fluorescence-activated cell sorting assay. BT was detectable in 40% of rats with cirrhosis. Compared with the group without BT, these animals exhibited diminished intestinal Paneth cell α-cryptdin 5 and 7 expression. In contrast, PVL was associated with BT in all animals but did not affect antimicrobial peptides. The decrease in Paneth cell antimicrobials was most pronounced in the ileum and the coecum. Other antimicrobials showed no changes or even an induction in the case of BT at different sites. Antimicrobial activity toward different commensal strains was reduced, especially in the distal ileum and the cecum in experimental cirrhosis with BT (excluding PVL). Compromised Paneth cell antimicrobial host defense seems to predispose to BT in experimental cirrhosis. Understanding this liver-gut axis including the underlying mechanisms could help us to find new treatment avenues.

A pharmacodynamic model of portal hypertension in isolated perfused rat liver.

To develop a pharmacodynamic model of portal hypertension from chronic hepatitis. Pathological changes and collagen depositions were analyzed using morphometry to confirm CCl₄-induced chronic hepatitis. At d₀, d₂₈, d₅₆ and d₈₄ of the process, the portal perfused velocities (μL/min) in isolated rat livers were exactly controlled with a quantified pump. The pressure (mmHg) was monitored with a Physiological System. The geometric concentrations of phenylephrine or acetylcholine were added to a fixed volume (300 mL) of the circulating perfusate. The equation, the median effective concentration and its 95% confidence intervals of phenylephrine or acetylcholine were regressed with Prism-4 software in non-linear fit and various slopes. In the isolated perfused rat livers with chronic hepatitis, both median effective concentrations were defined as the pharmacodynamic model of portal hypertension. At d₀, d₂₈, d₅₆ and d₈₄, the equations of portal pressure potency from the concentrations of phenylephrine used to constrict the portal vein in isolated perfused rat livers were Y = 0.1732 + 0.3970/[1 + 10((-4.3061-0.4407 X))], Y = -0.004934 + 0.12113/[1 + 10((-3.1247-0.3262 X))], Y = 0.0104 + 0.2643/[1 + 10((-8.8462-0.9579 X))], and Y = 0.01603 + 0.12107/[1 + 10((-5.1134-0.563 X))]; the median effective concentrations were 1.69 × 10⁻¹⁰ mol/L, 2.64 × 10⁻¹⁰ mol/L, 5.82 × 10⁻¹⁰ mol/L, and 8.24 × 10⁻¹⁰ mol/L, respectively. The equations from the concentrations of acetylcholine used to relax the portal vein were Y = -0.4548 + 0.3274/[1 + 10((6.1538 + 0.5554 X))], Y = -0.05391 + 0.06424/[1 + 10((3.8541 + 0.3469 X))], Y = -0.2733 + 0.22978/[1 + 10((3.0472 + 0.3008 X))], and Y = -0.0559 + 0.053178/[1 + 10((5.6336 + 0.5883 X))]; the median effective concentrations were 8.40 × 10⁻¹⁰ mol/L, 7.73 × 10⁻¹² mol/L, 5.98 × 10⁻¹¹ mol/L, and 2.66 × 10⁻¹⁰ mol/L, respectively. A pharmacodynamic model of portal hypertension in isolated perfused rat livers with chronic hepatitis was defined as the median effective concentrations of phenylephrine and acetylcholine.

Hipertensión portal: desarrollo de una respuesta inflamatoria sistémica asociada a síndrome metabólico

Portal hypertension (PH) is characterised by increase in portal venous pressure by obstruction of portal flow. As a consequence of PH, a collateral circulation is developed, which shifts an important part of portal flow to the systemic circulation. Furthermore, hepatic steatosis is another feature of PH in the rat, which is also, associated which different risk factors such as, obesity, diabetes, hypercholesterolemia and hypertrygliceridemia. Several mechanisms such as insulin resistance, cytokine production and oxidative stress participate in the development of this clinical pathology. An experimental model of pre-hepatic portal hypertension by triple partial portal vein ligation enables complications produced both short-term or acute and long-term or chronic outcome to be studied. Most of the splanchnic and systemic alterations produced in this experimental model are of an inflammatory nature, and for this reason the study of the physiological mechanisms involved are of great interest to the research of new anti-inflammatory therapies.

Morphological and Biomechanical Remodeling of the Hepatic Portal Vein in a Swine Model of Portal Hypertension

To obtain the morphological and biomechanical remodeling of portal veins in swine with portal hypertension (PHT), so as to provide some mechanical references and theoretical basis for clinical practice about PHT. Twenty white pigs were used in this study, 14 of them were subjected to both carbon tetrachloride- and pentobarbital-containing diet to induce experimental liver cirrhosis and PHT, and the remaining animals served as the normal controls. The morphological remodeling of portal veins was observed. Endothelial nitric oxide synthase expression profile in the vessel wall was assessed at both mRNA and protein level. The biomechanical changes of the hepatic portal veins were evaluated through assessing the following indicators: the incremental elastic modulus, pressure-strain elastic modulus, volume elastic modulus, and the incremental compliance. The swine PHT model was successfully established. The percentages for the microstructural components and the histological data significantly changed in the experimental group. Endothelial nitric oxide synthase expression was significantly downregulated in the portal veins of the experimental group. Three incremental elastic moduli (the incremental elastic modulus, pressure-strain elastic modulus, and volume elastic modulus) of the portal veins from PHT animals were significantly larger than those of the controls (P < 0.05), whereas the incremental compliance of hepatic portal vein decreased. Our study suggests that the morphological and biomechanical properties of swine hepatic portal veins change significantly during the PHT process, which may play a critical role in the development of PHT and serve as potential therapeutic targets during clinical practice.

Beneficial Effect of Ultra-Low-Dose Aspirin in Platelet Activity Alterations and Haemorrhage Observed in Experimental Portal Hypertension

Ultra-low-dose aspirin has shown a prothrombotic effect in the laser-induced thrombosis model. Several studies of our laboratory have shown a positive effect in rats with two different experimental models of portal hypertension: portal vein ligation, a model with an almost normal liver, and 30 days of bile duct ligation, a model with cirrhosis and presence of ascitis. In both models of portal hypertensive rats, bleeding time was prolonged and thrombi formation, in a laser-induced model of thrombi production, decreased. The hypotheses of the presented studies were that ultra-low-dose aspirin could decrease the bleeding complications in these models and that the mechanism for these effects could act thorough the COX pathway. In different studies, ultra-low dose of aspirin normalized the induced hemorrhage time, thrombi production, and platelet-endothelial cell interaction. The possible beneficial role of these doses of aspirin and mechanism of COX 2 inhibition are discussed.

The research of hemodynamic changes in portal hypertension combining with subtotal gastrectomy

Objective To build up a pig model of portal hypertension combined with subtotal gastrectomy,and study the hemodynamic changes of portal vein system.Methods 26 Susscrota domesticas are divided into three groups randomly.The experimental group ( EG,n =10) will receive the subtotal gastrectomy in the onestage operation,and will be subtotally coarctated the vena portae after one month.The portal hypertension group (PG,n =10) will receive the sham subtotal gastrectomy at first and followed by subtotally coarctated the vena portae.And the shamoperated group ( SG,n =6) will receive the sham subtotal gastrectomy at first and the sham subtotally coarctated the vena portae one month later.The portal pressure will be measured,and the hemodynamic changes in all groups will be detected by computer tomography and cast form.Results ( 1 ) The portal pressure in the EG and PG are statistically significance higher than the SG.And no difference was found between the EG and PG after the operation.(2) After subtotal gastrectomy,there are no new blood vessel appear in the gastric stump and the anastomosis between the stomach and the intestines.The blood supply of the gastric stump are mainly supported by the left gastric arteria and arteriae gastro-omentalis sinistra.The venous return of the gastric are mainly through the left gastric vein and left gastroepiploic vein.Conclusion ( 1 ) The method of subtotally coarctating the vena portae can build up a model of portal hypertension combined with subtotal gastrectomy.(2) The patients of portal hypertension who alreadly underwent subtotal gastrectomy is not suitable for the pericardial devascularization and the modified Sugiura procedure. Key words: Subtotal gastrectomy; Portal hypertension; Hemodynamic; Therapy

The Expression of PEDF and VEGF in the Gastric Wall of Prehepatic Portal Hypertensive Rats

Upper gastrointestinal bleeding of portal hypertension cases may result from gastric mucosal lesions due to portal hypertensive gastropathy. The pathological changes in the vessels of the gastric wall are very important in the pathogenesis of portal hypertensive gastropathy. However, the mechanisms of these pathological changes are not completely understood. In this study, we examined the expression levels of PEDF and VEGF in the gastric wall in rats with prehepatic portal hypertension. Eighteen healthy Wistar rats were randomly divided into groups A and B. Group A was used to establish the prehepatic portal hypertensive model and group B to evaluate a sham surgery. The VEGF and PEDF expression in the rat gastric wall were detected by immunohistochemical staining and western blotting. VEGF and PEDF were mainly expressed in the basal layer of the mucosal glands. The expression levels of VEGF and PEDF in group A were higher than that in group B at 7, 10 and 14 days after surgery. The expression levels of VEFG and PEDF in group B did not show significant changes. The results from the present study showed a significantly elevated expression of both VEGF and PEDF in the gastric walls during the development of portal hypertension. The expression of these proteins was mainly located in the basal layer of the gastric mucosa.

Morphological and biomechanical remodelling of the hepatic artery in a swine model of portal hypertension

To obtain the biomechanical and morphological remodelling of hepatic arteries in swine with portal hypertension. A number of 20 white pigs was used, of which 14 were subjected to liver cirrhosis and portal hypertension (PHT) induced by carbon tetrachloride and pentobarbital; the rest were used as the control group. The biomechanical remodelling of the hepatic arteries was measured, namely, the incremental elastic modulus (E inc), pressure-strain elastic modulus (E p), volume elastic modulus (E v), the incremental compliance (C), the opening angle and the stained microstructural components of the vessels. The percentages for the microstructural components and the histologic data significantly changed in the experimental group, three incremental elastic moduli (E inc, E p, and E v) of the experimental group were significantly larger than those of the control group (P<0.05); the compliance of hepatic arteries decreased greatly (P<0.05) too. The opening angle (OA) was considerably larger than that of control group (P<0.05). The study suggests that the morphological and biomechanical properties of swine hepatic arteries have changed significantly during the process of portal hypertension and that from biomechanical aspects, the hepatic arteries have also suffered from extensive remodelling, which in turn deteriorates the existing portal hypertension.

A Novel Canine Model of Portal Vein Stenosis Plus Thioacetamide Administration-Induced Cirrhotic Portal Hypertension With Hypersplenism

Current large animal models that could closely resemble the typical features of cirrhotic portal hypertension in human have not been well established. Thus, we aimed to develop and describe a reliable and reproducible canine cirrhosis model of portal hypertension. A total of 30 mongrel dogs were randomly divided into four groups: 1 (control; n = 5), 2 (portal vein stenosis [PVS]; n = 5], 3 (thioacetamide [TAA]; n = 5), and 4 (PVS plus TAA; n = 15). After 4-months modeling period, liver and spleen CT perfusion, abdominal CT scans, portal hemodynamics, gastroscopy, hepatic function, blood routine, the bone marrow, liver, and spleen histology were studied. The animals in group 2 (PVS) developed extrahepatic portosystemic collateral circulation, particularly esophageal varices, without hepatic cirrhosis and portal hypertension. Animals from group 3 (TAA) presented mild cirrhosis and portal hypertension without significant symptoms of esophageal varices and hypersplenism. In contrast, animals from group 4 (PVS + TAA) showed well-developed micronodular and macronodular cirrhosis, associated with significant portal hypertension and hypersplenism. The combination of PVS and TAA represents a novel, reliable, and reproducible canine cirrhosis model of portal hypertension, which is associated with the typical characteristics of portal hypertension, including hypersplenism.

Development of a Large Animal Model of Cirrhosis and Portal Hypertension Using Hepatic Transarterial Embolization: A Study in Swine

Purpose To develop a clinically relevant porcine model of liver cirrhosis with portal hypertension by means of hepatic transarterial embolization. Materials and Methods Institutional animal care and use committee approval was obtained for all experiments. Pigs received transcatheter arterial infusion of a 3:1 mixture of iodized oil and ethanol into the hepatic artery in volumes of 16 mL in group 1 (n = 4), 28 mL in group 2 (n = 4), and 40 mL in group 3 (n = 4) with intent of bilobar distribution. Hepatic venous pressure gradient (HVPG) measurement, liver function tests, and volumetry were performed at baseline, at 2 weeks, and before necropsy. Results Cirrhosis was successfully induced in three animals that received 16 mL of the embolic mixture and in all four animals that received 28 mL. The animals in the 40-mL group did not recover from the procedure and were euthanized within 48 h. Increases in HVPG after 6–8 weeks versus baseline reached statistical significance ( P < .05). Correlation between degree of fibrosis and volume of embolic agent did not reach statistical significance, but there was a trend toward increased fibrosis in the 28-mL group compared with the 16-mL group. Conclusions Transcatheter hepatic arterial embolization can be used to create a reliable and reproducible porcine model of liver cirrhosis and portal hypertension.

Portal hypertension correlates with splenic stiffness as measured with MR elastography

To investigate the correlation between MR elastography (MRE) assessed spleen stiffness and direct portal vein pressure gradient (D-HVPG) measurements in a large animal model of portal hypertension. Cholestatic liver disease was established in adult canines by common bile duct ligation. A spin echo based echo planar imaging (EPI) MRE sequence was used to acquire three-dimensional/three axis (3D/3-axis) abdominal MRE data at baseline, 4 weeks, and 8 weeks. Liver biopsies, blood samples, and D-HVPG measurements were obtained simultaneously. Animals developed portal hypertension (D-HVPG: 11.0 ± 5.1 mmHg) with only F1 fibrosis after 4 weeks. F3 fibrosis was confirmed after 8 weeks despite no further rise in portal hypertension (D-HVPG: 11.3 ± 3.2 mmHg). Mean stiffnesses of the spleen increased over two-fold from baseline (1.72 ± 0.33 kPa) to 4 weeks (3.54 ± 0.31 kPa), and stabilized at 8 weeks (3.38 ± 0.06 kPa) in a pattern consistent with changes in portal pressure. A positive correlation was observed between spleen stiffness and D-HVPG (r(2) = 0.86; P < 0.01). These findings indicate a temporal relationship between portal hypertension and the development of liver fibrosis in a large animal model of cholestatic liver disease. The observed direct correlation between spleen stiffness and D-HVPG suggest a noninvasive MRE approach to diagnose and screen for portal hypertension.

Gut-Brain Chemokine Changes in Portal Hypertensive Rats

Hepatic encephalopathy is a syndrome whose physiopathology is poorly understood; therefore, current diagnostic tests are imperfect and modern therapy is nonspecific. Particularly, it has been suggested that inflammation plays an important role in the pathogenesis of portal hypertensive encephalopathy in the rat. We have studied an experimental model of portal hypertension based on a triple partial portal vein ligation in the rat to verify this hypothesis. One month after portal hypertension we assayed in the splanchnic area (liver, small bowel and mesenteric lymph nodes) and in the central nervous system (hippocampus and cerebellum) fractalkine (CX3CL1) and stromal cell-derived factor alpha (SDF1-α) as well as their respective receptors (CX3CR1 and CXCR4) because of their key role in inflammatory processes. The significant increase of fractalkine in mesenteric lymph nodes (P<0.05) and its receptor (CX3CR1) in the small bowel (P<0.05) and hippocampus (P<0.01), associated with the increased expression of SDF1-α in the hippocampus (P<0.01) and the cerebellum (P<0.01) suggest that prehepatic portal hypertension in the rat induces important alterations in the expression of chemokines in the gut-brain axis. The present study revealed that portal hypertension is associated with splanchnic-brain inflammatory alterations mediated by chemokines.

Inhibition of Nitric Oxide Synthase in Hyperdynamic Circulation of Rats with Early or Late Cirrhosis Secondary to Common Bile Duct Ligation

Preventing internal hemorrhage extends the lifespan of rats with chronic bile duct ligation (CBDL), a common animal model of portal hypertension. We investigated hemodynamics during the early and late stages of cirrhosis caused by CBDL. We also evaluated the hemodynamic influence of NO, which is the chief vasodilator in hyperdynamic syndrome, by administration of an NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester: L-NAME; 10 mg/kg). ANIMALS/METHODS: In 24 Sprague-Dawley rats (9 sham rats and 15 CBDL rats), hemodynamics were assessed under conscious and unrestrained conditions 4 and 8 weeks after surgery. Before and 30 minutes after L-NAME administration, the cardiac index (CI) and regional blood flow were measured with the reference sample method using (141)Ce- and (113)Sn-microspheres (15 µm in diameter). A hyperdynamic systemic circulation and splanchnic hyperemia were observed after CBDL, and these changes increased with the progression of cirrhosis. L-NAME significantly diminished the hyperdynamic circulation and also reduced splanchnic hyperemia. In 4-week CBDL rats, a low hemoglobin concentration made an important contribution to the hyperdynamic circulation, and the portal collateral system collapsed when inflow to the portal territory was reduced by L-NAME treatment. In 8-week CBDL rats, systemic hemodynamics were closely linked to both the splanchnic circulation and the renal circulation before and after L-NAME administration, apart from hepatic artery blood flow. The distinctive hemodynamic changes of portal hypertension were found in 8-week CBDL rats. Thus, 8-week CBDL rats may be a better animal model of human portal hypertension than 4-week CBDL rats.

Vascular corrosion casting: analyzing wall shear stress in the portal vein and vascular abnormalities in portal hypertensive and cirrhotic rodents

Vascular corrosion casting is an established method of anatomical preparation that has recently been revived and has proven to be an excellent tool for detailed three-dimensional (3D) morphological examination of normal and pathological microcirculation. In addition, the geometry provided by vascular casts can be further used to calculate wall shear stress (WSS) in a vascular bed using computational techniques. In the first part of this study, the microvascular morphological changes associated with portal hypertension (PHT) and cirrhosis in vascular casts are described. The second part of this study consists of a quantitative analysis of the WSS in the portal vein in casts of different animal models of PHT and cirrhosis using computational fluid dynamics (CFD). Microvascular changes in the splanchnic, hepatic and pulmonary territory of portal hypertensive and cirrhotic mice are described in detail with stereomicroscopic examination and scanning electron microscopy. To our knowledge, our results are the first to report the vascular changes in the common bile duct ligation cirrhotic model. Calculating WSS using CFD methods is a feasible technique in PHT and cirrhosis, enabling the differentiation between different animal models. First, a dimensional analysis was performed, followed by a CFD calculation describing the spatial and temporal WSS distributions in the portal vein. WSS was significantly different between sham/cirrhotic/pure PHT animals with the highest values in the latter. Up till now, no techniques have been developed to quantify WSS in the portal vein in laboratory animals. This study showed for the first time that vascular casting has an important role not only in the morphological evaluation of animal models of PHT and cirrhosis, but also in defining the biological response of the portal vein wall to hemodynamic changes. CFD in 3D geometries can be used to describe the spatial and temporal variations in WSS in the portal vein and to better understand the forces affecting mechanotransduction in the endothelium.

OP10 Relaxin inhibits human myofibroblast contractility and modulates portal hypertension in vivo

IntroductionThe peptide hormone relaxin (H2-RLN) has a broad range of biological activities including antifibrotic, anti-inflammatory and haemodynamic effects in a range of target tissues. Increased intrahepatic vascular resistance in cirrhosis...

Antiangiogenic therapies in portal hypertension: A breakthrough in hepatology

Portal hypertension is the most important complication that develops in patients with cirrhosis. Several studies have shown that angiogenesis (i.e. splanchnic neovascularization) driven by VEGF and other proangiogenic molecules, like PDGF, may be a major mechanism involved in portal hypertension, hyperdynamic splanchnic circulation and portosystemic collateralization. According with this, antiangiogenic therapies, like sorafenib or sunitinib, have been recently shown to reduce portosystemic collateral circulation, improve splanchnic hyperdynamics and decrease portal pressure in experimental model of portal hypertension. This effect was associated to a decrease in VEGF, PDGF expression and splanchnic neovascularization. In addition, these therapies were associated with a decrease in both splanchnic and intrahepatic inflammatory infiltrates, in hepatic stellate cell activation and in intrahepatic fibrosis. These data suggest that antiangiogenic therapies may therefore, by limiting liver fibrosis and inflammation in cirrhosis, prevent the occurrence of severe complications, such as portal hypertension and potentially liver cancer.