Pathophysiology Of Portal Hypertension Research Articles

The genetics of portal hypertension: Recent developments and the road ahead.

Portal hypertension (PH), defined as a pathological increase in the portal vein pressure, has different aetiologies and causes. Intrahepatic PH is mostly secondary to the presence of underlying liver disease leading to cirrhosis, characterized by parenchymal changes with deregulated accumulation of extracellular matrix and vascular abnormalities; liver sinusoidal endothelial cells and hepatic stellate cells are key players in PH progression, able to influence each other. However, PH may also develop independently of parenchymal damage, as occur in portosinusoidal vascular disorder (PSVD), a group of clinical and histological entities characterized by portal vasculature dysfunctions. In this particular group of disorders, the pathophysiology of PH is still poorly understood. In the last years, several genetic studies, based on genome-wide association studies or whole-exome sequencing analysis, have highlighted the importance of genetic heritability in PH pathogenesis, both in cirrhotic and non-cirrhotic cases. The common PNPLA3 p.I148M variant, one of the main determinants of the susceptibility to steatotic liver disease, has also been associated with decompensation in patients with PH. Genetic variations at loci influencing coagulation, mainly the ABO locus, may directly contribute to the pathogenesis of PH. Rare genetic variants have been associated with familiar cases of progressive PSVD. In this review, we summarize the recent knowledges on genetic variants predisposing to PH development, contributing to better understand the role of genetic factors in PH pathogenesis.

Current diagnostics and treatment of portal hypertension

In industrial nations portal hypertension is mostly aconsequence of liver cirrhosis and is aprerequisite for complications, such as esophageal varices and ascites. The pathophysiology of portal hypertension is complex. It is defined as an increase in the hepatovenous pressure gradient to > 5 mm Hg, with complications to be expected at ≥ 10 mm Hg. Measurement of the pressure of the hepatic vein occlusion is the gold standard for estimating portal pressure but this is not very practical. Liver elastography, in particular, has proven to be an effective noninvasive tool to identify patients with clinically significant portal hypertension (CSPH). Current treatment concepts address the CSPH even before the onset of complications to reduce the likelihood of decompensation. In addition to beta blockers, a transjugular intrahepatic portosystemic shunt is the most important procedure to lower portal vein pressure and enables an improvement in the prognosis of selected patients.

Fontan-associated liver disease.

Fontan-associated liver disease.

Serum Proteomics Uncovers Biomarkers of Clinical Portal Hypertension in Children With Biliary Atresia.

Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large‐scale proteomics. We applied the slow off‐rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum samples of children with BA with and without clinical evidence of PHT in validation and discovery cohorts enrolled in the Biliary Atresia Study of Infants and Children. Serum proteomics data was analyzed using logistic regression to identify protein(s) with an area under the receiver operating characteristic curve (AUROC) ≥ 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs ≥ 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs ≥ 0.90 in both cohorts, with high positive‐ and negative‐predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large‐scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT.

Cyclic GMP in Liver Cirrhosis-Role in Pathophysiology of Portal Hypertension and Therapeutic Implications.

The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the “NO-paradox”, referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.

Pathophysiology and Management of Variceal Bleeding

Cirrhosis is the fifth leading cause of death in adults. Advanced cirrhosis can cause significant portal hypertension (PH), which is responsible for many of the complications observed in patients with cirrhosis, such as varices. If portal pressure exceeds a certain threshold, the patient is at risk of developing life-threatening bleeding from varices. Variceal bleeding has a high incidence among patients with liver cirrhosis and carries a high risk of mortality and morbidity. The management of variceal bleeding is complex, often requiring a multidisciplinary approach involving pharmacological, endoscopic, and radiologic interventions. In terms of management, three stages can be considered: primary prophylaxis, active bleeding, and secondary prophylaxis. The main goal of primary and secondary prophylaxis is to prevent variceal bleeding. However, active variceal bleeding is a medical emergency that requires swift intervention to stop the bleeding and achieve durable hemostasis. We describe the pathophysiology of cirrhosis and PH to contextualize the formation of gastric and esophageal varices. We also discuss the currently available treatments and compare how they fare in each stage of clinical management, with a special focus on drugs that can prevent bleeding or assist in achieving hemostasis.

Placental growth factor levels neither reflect severity of portal hypertension nor portal-hypertensive gastropathy in patients with advanced chronic liver disease

Background & AimsExperimental data indicates that placental growth factor (PLGF) is involved in the pathophysiology of portal hypertension (PH) due to advanced chronic liver disease (ACLD). We investigated serum levels of PLGF and its “scavenger”, the receptor soluble fms-like tyrosine kinase-1 (sFLT1, or sVEGFR1), in ACLD patients with different severity of PH and portal-hypertensive gastropathy (PHG). MethodsPLGF and sVEGFR1 were measured in ACLD patients with hepatic venous pressure gradient (HVPG) ≥6 mmHg (n = 241) and endoscopic evaluation of PHG (n = 216). Patients with pre-/posthepatic PH, TIPS, liver transplantation and hepatocellular carcinoma were excluded. ResultsThirty-two (13%) patients had HVPG 6–9 mmHg, 128 (53%) 10–19 mmHg and 81 (34%) ≥20 mmHg; 141 (59%) had decompensated ACLD (dACLD). PLGF (median 17.2 vs. 20.8 vs. 22.4 pg/mL; p = 0.002), sVEGFR1 (median 96.0 vs. 104.8 vs. 119.3 pg/mL; p < 0.001) levels increased across HVPG strata, while PLGF/sVEGFR1 ratios remained similar (0.19 vs. 0.20 vs. 0.18 pg/mL; p = 0.140). The correlation between PLGF and HVPG was weak (Rho = 0.190,95%CI 0.06–0.31; p = 0.003), and the PLGF/sVEGFR1 ratio did not correlate with HVPG (p = 0.331). The area-under-the-receiver operating characteristics (AUROC) for PLGF to detect clinically significant PH (CSPH;i.e. HVPG ≥ 10 mmHg) yielded only 0.688 (0.60–0.78; p < 0.001).When compared to ACLD patients without PHG, PLGF levels (20 without vs. 21.4 with mild vs. 17.1 pg/mL with severe PHG, respectively; p = 0.005) and PLGF/sVEGFR1 ratios (0.20 vs. 0.19 vs. 0.17; p = 0.076) did not increase with mild and severe PHG. ConclusionWhile PLGF levels tended to increase with severity of PH, the PLGF/sVEGFR1 ratio remained stable across HVPG strata. Neither PLGF nor the PLGF/sVEGFR1 ratio had diagnostic value for prediction of CSPH. The severity of PHG was also not associated with stepwise increases in PLGF levels or PLGF/sVEGFR1 ratio.

Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension.

Liver cirrhosis is a frequent condition with high impact on patients’ life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.

Plasma renin activity and aldosterone concentration in dogs with acquired portosystemic collaterals

BackgroundThe renin‐angiotensin‐aldosterone system (RAAS) is activated in humans with portal hypertension (PH) associated with liver disease. However, involvement of RAAS in dogs with intrahepatic PH is not clear.ObjectiveTo measure plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in dogs with PH (chronic hepatitis [CH] and primary hypoplasia of the portal vein [PHPV]), dogs with extrahepatic congenital portosystemic shunt (EH‐CPSS), and healthy dogs and to determine whether the RAAS is activated in dogs with PH.AnimalsTwenty‐seven dogs with acquired portosystemic collaterals (APSCs; 15 dogs with CH, 12 dogs with PHPV), 9 dogs with EH‐CPSS, and 10 healthy dogs.MethodsRetrospective study. Plasma renin activity and PAC were measured by radioimmunoassay.ResultsPlasma renin activity was significantly higher in the CH group (median, 4.4 ng/mL/h) than in the EH‐CPSS (median, 1.0 ng/mL/h; P < .01) and the healthy (median, 1.1 ng/mL/h; P < .01) groups. No significant differences were found between the PHPV group (median, 2.2 ng/mL/h) and other groups. Plasma aldosterone concentration was significantly higher in the CH (median, 111.0 pg/mL) and PHPV (median, 89.5 pg/mL) groups than in the EH‐CPSS (median, 1.0 pg/mL; P < .001, P < .01, respectively) and healthy (median, 14.5 pg/mL; P < .001, P < .05, respectively) groups.Conclusions and Clinical ImportanceActivation of the RAAS contributes to the pathophysiology of intrahepatic PH in dogs, suggesting that spironolactone may not only be effective for the treatment of ascites but also for the suppression of intrahepatic PH.

Long-term drug treatments to improve prognosis of patients with liver cirrhosis and to prevent complications due to portal hypertension

Portal hypertension in patients with liver cirrhosis can be improved, not only by surgical or interventional shunt placements, but also by drug-only treatment. Many recent studies addressed the question whether any of these substances can improve survival of patients with liver cirrhosis when administered continuously for months and years. Non-selective beta-blockers (NSBB), statins, antibiotics, enoxaparin and albumin have been shown to possess many beneficial effects in the pathophysiology of portal hypertension or on events leading to decompensation of liver cirrhosis. Accordingly, they represent candidate drugs for long-term treatment to improve patient survival. In contrast to NSBB, antibiotics and albumin, which have clearly defined indications in the treatment of complications related to portal hypertension, the role of statins and anticoagulants in the management of these patients remains to be further elucidated. Recent studies came to opposing results when a permanent treatment was tested to improve patient prognosis or to prevent liver decompensation. At present, there is no reason to change our everyday practice beyond established management proposals published in practice guidelines. This paper gives an overview of present and future indications for treatment with NSBB, antibiotics, statins, anticoagulants and albumin with special reference to studies aiming at improving prognosis of patients with liver cirrhosis.

Portal hypertension: Imaging of portosystemic collateral pathways and associated image-guided therapy.

Portal hypertension is a common clinical syndrome, defined by a pathologic increase in the portal venous pressure. Increased resistance to portal blood flow, the primary factor in the pathophysiology of portal hypertension, is in part due to morphological changes occurring in chronic liver diseases. This results in rerouting of blood flow away from the liver through collateral pathways to low-pressure systemic veins. Through a variety of computed tomographic, sonographic, magnetic resonance imaging and angiographic examples, this article discusses the appearances and prevalence of both common and less common portosystemic collateral channels in the thorax and abdomen. A brief overview of established interventional radiologic techniques for treatment of portal hypertension will also be provided. Awareness of the various imaging manifestations of portal hypertension can be helpful for assessing overall prognosis and planning proper management.

Von Willibrand Factor Antigen as a Non Invasive Predictor of Portal Hypertension in Patients with Liver Cirrhosis

In cirrhotic livers, increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension (PH) and is caused by structural abnormalities in the hepatic vascular architecture and an increased hepatic vascular tone. Von Willebrand factor antigen (vWF Ag) is released by activated endothelial cells (ECs) and therefore represents an indicator of EC activation and plays a crucial role in high shear stress, depending on primary hemostasis. The aim of this work was to evaluate the diagnostic performance of vWF-Ag to detect clinically significant PH suggested by portal vein velocity (PVV) in patients with liver cirrhosis and to evaluate vWF-Ag levels in the prediction of decompensation. Patients and methods: vWF Ag was measured in thirty patients with liver cirrhosis and twenty healthy control subjects and results were correlated with portal hypertension as suggested by portal vein velocity. Results: Levels of vWF Ag were significantly higher in patients with cirrhosis than healthy control subjects while levels of PVV were significantly lower. vWF Ag significantly increase in presence of ascites and shrunken liver. Levels of vWF show significant correlation with PVV and the best diagnostic cutoff value for portal hypertension was found to be 270 U/dL. Conclusion: Our study shows an impressive correlation between portal hypertension and vWF levels thus can be used as noninvasive predictor of clinically significant portal hypertension (CSPH) in patients with liver cirrhosis.

Molecular pathophysiology of portal hypertension.

Over the past two decades the advances in molecular cell biology have led to significant discoveries about the pathophysiology of portal hypertension (PHT). In particular, great progress has been made in the study of the molecular and cellular mechanisms that regulate the increased intrahepatic vascular resistance (IHVR) in cirrhosis. We now know that the increased IHVR is not irreversible, but that both the structural component caused by fibrosis and the active component caused by hepatic sinusoidal constriction can be, at least partially, reversed. Indeed, it is now apparent that the activation of perisinusoidal hepatic stellate cells, which is a key event mediating the augmented IHVR, is regulated by multiple signal transduction pathways that could be potential therapeutic targets for PHT treatment. Furthermore, the complexity of the molecular physiology of PHT can also be appreciated when one considers the complex signals capable of inducing vasodilatation and hyporesponsiveness to vasoconstrictors in the splanchnic vascular bed, with several vasoactive molecules, controlled at multiple levels, working together to mediate these circulatory abnormalities. Added to the complexity is the occurrence of pathological angiogenesis during the course of disease progression, with recent emphasis given to understanding its molecular machinery and regulation. Although much remains to be learned, with the current availability of reagents and new technologies and the exchange of concepts and data among investigators, our knowledge of the molecular basis of PHT will doubtless continue to grow, accelerating the transfer of knowledge generated by basic research to clinical practice. This will hopefully permit a better future for patients with PHT.

The mechanism about the role of RhoA/ROCK singal pathway in portal hypertension

The hepatic portal system is a unique circulatory system that connects two systems of capillary beds ; one in the wall of the small intestine and spleen and the second in the sinusoidal area of the liver.Therefore,alterations in vasoreactivity (vasodilation and vasoconstriction) play a critical role in the pathophysiology of portal hypertension (PHT).The RhoA/ ROCK pathway exerts an important role in the Ca2+-independent mechanism in vascular smooth muscle (VSM).This mechanism not only modulates the constriction of intrahepatic small vessels and hepatic stellate cells (HSCs) but also effects the hyperdynamic circulation due to vascular hyporesponsiveness.Understanding the detailed mechanism and role of the RhoA/ROCK signal pathway in portal hypertension could be of great utility in providing a new target for portal hypertension therapy. Key words: Portal hypertension; RhoA/ROCK pathway ; Hepatic stellate cells ; Vascular hyporesponsiveness ; Hyperdynamic circulation

Historical overview and review of current day treatment in the management of acute variceal haemorrhage.

Variceal haemorrhage is one of the most devastating consequences of portal hypertension, with a 1-year mortality of 40%. With the passage of time, acute management strategies have developed with improved survival. The major historical treatment landmarks in the management of variceal haemorrhage can be divided into surgical, medical, endoscopic and radiological breakthroughs. We sought to provide a historical overview of the management of variceal haemorrhage and how treatment modalities over time have impacted on clinical outcomes. A PubMed search of the following terms: portal hypertension, variceal haemorrhage, gastric varices, oesophageal varices, transjugular intrahepatic portosystemic shunt was performed. To complement this, Google™ was searched with the aforementioned terms. Other relevant references were identified after review of the reference lists of articles. The review of therapeutic advances was conducted divided into pre-1970s, 1970/80s, 1990s, 2000-2010 and post-2010. Also, a summary and review on the pathophysiology of portal hypertension and clinical outcomes in variceal haemorrhage was performed. Aided by the development of endoscopic therapies, medication and improved radiological interventions; the management of variceal haemorrhage has changed over recent decades with improved survival from an often-terminating event in recent past.

The study of hepatic hemodynamics: research activity or clinical tool?

Portal hypertension is a progressive complication of cirrhosis. Therefore, the management of a patient with cirrhosis and gastrointestinal bleeding depends largely on the stage of the portal hypertension. The patient may be in the pre-variceal stage or present with acute variceal bleeding, in which case the objectives are to control the current hemorrhage and prevent recurrence. In clinical practice, the severity of portal hypertension can be estimated, reliably and safely, by transjugular measurement of the hepatic venous pressure gradient (HVPG). After a brief review of the pathophysiology of portal hypertension in cirrhosis, the authors describe the technique used to measure transjugular HVPG, its prognostic value in patients with cirrhosis, the pros and cons of including this procedure in routine work-ups of these patients, and its potential roles in monitoring responses to treatment and in the preoperative assessment of cirrhotic patients undergoing hepatic resection.

Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats

Resveratrol, a polyphenol found in a variety of fruits, exerts a wide range of beneficial effects on the endothelium, regulates multiple vasoactive substances and decreases oxidative stress, factors involved in the pathophysiology of portal hypertension. Our study aimed at evaluating the effects of resveratrol on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl₄ cirrhotic rats. Resveratrol (10 and 20 mg/kg/day) or its vehicle was administered to cirrhotic rats for two weeks and hepatic and systemic hemodynamics were measured. Moreover, we evaluated endothelial function by dose-relaxation curves to acetylcholine, hepatic NO bioavailability and TXA2 production. We also evaluated liver fibrosis by Sirius Red staining of liver sections, collagen-1, NFκB, TGFβ mRNA expression, and desmin and α-smooth muscle actin (α-SMA) protein expression, as a surrogate of hepatic stellate cell activation. Resveratrol administration significantly decreased portal pressure compared to vehicle (12.1 ± 0.9 vs. 14.3 ± 2.2 mmHg; p <0.05) without significant changes in systemic hemodynamics. Reduction in portal pressure was associated with an improved vasodilatory response to acetylcholine, with decreased TXA2 production, increased endothelial NO, and with a significant reduction in liver fibrosis. The decrease in hepatic fibrosis was associated with a reduced collagen-1, TGFβ, NFκB mRNA expression and desmin and α-SMA protein expression. Resveratrol administration reduces portal pressure, hepatic stellate cell activation and liver fibrosis, and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting it may be a useful dietary supplement in the treatment of portal hypertension in patients with cirrhosis.

Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents

Sinusoidal vasoconstriction, in which hepatic stellate cells operate as contractile machinery, has been suggested to play a pivotal role in the pathophysiology of portal hypertension. We investigated whether sphingosine 1-phosphate (S1P) stimulates contractility of those cells and enhances portal vein pressure in isolated perfused rat livers with Rho activation by way of S1P receptor 2 (S1P(2) ). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P(2) antagonism on portal hypertension was examined. Intravenous infusion of the S1P(2) antagonist, JTE-013, at 1 mg/kg body weight reduced portal vein pressure by 24% without affecting mean arterial pressure in cirrhotic rats induced by bile duct ligation at 4 weeks after the operation, whereas the same amount of S1P(2) antagonist did not alter portal vein pressure and mean arterial pressure in control sham-operated rats. Rho kinase activity in the livers was enhanced in bile duct-ligated rats compared to sham-operated rats, and this enhanced Rho kinase activity in bile duct-ligated livers was reduced after infusion of the S1P(2) antagonist. S1P(2) messenger RNA (mRNA) expression, but not S1P(1) or S1P(3) , was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P(2) expression, determined in S1P 2LacZ/+ mice, was highly increased in hepatic stellate cells of bile duct-ligated livers. Furthermore, the increase of Rho kinase activity in bile duct-ligated livers was observed as early as 7 days after the operation in wildtype mice, but was less in S1P 2-/- mice. S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P(2) . The S1P(2) antagonist merits consideration as a novel therapeutic agent for portal hypertension.

Statins and Portal Hypertension: A New Pharmacological Challenge

Portal hypertension is a hemodynamic abnormality that involves a high risk of disability as well as a reduced life expectancy in patients with cirrhosis. Progress in the knowledge of pathophysiology of portal hypertension has opened a new perspective for different pharmacological approaches. In this context, the pleiotropic actions of statins on endothelial cell function have emerged as new options to reduce portal pressure levels by targeting multiple molecular pathways involved in hepatic vascular homeostasis. We highlight how statins may target some molecular pathways involved in the pathophysiology of portal hypertension and how these drugs may correct impaired hepatic vascular tone.

Functional aspects on the pathophysiology of portal hypertension in cirrhosis

Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)and CIBERehd, SpainPortal hypertension is a severe and frequent complication ofchronic liver disease. Its consequences, bleeding from gastro-esophageal varices and portal hypertensive gastropathy, ascites,spontaneous bacterial peritonitis, hepatorenal syndrome, hepato-pulmonary/portopulmonary syndromes, and hepatic encephalop-athy, represent the first cause of death and liver transplantationin patients with cirrhosis. The primary factor in the developmentof portal hypertension is a marked increase in hepatic vascularresistance (HVR) to portal blood flow, which was classicallyattributed to distortion of the liver architecture inherent to cir-rhosis. However, over the past 20 years, a better understandingof the liver microcirculation has demonstrated that a dynamiccomponent due to an increased hepatic vascular tone furthercontributes to augment HVR. Secondarily to the increased HVR,there is a progressive splanchnic vasodilatation that incrementsportal blood flow, which aggravates and perpetuates the portalhypertension syndrome [1] (Fig. 1).Intrahepatic vascular regulationThe analysis of the structural factors (fibrosis, vascular remodel-ing, vascular occlusion, nodule formation) contributing toincrease HVR is out of the scope of this review that will focuson the dynamic component of the increased HVR.During progression to cirrhosis, sinusoidal endothelial cells(SEC) become dysfunctional and among other features acquire avasoconstrictor phenotype, characterized by elevated productionof vasoconstrictors and reduced release of vasodilators. Theresulting imbalance promotes the contraction of different cellsof the cirrhotic liver, such as hepatic stellate cells (HSC), portalmyofibroblasts and vascular smooth muscle cells that lead toincreased hepatic vascular tone and portal pressure. HSC in turnalso experience a profound phenotypical transformation, withmorphologic and functional consequences: loss of vitamin Adroplets, alpha-smooth muscle actin overexpression, hyper-response to vasoconstrictors and enhanced proliferative and fibr-ogenic activity. Interestingly, in experimental models of cirrhosis,strategies aimed at improving the hepatic vascular tone by tar-geting SEC have also been shown to improve liver fibrosis. Thismay be due to the fact that cellular phenotype alterations sharepathophysiological mechanisms, but also because SEC phenotypeamelioration positively affects HSC phenotype [2].Increase of vasoconstrictors in the liverIncreasedactivityof several endogenous vasoconstrictors,such asendothelin, norepinephrine, angiotensin II, vasopressin, leukotri-enes, and thromboxane A