Review
Vascular endothelial dysfunction in cirrhosis

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Endothelial dysfunction is regarded as an early key event in multiple diseases. The assessment of vascular nitric oxide (NO) level is an indicative of endothelial dysfunction. In liver cirrhosis, on one hand, endothelial dysfunction is known as impaired endothelium-dependent relaxation in the liver microcirculation and contributes to increased intra-hepatic vascular resistance, leading to portal hypertension. On the other, increased production of vasodilator molecules mainly NO contributes to increased endothelium-dependent relaxation in the arteries of the systemic and splanchnic circulation. The aims of this review are to summarize and discuss: (1) unique characteristics of sinusoidal endothelial cell (SECs) and SEC dysfunctions in cirrhosis, and (2) endothelial dysfunctions in the arterial splanchnic and systemic circulation in cirrhosis with portal hypertension.

Introduction

In recent years, endothelial function has been given considerable attention in health and diseases. Endothelial cells play important roles in the regulation of vasomotor tone, vascular homeostasis, and inflammatory processes through the production of a wide variety of substances in response to various physical and chemical stimuli [1], [2].

Endothelial dysfunction can be defined as an impairment of normal endothelial functions, which are caused by the loss of balance between vasoconstrictors and vasodilators, growth promoting and inhibiting factors, pro-atherogenic and anti-atherogenic and pro-coagulant and anti-coagulant factors. Chronic exposure to physical and chemical stimuli can lead to the endothelial dysfunction [1].

Endothelial dysfunction is regarded as an early key event in multiple diseases [1]. In atherosclerosis, endothelial dysfunction has been shown to precede the development of clinically detectable atherosclerotic plaques in the coronary arteries [3]. Endothelial dysfunction has also been considered a pivotal event in the development of microvascular complications in diabetes mellitus [4]. In liver cirrhosis, on one hand, endothelial dysfunction, known to impair endothelium-dependent relaxation in the liver microcirculation contributes to increased hepatic vascular resistance, leading to portal hypertension. On the other hand, in arteries of the splanchnic circulation increased production of vasodilator molecules mainly nitric oxide (NO) contributes to increased endothelium-dependent relaxation, which precedes the development of the hyperdynamic circulatory syndrome observed in cirrhosis with portal hypertension [5], [6], [7].

The assessment of vascular NO level in endothelial cells and blood circulation is indicative of endothelial dysfunction. NO has been not only recognized as an essential vasodilator molecule [8], [9], but also known to participate in various processes that are beneficial to vascular homeostasis, such as the reduction of vascular smooth muscle migration and growth [10], platelet aggregation and thrombosis [11], monocyte and macrophage adhesion and inflammation [12]. Patients with type 2 diabetes almost invariably have endothelial dysfunction with decreased NO availability. Increased generation of reactive oxygen radicals (ROS) in endothelium has been proposed as a mechanism of reduced NO-mediated vasodilation and hypertension observed in diabetes [13]. Similar to cirrhotic patients with portal hypertension [14], patients with hyperthyroidism show similar hemodynamic abnormalities, which are associated with a significant increase in arterial vasodilatation accompanied with increased production of endothelial NO [15].

The abnormalities observed in the hepatic microcirculation are considered the primary event that leads to the portal hypertension and the subsequent arterial vasodilation in the systemic and splanchnic circulations in cirrhosis [16], [17], [18], [19]. The aims of this review are to summarize and discuss: (1) unique characteristics of sinusoidal endothelial cells (SEC) and SEC dysfunctions in cirrhosis, and (2) endothelial dysfunctions in the arterial splanchnic circulation in cirrhosis with portal hypertension.

Section snippets

Hypoactive endothelial cells in cirrhosis: SEC dysfunctions in the hepatic microcirculation

The liver receives a dual vascular supply. The portal vein brings to the liver all the blood, which has previously passed through the gastro-intestinal and splenic vascular bed. Approximately 80–90% of blood is supplied through the portal vein. The rest comes from the hepatic artery, which is essential for oxygen supply to the liver. Blood from both portal vein and hepatic artery mixes together in the hepatic sinusoids (vascular spaces lined by a fenestrated endothelium) and then drains out of

Role of NO

In contrast to the hypoactive endothelial cells in the hepatic microcirculation in cirrhosis, the hyperactive endothelial cells with an increase in NO production are one of important features observed in the arteries of the systemic and particularly the splanchnic circulation in cirrhosis and other entities with portal hypertension. This leads to systemic and splanchnic vasodilatation and the subsequent development of the hyperdynamic circulatory state [16], [17], [18], [19]. Endothelial

Conclusion

Focusing on endothelial cells, we summarized mechanisms and factors that play roles in endothelial dysfunction in cirrhosis. As the first contact cells to blood circulation in the liver, SECs play important roles in regulating liver function and intrahepatic vascular resistance. The regulatory mechanisms of molecular events in SECs are complex, considering the numerous interactions with different types of cells and substances. It will be interesting to investigate cell surface proteins on SECs

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